The Israel Society for Neuroscience—ISFN—was founded in 1993 by a group of Israeli leading scientists conducting researchin the area of neurobiology. The primary goal of the society was to promote and disseminate the knowledge and understandingacquired by its members, and to strengthen interactions between them. Since then, the society holds its annual meeting everyyear in Eilat usually during December. At this annual meetings, the senior Israeli neurobiologists, their teams, and their graduatestudents, as well as foreign scientists and students, present their recent research findings in platform and poster presentations, andthe program of the meeting is mainly based on the 338 received abstracts which are published in this volume. The meeting alsooffers the opportunity for the researchers to exchange information with each other, often leading to the initiation of collaborativestudies. Both the number of members of the society and those participating in the annual meeting is constantly increasing, and itis anticipated that this year about 600 scientists will convene at the Princess Hotel in Eilat, Israel.http://www.isfn.org.il.Further information concerning the Israel Society for Neuroscience can be found at Committee:Shlomo Rotshenker (President)Hebrew University of JerusalemTalma BrennerHadassah–Hebrew University Medical CenterYoram Rami GrossmanBen Gurion University of the NegevMmouna MarounUniversity of HaifaYoel YaariHebrew University of JerusalemGal YadidBar-Ilan UniversityZvi Wollberg (Past President)Tel Aviv UniversityLili Anglister (Treasurer)Hebrew University of JerusalemMichal Gilady (Administrator)Rishon Le Zion Aggregation of the amyloid-beta (A-beta) peptide in the extracellularspace of the brain is central to Alzheimer's disease(AD) pathogenesis. Recent findings have shown thatsynaptic activity promotes release of A-beta through vesicleexocytosis. However, the relationship between vesicularrelease of A-beta and neurotransmitter release remainsobscure. Current hypothesis of AD suggests that elevatedneuronal activity leads to increased extracellular concentrationof A-beta, which in turn triggers reduction in thenumber, strength, and plasticity of synaptic connections,eventually resulting in memory impairments. Accordingto this hypothesis, decreased synaptic activity should promotememory function through reducing A-beta level. However,on the other hand, memory-related forms of synapticplasticity are manifested as increase in synaptic activity.To understand this paradox, we study the relationshipbetween different patterns of synaptic activity, A-beta release,and synaptic transmission using FM-based functionalimaging at the level of single synapse and in synaptic networks.Our results show that acute accumulation of endogenouslyreleased A-beta enhances presynaptic activity for singlespikes that mimic background activity through increasingrelease probability and the number of functional presynapticterminals. However, A-beta does not affect presynapticactivity associated with temporally correlated burstof spikes. These results suggest that A-beta might be a keymolecule transforming hippocampal synapses to a low-passfilter mode, resulting in decreased short-term facilitation oftransmitter release during bursts. We hypothesize that elevationof background presynaptic activity by A-beta mightbe a trigger for homeostatic down-regulation in the numberand plasticity of synapses and, eventually, memory declinein AD. Neurodegenerative disorders pathology can be characterizedby both chronic inflammation and oxidative stress. Themostdominant source of inflammatory and oxidative stress mediatorslike nitric oxide (NO), prostaglandins, and cytokinesare activated microglia. We used lipopolysaccharide (LPS) inorder to induce oxidative stress in microglia. L-Carnosine isknown as an efficient endgenous antioxidant. The aim of thisstudy was to gain insight into the role of L-Carnosine and NAcetyl-L-Carnosine (NACar), a lipophilic synthetic derivativeof L-Carnosine, on NO synthesis inmicroglia. It is shownhere for the first time that L-Carnosine (10–20 mM) can inhibitLPS-induced NO synthesis by 75% in microglia. NACarwas even more potent than its parent drug, L-Carnosine, ininhibiting LPS-induced NO synthesis. It inhibits NO releaseby 40% to 80% at concentration as low as 0.5 mM. Our resultssuggest that L-Carnosine and NACar may play a protectiverole in oxidative stress process in the brain. Furtherstudies are needed aiming to understand the mechanism bywhich L-Carnosine and NACar act and to use these compoundsas a potential treatment strategy for strategy for neurodegenerativediseases. Nitric oxide (NO) is produced in the brain by both neuronsand astrocytes. Until recently, astrocytic NO production hasbeen demonstrated mainly as a slow reaction to detrimentalevents through the activity of an inducible NOS isoform(iNOS). Prior data from our laboratory described for the firsttime rapid astrocytic NO release in brains of healthy animals.To further explore the role of astrocytic-produced NO,we examined the iNOS knockout (KO) mouse. NO imagingand biochemical assays revealed compensatory NOS activityin mutants' brain, which resulted in 30% higher basal NOlevels compared with control animals. Evaluation of the mutants'behavior in several behavioral tests revealed increasedanxiety-like responses, with no differences in motor activity. To further characterize the behavioralphenotype, we compared the performance of mutant miceto their controls in their response to stress. Seven days afterexposure to predator scent stimulation (PSS), mutantsexhibited higher anxiety-like behavior in the elevated-plusmaze and stronger acoustic startle response. No such differencesbetween groups were observed without the stress exposure.Plasma corticosterone levels were significantly higherin mutant mice following PSS, further demonstrating theirheightened sensitivity to stress. Interestingly, mutant miceperformed better on the Morris water maze (MWM) undercontrol conditions. The possibility of improved cognition inthese mice was not supported as these mutants failed to showimproved performance in the object recognition test. TheMWM results are probably due to enhanced motivation underwater maze stress conditions in mutant mice comparedto controls. Taken together, our results confirm higher susceptibilityto stressful conditions in an astrocytic NOS mousemutant.Supported by a grant from the Israel Science Foundation to Y.A. μg/0.5 mL) to the hippocampus impairedextinction, but not acquisition of the IA task. However,the direct cannabinoid agonist WIN 55 212-2 (0.5 mg/kg or6 ng/0.5 mL) had no effect on the acquisition or extinctionof IA in the hippocampus, but impaired LTP in the hippocampalCA1 area and in the CA1/subiculum-NAc pathway.Importantly, using an inhibitor of cannabinoid reuptakeand breakdown AM404 (200 ng/0.5 mL) was found to facilitateextinction of IA. These observations are consistent withcannabinoid effects on memory, and suggest a twofold effectof cannabinoids on memory within the hippocampus: impairingand facilitating. This effect seems to be dependent onthe memory task under examination.The inability to extinguish maladaptive fear responses isa hallmark of anxiety disorders, particularly posttraumaticstress disorder. Thus, suppression of the fear response viathe behavioral paradigm of extinction receives increasing attention,since it could become an effective intervention fortreating fear-related disorders. The endocannabinoid system,particularly CB1 receptors, has recently emerged as considerablyimportant in the extinction of fear-related learning.However, interest in their therapeutic applications has beenrestrained by potentially harmful consequences on memory.Given the well-established role of the hippocampus in learningand memory processes, it is likely that the adverse effectsof cannabinoids on memory are attributable to their actionswithin this brain region. The nucleus accumbens representsa brain area that is critical to the expression of rewardingand addictive properties of several classes of abuseddrugs including cannabinoids. Thus, we set out to examinethe role of CB1 receptors in extinction learning and plasticityin the hippocampal-accumbens pathway. To that end, wehave used 2memorymodels: light-dark inhibitory avoidance(IA) and LTP. We found that microinjecting the CB1 antagonistAM251 . There are 17protein-coding genes in HLOD-1 region and most of themare brain-expressed with potential pathophysiological relevanceto schizophrenia. These findings are supported bythose of Levinson et al. (1998) and Mowry et al. (2000) inthe same region. Transmembrane protein mechanisms such as ion channelsand their activity are at the essence of neuronal transmission.The most accurate method, so far, for determiningion channel kinetic mechanisms is single-channel recordingand analysis. Nevertheless, single-channel recordings carryseveral holdups and complexities, especially when dealingwith voltage-gated channels. We have previously developeda method for fitting cell-attached and whole-cell voltageclampdata to kinetic models of ion channels using geneticsearch algorithms (GAs). Here, we show the applicationof this method for testing several previously publishedand newly conceptualized kinetic models to voltage-gatedsodium channels currents recorded, in cell-attached configurationof the patch-clamp technique, from layer 5 pyramidalneurons of the rat cortex. The results emphasize the inabilityof the commonly used Hodgkin-Huxley paradigm to matchand reproduce recorded currents from mammalian corticalneurons. Further, initial tests suggest a trend towards a simplified Markovscheme that adequately reproduces measuredsodium currents. Finally, experiments were performed to testthe robustness of the best putative Markov models, usingMonte Carlo simulations. P = .01), with increased relative risk (odds ratio) of1.8. Since mitochondrial DNA is small relative to nuclearDNA, a total mitochondrial genome analysis was possiblein a hypothesis-free manner. However, mitochondrial DNAhaplogroups are highly variable in human population and itwill be necessary to replicate our results in other human ethnicgroups.Haplotypes and haplogroups are linked sets of commonDNA variants, acting as susceptibility or protective factorsto complex disorders. Growing evidence suggests that dysfunctionof mitochondrial bioenergetics contributes to theschizophrenia phenotype. We studied mitochondrial DNAhaplogroups in schizophrenia patients. Since mitochondriaare inherited from the mothers, we used healthy fathers asan ideal case-control group. Analysis of the distribution ofmitochondrial haplogroups in schizophrenia patients comparedto their healthy fathers (202 pairs) resulted in an overrepresentationof the mtDNA lineage cluster, HV, in the patients as a tool to assess the functional relevance ofthese plastic changes. Finally, I will discuss the use of sensorysubstitution devices (SSDs) in the context of blindness. InSSDs, visual information captured by an artificial receptor isdelivered to the brain of a blind person using nonvisual sensoryinformation via a human-machine interface. I will showthat the use of an auditory-to-visual sensory substitution devicecalled “the vOICe” yields successful performance on objectrecognition tasks, and specific recruitment of ventral anddorsal visual structures both in blind and sighted experts. Iwill close by discussing the importance of “the vOICe” as adevice to be used for daily activities  and its potential use to “guide” the visualcortex to “read” and interpret visual information arrivingfrom a retinal prosthesis.A. A. is supported by the Human Frontiers Science Programand an EU 7th Framework Program grant. Converging evidence from numerous ERP and MEG studiespoints to a neural response which discriminates faces fromnonface objects, peaking at around 170 milliseconds followingstimulus onset. Here we ask whether this discriminationat the neural level correlates with conscious detection of aface, or with its mere presence in the visual field. To investigatethis, we used “continuous flash suppression,” a binocularrivalry technique that effectively causes unawareness ofthe stimulus presented to one eye. In each trial, a face or anEaster egg was continuously presented to one eye, but wastemporarily masked after a delay by a dynamic stimulus presentedto the other eye. In a control condition, the face oregg was physically removed for the duration of the dynamicmask. In both conditions, the subjects' subjective experiencewas of two presentations of a face or of an egg. The onsetof the first face elicited a typical N170 face-specific responsein both conditions. In contrast, the subjective reappearanceof the face elicited a face-specific N170 response only inthe control condition, when physical face onset was introduced.Thus, extrastriate object-selective responses reflectthe physical presence of relevant input, and are not correlatedwith conscious awareness. P < .08).In the FST, the “withdrawal” rats exhibited significantly moreimmobility, the depressive-like behavior, than control rats,indicating that the hormone regimen was successful in mimickingthe post-partum period. The results suggest that fluctuationsin estradiol levels can lead to the onset or exacerbationof OC symptoms.Obsessive-compulsive disorder (OCD) is a psychiatric disorderpsychiatric disorder affecting 1–3% of the populationand characterized by intrusive unwanted thoughts (obsessions)and repetitive ritualistic behaviors (compulsions).Sex differences have been found in the phenomenology andcourse of this disorder, and women have been reported to bevulnerable to an onset or exacerbation of symptoms duringpremenstruum, pregnancy and postpartum. This suggests apossible involvement of gonadal hormones in the pathopysiologyof OCD. In the signal attenuation rat model of OCD,“compulsive” behavior is induced by attenuating a signal indicatingthat a lever-press response was effective in producingfood. The present study tested the effects of chronic administrationand of withdrawal from chronic administration of 17beta estradiol on compulsive lever-pressing of pre-pubertalfemale rats, in an attempt to mimic late gestation and postpartum.In order to assess the efficacy of the hormone regimenin mimicking the postpartum period, rats were assessedfor postpartum depression using the “forced swimtest” (FST), an animal model of depression. Rats that wereinjected with 17 beta estradiol for 7 days and then underwenta withdrawal phase for 3 days tended to exhibit more compulsivelever-pressing compared to control animals ( μg/kg)and the atypical APD clozapine (5 mg/kg), but was resistantto the typical APD haloperidol . Herewe show that haloperidol is able to restore LI only whenadministered with 17 beta-estradiol (50 μg/kg). Furthermore,under conditions that yield LI in both OVX andsham female rats, amphetamine disrupts LI in all rats, butrestoration of LI by haloperidol in amphetamine-treated ratsis observed only in sham rats. While resistance of disruptedLI to haloperidol in the absence of estrogen is in line withreduced efficacy of haloperidol in menopausal women,our results suggest that propsychotic action of dopamine(DA) releaser apparently does not require estrogen. Thisdifferential sensitivity of OVX rats to DA stimulation and DAblockade may have important implications for the clinicaldevelopment of schizophrenia and APD treatment in womenbecause it suggests that naturally occurring reduction inhormonal levels may increase the danger of relapse/severityof symptoms while concomitantly reducing the efficacy ofconventional treatment.Elevated relapse rates and symptoms remission inschizophrenic schizophrenic women tend to correlatewith low and high estrogen levels, respectively. Consequently,the estrogen hypothesis of schizophrenia postulatesthat estrogen is a neuroprotective factor delaying the onsetof schizophrenia and reducing its severity in women.Latent inhibition (LI), the capacity to ignore stimuli thatreceived nonreinforced preexposure prior to conditioning,is disrupted in acute schizophrenia patients and in ratsand humans treated with the psychosis inducing drugamphetamine. Disruption of LI is reversible by typical andatypical antipsychotic drugs (APDs). Our previous resultssuggested that LI was disrupted in ovariectomized (OVX)rats and could be restored by 17 beta-estradiol , it remains to be determinedwhether extracellular or intracellular A-beta accumulationinitiates the disease process. Intraneuronal A-beta accumulationis increasingly linked with early preplaque synaptic andpathological abnormalities occur in brain of AD patients andtransgenic animals. Understanding the mechanisms that underlineA-beta accumulation in neurons and its relation withthe extracellular A-beta pool, may be beneficial in developingtherapeutic tools for AD treatment. We developed a novelapproach to inhibit A-beta production via antibodies againstthe beta-secretase cleavage site of APP. This approach limitsAPP processing by beta -secretase, mainly through the endocyticpathway and overcomes some of the limitations ofBACE1 (beta-secretase) inhibition methodologies. Antibetasiteantibodies bind human APP expressed by AD cellularmodel and internalize into the cells after APP binding atthe plasma membrane. Antibodies mediated inhibition ofbeta-secretase cleavage led to a 50% reduction of intracellularA-beta levels. Intracerebroventricular injection of theseantibodies to non transgenic mice in which neprilysin activitywas inhibited led to 60% and 80% reduction in intracellularand extracellular brain A-beta levels, respectively,highlighting the therapeutic potential of these antibodies.Moreover, systemic administration of antibeta-site antibodyto tg2576 mice facilitated a beneficial effect on the mice cognitivefunction and did not lead to any adverse effects. Tothe best of our knowledge this is the first attempt to inhibitbeta-secretase cleavage of APP by blocking the cleavage siteupon the substrate rather then a total inhibition the enzyme.This approach overcomes some of the limitations presentedby both BACE1 inhibition methodologies and A-beta-basedimmunotherapies. Performance errors induced by perturbation during reachingmay drive adaptation differentially based on sensory modalitiesconveying them. Here we demonstrate that state estimatesbased on vision and proprioception differentially influenceadaptive strategies used in force fields. We studiedthe contributions of visual and proprioceptive feedback ina reaching task. Separate groups of human subjects adaptedto viscous force fields with or without concurrent visual feedbackof their hand trajectory and were retested after 24 hours.We found comparable levels of endpoint accuracy after adaptationto force field with and without visual feedback, however,hand paths differed consistently. With visual feedback,induced deviations in initial direction of hand movementswere rapidly reduced and paths became rectilinear. On day2, adaptive changes in initial direction were accelerated andendpoint variability was reduced. Without visual feedback, hand paths remained highlycurved. While endpoint errors were reduced on day 2, initialdirections and curvature remained unchanged. The resultsindicate two different strategies to achieve final positionaccuracy-one through changes in trajectory and anotherthrough changes in endpoint variability. In the presence ofcombined visual and proprioceptive feedback, adaptation isdominated by control of trajectory and adjustments in direction.With proprioceptive feedback alone, compensationfor the perturbed dynamics is achieved primarily by adaptationof final equilibrium position. We argue that such starkdifference in the adaptive responses depends on the sensorysources of the estimates for trajectory and for final reach position.Our findings also support the notion that separateadaptive mechanisms operate to adjust trajectory and endpointaccuracy.Supported by BSF, ISF, Johnson & Johnson Fund for InnovativeScience, Rosetrees Trust, Ida Baruch Fund. Apnea, a repeated suspension of breathing during sleep, isa prevalent sleep disorder with significant impact on dailylife as well as on general health. We combined the followinginformation to generate a potential treatment:it is largely held that odorants fail to wake humansfrom sleep;odorants modify respiratory patterns. Given this, wehypothesized that providing an odorant during apneamay “jumpstart” the respiratory pattern without wakingthe individual.F = 49, P < .0001) reflecting equally vigorous nasalrespirations during stage 1 and 2 sleep , andequally significantly reduced respiratory magnitude in SWSand REM . Whereas odorant presentationshad no influence on respiratory magnitude during Stages 1and 2 sleep , they induced a significantrecovery in magnitude of nasal respiration during SWS andREM , to levels even slightly higher thanthose seen at Stages 1 and 2 with and without odor. Thesepilot data point to feasibility of using odorants to treat sleepapnea.To address this, we first set out to test the influence ofdifferent odorant regimens on patterns of sleep and sleeprespiration.Subjects slept in a stainless-steel-coated odorantnonadherent room where we measured an electroencephalogram,electrooculogram, electromyogram, electrocardiogram,blood oxygenation, as well as overall and nasalrespiration. Subjects wore a small nasal mask where we coulddeliver odorants in a controlled fashion, with no nonolfactorycues as to odorant onset and offset. The odorant lavenderoil was presented to sleeping subjects . In an initial analysis of nasal respiration in thefirst subject, without odors we found a main effect of sleepstage  was found to increase theprevalence of altered stress responses which corresponded toboth mood and anxiety disorders' symptoms and thus wassuggested as a model of induced predisposition for these disorders. The current study utilizedthe juvenile stress model and examined its effects onmorphine intake in adulthood. Consumption of water aloneand/or water + morphine sulfate (0.5 mg/cc) was monitoredover several weeks. In comparison with control rats, adultjuvenile stressed rats exhibited a higher morphine preference(morphine intake/ (morphine + water intake)). Recentfindings suggest that exposure to juvenile stress may alterdevelopment-related processes and possibly sensitize stressresponses mechanisms . Taken togetherwith the current data, it is suggested that such sensitizedstress responses mechanisms may increase drug seeking behaviors.These findings support the validity of an animalmodel for the study of the consequences of exposure to stressearly in life regarding drug dependence or drug seeking behaviorsin adulthood. αCaMKII mRNA. Our results imply that L-LTPshould produce an increase in the total amount of αCaMKIIand fraction phosphorylated at potentiated synapses, whichis consistent with experimental observations . Through bifurcation analysis, we identify the key parametersthat determine whether the system is in a bistableregion, this could indicate the key parameters that should bemeasured experimentally. We also demonstrate that a partialblock of αCaMKII translation in the induction phase ofL-LTP can block L-LTP, but a partial block of translation inthe maintenance phase might not block L-LTP.Long term memory as well as synaptic plasticity outlast thelifetimes of the proteins that encode synaptic efficacies. Sincesynaptic plasticity is synapse-specific it is essential to identifya mechanism that can sustain changes in synaptic efficaciesis a synapse specific manner. One key observation that mightsupply a possible mechanism is that the consolidation of longterm memory and long term plasticity depends on the productionof new proteins. Here we suggest that a feedbackloop between a translation factor and a plasticity related kinasemight provide this stability. Specifically we examine theCaMKII-CPEB pair as a possible instantiation of this idea.Experimental evidence suggests that during the normal brainfunction most of the CaMKII (83%) is synthesized in dendritesthrough local translation . Here we propose that the synthesis of CaMKII atactive synapses can be regulated through a local translationalswitch. The proposed translational switch might provide aself-sustaining mechanism to regulate the de novo synthesisof plasticity-related proteins during the maintenance phaseof late long-termpotentiation (L-LTP). Our results show thata bistable switch can arise from CPEB mediated polyadenylationof  We present a hierarchal model and supporting data on spatialrepresentation during exploration, based on successivephases of spatial information processing: (1) piloting —egocentric space representation constructedby traveling from one landmark to the next, changingheading direction (origin point for path integration) betweenlandmarks; (2) orienting —spaceis represented in relation to a fixed place that is a terminalfor repeated sequential processing, with the traveling pathsvarying yet heading direction points to the fixed location; (3) navigating(continuous processing)—space representation (map) isconstructed by orienting (continuously updating heading direction)in relation to several places. Empirically, we demonstratea transition from sequential to parallel processing duringgerbil exploration. Tested in an unfamiliar dark openfield, gerbils explored it using a looping mechanism: travelingslowly in an undulating path that forms a loop by returningto a previously visited place. In looping the gerbilsrarely returned more than once to a previously visited place,with no apparently fixed heading direction. Gradually, gerbilsshifted from looping to a home base mechanism, spendingincreasingly greater time in one place and repeatedly returningto it. Exploration became organized in relation to afixed place, with varying paths that share a heading directioncomputed in relation to that place. We suggest this shift fromlooping to home base to reflect a change from momentaryto fixed heading direction and thus from piloting to the orientingphase of the model. As the model involves transitionfrom orienting to navigating, a transition from home baseto a higher level of spatial organization is predicted. Possibleimplications of the model to effect of spatial representationdamaging  are yet to be explored.Supported by the Israel Science Foundation. Rat Hippocampal neurons encode the current locationof the animal via place fields. Changes to distal cuesin the animal's environment can modulate this encoding, a phenomenon termed place field remapping. In a spatialmemory task on a + maze hippocampal cell activity wasalso influenced by locations that were recently visited, orare forthcoming . Thus,hippocampal neurons can jointly express contextual andmnemonic information that relates to the present, past, andfuture. This type of processing fits the view that the hippocampussupports episodic memory, and that memory demandscan modulate hippocampal coding. The present experimenttested the effects of changing memory demands onretrospective and prospective coding, and examined if modulationsof retrospective and prospective coding share thesame dynamics as stimulus-induced place field remapping.We trained rats to perform a win-stay task with serial reversalson a + maze. Hippocampal unit activity was recordedas rats placed on either a North or a South start arm navigatedto the correct East or West rewarded goal arm. In anovel condition, the start and goal arms were switched, sothat the North and South arms served as the goal arms andthe East and West arms served as the start arms. Preliminarydata showed that all place fields remapped in the novel condition.Concurrently, performance decreased in the Novelcondition from 91% to 74% correct, as did the percent offields showing prospective or retrospective coding . In contrast, the percentof fields coding location alone increased in the novel conditionfrom 20% to 77%, though the fields were less stable. Weare collecting additional data from CA1/CA3 fields in orderto better understand the influence of changes to memory demandon hippocampal on-line processing. The notion that synaptic plasticity supports long-termmemorystorage while persistent neuronal spiking activity maintainsthese memories in a short-term active form is widelyheld in theoretical neuroscience. We show that synapses canalso effectively implement active memory function throughtheir short-term plasticity. In this account, the short-termsynaptic variables are used as a “buffer” which is loaded,read-out and refreshed by neural activity. The refresh rate islow, since it depends on the slow time constants associatedwith synaptic dynamics. The feasibility of this mechanismis demonstrated in a biologically plausible spiking networkmodel. The resulting “working memory” system is robust,metabolically efficient, and can help explain recent electrophysiologicalresults. This study addresses the issue of relations that exist betweentopology and dynamics of large sparsely connectedneural networks. In particular, it examines the hypothesisthat topology governs the source separation ability of neuralnetworks endowed with structural characteristics of corticalnetworks. For this purpose, extensive simulations of networkswith different topologies and similar structural features were carriedout. Networks responses to various stimuli were analyzed interms of neural recruitment order during a network burst.The latter measure is assumed to convey information relevantto source separation. The results showed that the responsesof networks with Gaussian in-degree and Scale Free(SF) out-degree distributions to different stimuli varied significantlymore than those of Erdös Rényi (ER) networks andnetworks with SF in-degree and Gaussian out-degree distributions.These results support the hypothesis that topologydoes indeed play a crucial role in source separation tasks executedby neural networks. The axon diameter distribution (ADD) is an importantanatomical feature of nerve fascicles both in normal and abnormaldevelopment. Axon diameter directly affects nervefunction. It is well known that in myelinated axons, the conductionvelocity is directly proportional to axon diameter.Thus, large-diameter axons generally arise in pathways thatrequire short conduction times while smaller axons arise inpathways that can tolerate longer conduction times. In addition,it is hypothesized that in amyotrophic lateral sclerosis(ALS) large diameter axons are damaged selectively, whilein autism, small-diameter axons are over-expressed. Despiteits importance, the ADD within nerve fascicles has not beenmeasurable in-vivo, and currently can only be assessed by invasivehistological means. Here, we propose a new magneticresonance-imaging- (MRI-) based approach called AxCaliberthat utilizes diffusion MRI to extract the ADD, in-vivoand noninvasively. Diffusion MRI measures the micron-scaledisplacements of water molecules; by altering the diffusiontime and diffusion weighting morphological parameters ofthe tissue, such as the ADD and axonal density, can be measuredexperimentally. In this work, AxCaliber was used to extractthe ADD within the corpus callosum (CC) of the rat.Using AxCaliber we were able to segment the CC to at least 3distinct regions corresponding to the body, genu, and spleniumof the CC. A narrow ADD with a mean of about 1micron characterized the genu and splenium while the bodyof the CC had a much broader distribution with a mean ofabout 4-5 microns. This segmentation resembles the knownmorphological arrangement of the CC as measured from histology.Applications of AxCaliber are expected in longitudinalstudies designed to follow nerve growth in normal andabnormal development, as well as in diagnosing disordersand diseases affecting specific populations of axons in theCNS and PNS. In conditioned taste aversion (CTA) a single gustatory experience(exposure to novel taste) is followed by visceraltrauma. Consequently, the animal develops an aversion forthe aversive taste. The memory of aversion is robust, however,repeated exposures to the taste without the associationwith the malaise leads to extinction of CTA. It is assumedthat consolidation and extinction of CTA are each subservedby different neuronal mechanism and various parts of thebrain are involved in these mechanisms. The neural circuitthat underlies the acquisition and the extinction of CTA includesthe amygdala and the insular cortex. Recently researchfrom our laboratory has shown that the ventromedial prefrontalcortex (vmPFC) has a role in extinction of CTA. Inthe current study, we examined the differential activationof the phosphorylation levels of Akt, a serine/threonine kinase,which is a critical enzyme in signal transduction pathways,in the amygdala-prefrontal cortex-insular cortices circuitduring acquisition and extinction of CTA. Our resultsshow that following CTA acquistion there is an increasedlevel of AKT phosphorylation in the amygdala, insular cortexand the prefrontal cortex. In contrast, following extinctiontraining there was a decrease of Akt phosphorylation inthe amygdala and PFC while no change was found in the IC.These results hint on the possibility that the amygdala-PFC-insularcortex circuit is differentially involved in acquisitionand extinction of CTA. Stimuli that elicit synesthesia activate cortical color regions of the brain, including V4.While it has been demonstrated that synesthesia is a genuineperceptual phenomenon, its underlying neural substratesare not well understood. For example, the overall integrityof the visual system has never been assessed and itis not known whether differences in sensory-perceptual processingare associated with the condition. Here, we lookedat visual evoked potentials (VEPs) to determine differencesin sensory-perceptual processing using stimuli that differentiallyactivate the magnocellular and parvocellular pathwaysof the visual system. High and low spatial frequency gratings(Gabors) and luminance-contrast squares were presented to15 synesthetes and 15 controls. We report for the first time,early sensory-perceptual differences in synesthetes. The differenceswere associated with stimuli that do not elicit synestheticcolor experiences and were manifest in early C1 and P1components of the visual evoked potential (VEP). The findingswere not confined exclusively to either magnocellular orparvocellular stimuli, but rather indicate widespread differencesin the way that synesthetes process visual informationduring early time windows. It has been shown that in the apical dendrite of L5 pyramidalneurons, when a back-propagating action potential coincideswith distal synaptic input, a dendritic calcium spikeis generated, leading to the generation of a burst of actionpotentials at the soma. Many questions have been raised regardingthe physiological role of this calcium spike. Lately, adifferent question has been raised whether the calcium concentrationbeing used in the typical ACSF truly reflects theconcentration in the CSF. Recent studies have shown that thecalcium concentration in the ACSF is higher than in the CSFin vivo. We have performed in vitro recordings from acutebrain slices, using the whole-cell configuration of the patchclamptechnique in the current-clamp mode from L5 pyramidalneurons. Regenerative calcium spikes were recordedand compared with calcium concentrations similar to theACSF and CSF in the bath solution. Our results suggest thatwhile the back-propagating action potential is robust underreduced extracellular calcium concentration, the dendriticcalcium spike is suppressed by this modification. Human mesenchymal stem cells reside in the bone marrowand are known for their ability to differentiate alongthe mesenchymal lineage . Recentworks suggest the possibility that these cells are also capableof differentiating towards the neuroectodermal lineage.We aimed at inducing dopaminergic differentiation on humanmesenchymal stem cells as a possible source for autologoustransplantation for Parkinsonian patients. Usinglentiviral gene delivery, we sought to reprogram the bonemarrow derived mesenchymal stem cells towards dopaminergicdifferentiation through delivery of LMX1a, which wasreported to be a key player in dopaminergic differentiationin both developmental animal models and embryonic stemcells. Transduction of cells with fluorescent reporter genesconfirmed efficiency of gene delivery. Upon incubation of theLMX1a transduced cells in differentiation medium we observedincreased concentration of the LMX1a transcriptionfactor in the cell nuclei. Several specific dopaminergic developmentalgenes were upregulated suggesting the generationof dopaminergic precursors derived from adult human bonemarrow. Moreover, the transduced cells secreted significantlyhigher level of dopamine in comparison to untransducedcells. To our knowledge, this is the first time in which a factorinvolved in the natural dopaminergic neuron developmentdirects adult stemcells towards the dopaminergic phenotype.Using ex vivo gene delivery to adult stem cells, our resultsshed a new light on the molecular processes involved in adultstem cell dopaminergic differentiation, suggesting that thetranscriptional cascade of adult stem cell dopaminegic differentiationhas parallel pathways to that of embryonic stemcells. The allele E4 of apolipoprotein E (apoE4), which is the majorgenetic risk factor for Alzheimer's disease (AD), is associatedhistopathologically with elevated levels of brain amyloid.This led to the suggestion that the pathological effectsof apoE4 are mediated by cross talk interactions ofapoE4 with A beta and to the consequent accentuation of thepathological effects of the amyloid cascade. The A beta relatedprocesses which are affected by apoE4 and the cellularand molecular mechanisms which underlie their pathologicalconsequences are not known. We have recently shownthat inhibition of the A beta degrading enzyme neprilysinby intracerebroventricular infusion of thiorphan into brainsof wild type apoE3 and apoE4 mice, results in a rapid andsimilar increase of their total brain A beta levels. However,the nucleation and aggregation of A beta in these mice weremarkedly affected by apoE and were particularly and specificallyenhanced in the apoE4 mice. We presently employed theneprilysin inhibition paradigm to analyze the brain pathologicaland cognitive effects which are induced by apoE4 andapoE3 at distinctive time intervals following activation ofthe amyloid cascade and of the extent to which they correlatespatially and temporally with the accumulation of intraneuronalA beta. This revealed that apoE4 stimulates isoform specificallythe accumulation of intraneuronal A beta inhippocampal CA1 neurons. Furthermore, the accumulationof A beta in the CA1 neurons correlates spatially and temporarily(t 1/2 ∼ 1 week) with enhanced lysosomal activationand apoptosis of these neurons and with the occurrence ofmarked cognitive deficits. These findings render this modeluniquely suitable for detailed kinetic analysis of the earlystages of the amyloid cascade and of the biochemical mechanismsunderlying the effects thereon of apoE4 and other riskfactors of AD.Supported by The US-Israel Binational Foundation and theJoseph and Inez Eichenbaum Foundation. Rat pheochromocytoma (PC12) cells have been extensivelystudied as a model for neuronal cell line since their firstcloning in 1976, because of their neuronal-like properties.Removal of the serum from the growth medium of PC12wild type (PC12-wt) cells induces cell death by apoptosis.A mutant clone of PC12 cells (PC12-m), can survive up to5 days in a serum-free medium. Furthermore, it has beenshown that PC12-m cells secrete an unknown factor thatprevents PC12-wt cells from serum deprivation-induced celldeath; PC12-m cells were grown in a serum-free mediumfor 5 days and the condition medium (CM) was collected.When PC12-wt cells were grown in CM, they survived forup to 5 days. Here we show that the survival of PC12-wtcells in the CM was prevented when an inhibitor of theTrkA receptor, K252a, was added together with the CM,thus showing that cell survival is mediated via TrkA receptor.This factor present in the CM is probably not NGF(which previously has been shown to rescue PC12 cells fromserum deprivation-induced death), because boiling of theCM for 10 minutes did not prevent PC12-wt survival capabilities,as opposed to boiling of serum-free medium withNGF. Unlike NGF, acute treatment of PC12-wt cells with CMfailed to induce ERK activity, suggesting that the secretedfactor acts via a mechanism different than NGF. Interestingly,CM from PC12-m cells also prevented cell death ofPC12-wt cells induced by high concentration of cocaine, independentof the TrkA receptor. These results suggest thatthe CM has neuroprotective abilities; however, the signalingpathways which underlie these abilities are different fromthose induced by NGF, and dependent on the type of insultused. Voltage-activated (Kv) and leak (K2P) potassium channelsplay key yet distinct roles in electrical signaling in the nervoussystem. Here, we examined how differences in the operationof the activation and slow inactivation pore gates ofKv and K2P channels underlie their unique roles in electricalsignaling. Shaker Kv and KCNK0 leak channels demonstrateopposite closed and open pore conformational stabilityphenotypes, respectively. Replacement of the pore domain ofthe Shaker channel with that of KCNK0 resulted in a substantialstabilization of the open pore conformation. Systematicreplacement of activation gate hydrophobic residues ofthe Shaker channel to the corresponding glycine residues ofKCNK0 resulted in dramatic open-state stabilization effects.Complementary experiments revealed dramatic closed statestabilization effects. By using macroscopic and single channelrecordings we were able to monitor the conformationalstates (whether closed or open) of both the activation and inactivationgates of KCNK0. Our results revealed that (1) leakpotassium channels also possess a lower activation gate, (2)that the activation gate is an important determinant controllingthe intrinsic conformational stability of the potassiumchannel pore, (3) the lower activation and upper slow inactivationgates of leak channels cross-talk and (4) in contrast toKv channels, where the two pore gates are negatively coupled,that is, the opening of the lower activation gate stimulatesthe closure of the upper slow inactivation gate, the two gatesare positively coupled in K2P channels. Our results demonstratehow basic thermodynamic properties of the potassiumchannel pore, particularly, intrinsic conformational stabilityand coupling between the pore gates, underlie the specializedroles of Kv and K2P channel families in electrical signaling. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerativedisorder of the motor system causing damage to boththe upper and lower motor neurons (UMN/LMN). To date,there are no imaging techniques available for objectively assessingthe UMN damage.The purpose is to evaluate the cerebral white matter quantitativelyusing diffusion tensor imaging (DTI) and high bvaluediffusion weighted imaging (DWI).b = 1000 s/mm2) andhigh b-value DTI . Twenty-threeUMN ALS patients and 20 age match healthy volunteerswere scanned on a 3T GE MRI scanner. Diffusion tensortracktography (DTT) was used and mean FA, Prob and Dispwere calculated for the motor and sensory fibers separately.MR protocol included T1, T2, DTI (P < .05) inboth the motor and sensory fibers. Reduced FA, Prob, and increaseDisp values were also detected in the study group comparedto the control group in the high b-value coronal dataset (P < .05 only for FA). Histogram analysis of FA, Prob, andDisp revealed no differences between the two groups. No correlationwas found between FA, Disp, and Prob values andALSFRS-R or with disease duration. Sub group of ALS patientswith Buluar onset demonstrate significant correlationbetween FA and Eigenvalues to disease duration.On the data from axial images, reduced FA was detected inthe study group compared to the control group . Amyloidbetais generated by proteolytic cleavage of the ubiquitousamyloid precursor protein (APP) which has important physiologicalfunctions. Current drug treatments for AD providesymptomatic relief of cognitive and memory impairmentswithout addressing neurodegeneration and the underlyingcauses of the disease. Immunotherapy emerged recently asan approach to prevent amyloid-beta accumulation. Studiesusing AD transgenic mice as well as clinical trials provide encouragingdata for immunotherapy as an effective approachto reduce amyloid-beta toxicity with the potential to slow or arrest disease progression, provided that key safety issuesare addressed and adverse reactions are reduced. The key todevelop safe and effective AD immunotherapies lies in designingvaccines and antibodies that are highly specific foramyloid-beta, do not cross react with endogenous functionalproteins such as APP and do not activate cytotoxic T-cellresponses. Our immunotherapy programs consist of “freeendspecific” antibodies and chimeric-peptide vaccines thatrecognize specifically the free N-terminus or C-terminus ofamyloid-beta peptide and, consequently, are capable of discriminatingbetween toxic amyloid-beta peptides and functionalendogenous APP peptides. In addition, our vaccinesuse very short “free-end” peptide fragments that are devoidof harmful T-cell epitopes. This “free-end specific” immunizationconcept is likely to minimize the risks for an autoimmuneresponse and has the therapeutic potential to promoteclearance of amyloid-beta in a safe and effective manner. The frequency of electrical brain activity is commonlythought to be functionally meaningful. However, exactlywhat functional brain networks mediate activity at given frequencybands remains largely unknown. The alpha rhythmis considered the hallmark of the brain resting state and canbe modulated by simply opening or closing eyes. This studyaimed to match individually characterized EEG rhythms andsimultaneously acquired whole brain functional magneticresonance (fMRI) BOLD activation associated with spontaneousvariations of the alpha rhythm (8–12 Hz), Subjectswere instructed to close/open their eyes every 30 seconds.EEG activity was recorded from 32 electrodes simultaneouslywith whole brain fMRI in a 3T GE scanner. Activity in the alphaband was defined for each subject. Electrodes at whichactivity was maximal were then selected. The signal filteredat the individually-defined frequency ranges was then convolvedwith the corresponding fMRI signal and used as aregressor for statistical parametric mapping. Preliminary resultsshow that eyes closed and open are associated with distinctwidely distributed activation patterns. Preliminary resultsfor alpha band-related BOLD signals showed differentialpeak activation distributions in occipital and frontal areas.Using EEG based fMRI analysis we then showed thatthe a priori defined oscillatory bands are associated with distinctwidely distributed activation patterns. The significanceof combined measurements will be discussed. It is known that the neuroendocrine system and the autonomicnervous system are regulators of brain-immune interaction.However, the functional significance of this interactionunder a variety of conditions is not fully understood.The objective is to investigate the effect of stress paradigm onbehavioral tests, immune parameters, and tumor progressionand survival of lymphoma-bearing mice.C3H mice were either exposed to an electric shock followedby 3 reminders (once a week) or were left untreated. Followingstress paradigm mice behavior was tested in elevated plusmaze, staircase, hot plate and open field, and NK cell activitywas measured. In addition, mice were tested for proliferationof lymphocytes, spleen weight and number of leucocytesin spleen. Different mice were vaccinated twice with the immunoglobulinof the B-cell lymphoma 38C-13 and antiidiotypeantibodies in sera of mice were determined by ELISA.Other mice were inoculated with tumor cells and monitoredfor tumor development and for survival.P < .05). Whenmice were immunized with an idiotype-vaccine, those exposedto stress paradigm produced higher levels of antiidiotypeantibodies (P < .01). In addition, proliferation inthe presence of mitogenes was higher in exposed group, sodid number of leucocytes in spleen. Exposed mice revealedattenuated tumor growth (P < .05), with no difference insurvival.No major differences were found in behavior between thestressed mice and control mice. However, significant differencewere found in immunological and cancer parameters.The mice exposed to stress paradigm had higher cytolyticactivity than did the standard group , PD patients(n = 17) and controls (n = 21) performed the card bettingtask as well as immediate and delayed recognition tasksthat assess declarative functioning. PD patients were indeedimpaired on the card betting task and AD patients were impairedon the “declarative” tasks. However, in contrast to ourhypothesis, AD patients did not perform better than controlson the card betting task. In summary, this study addsto previous demonstrations of a double dissociation betweenthe declarative and procedural systems in humans. However,there is no evidence for interference between these two systemsin the acquisition of the card betting task.The division of memory systems into declarative and proceduralis well established. The declarative system is involvedin the acquisition and use of episodic and semantic memory,and is related to the hippocampal system. The proceduralsystem is involved in the acquisition of habits andskills, and depends on the striatum. Although the two systemsare thought to interact, the nature of interaction is notwell understood. Animal studies have suggested that undersome conditions the two systems may interfere with eachother. Specifically, rats sustaining lesions to the hippocampusperformed better than intact rats in a procedural task.The present study tested whether such interference may alsooccur in humans. Healthy subjects, patients with Parkinson'sdisease (PD), in which the dopaminergic input to the striatumdegenerates, and patients with mild Alzheimer disease(AD), in which the hippocampal system is the first to degenerate,were tested in a card betting task. This task is uniquein that about half of normal subjects do not acquire it, suggestingthat it is particularly sensitive to interference arisingfrom the declarative system. It was therefore hypothesizedthat whereas PD patients will not be able to acquire the task,AD patients will perform better than controls, due to a deficientdeclarative system. AD patients ( μM) into theright ventricles of adult Sabra rats. Zinc-induced neurodegenerationprecluded recordings in the right  hippocampi.Sharp electrodes current-clamp, whole-cell patchclamprecordings of T currents and immunostainings forCaV3.2 were performed in slices from the contralateral hippocampi.We found that the bursting activity in CA1 pyramidalcells was suppressed by specific blockage of the T-typecalcium current in 1/3 of the tested cells. Two days followingzinc injection the densitiy of T current was markedly (3-4fold) increased in approximately 1/3 of the neurons comparedto neurons in the control group. Congruently, immunostainingsdisclosed an increase in CaV3.2 abundance inCA1 pyramidal cells in hippocampi from zinc injected rats.Our findings show that an increase in brain zinc causes upregulationof CaV3.2 abundance leading to an increase in Tcurrent and associated neuronal bursting. They support ourhypothesis that an increase in free zinc during or shortly afterSEmay contribute to epileptogenesis. These findings havetherapeutic implications for the prevention of epilepsy followingbrain insults.A single episode of status epilepticus (SE) caused by pilocarpine,triggers multiple changes in neuronal structure andfunction (referred to as epileptogenesis) that ultimately leadto chronic epilepsy. One striking change is the upregulationof CaV3.2 T-type calcium current, which causes many hippocampalpyramidal cells to display intrinsic bursting behavior.The processes which couple SE to T current upregulationare not known. We hypothesized before that SE-induced accumulationof zinc may play a role in these processes andwe have found, that intracerebroventricular injection of zinctransforms about 60% of CA1 pyramidal cells into burstingneurons. Therefore, we examined here whether zinc alsoinduces an increase in T current density in these neurons.We injected saline with or without ZnCl2 , and may significantly contributeto the disease progression. One of the pathological hallmarksof AD is chronic microglial activation and consequentover-production of proinflammatory mediators suchas prostaglandins, cytokines and nitric oxide (NO). The latter,at high concentrations, may be neurotoxic and can beinvolved in the neurodegeneration process. Kinins are potentstimulators of the production and release of NO inmany cells. Whether this is universal, remains to be investigated.Recent reports suggest a possible neuroprotective roleof bradykinin (BK), probably mediated by microglial cells.The aim of the present study was to investigate the role ofBK in the regulation of basal and lipopolysaccharide (LPS)-induced NO synthesis in a microglial cell line, BV2, andto assess the involvement of each of the two BK receptors,B1 and B2, in this effect. Long-term (24–48 hours) exposureof cells to BK (10 nM) reduced basal NO release by 75%. B1receptor agonist, [Lys-des-Arg9]-BK, had the same effect asBK, 70% reduction of NO synthesis at a concentration of10 nM. BK also attenuated LPS-induced NO production by30% and 50% at concentrations of 1 nM and 10 nM, respectively.The B1 receptor agonist also attenuated LPS-inducesNO production by 30% at 1 nM. These preliminary resultsimply a novel neuroprotective role of BK via attenuation ofNO released from microglial cells under both basal and inflammatoryconditions.This research was supported by the Israel Science Foundation (Grant no. 349/07). μM) differentially suppressed L-type and T-typecalcium channel currents ; the effects on ITwere faster and more prominent than the effects on IL; (2)the effects of LPC on IL started after long delays (50–100 seconds),exhibited slow onset kinetics and were reversible onlyafter washout with BSA; (3) the effects of LPC on IL wereboth dose-dependent and voltage-dependent with a rightwardshift in the activation curve of about 9 mV; (4) the effectsof LPC on IL persisted after block of G-proteins withGDPbetaS and after block of PKC with GF 109203X; (5) theeffects of LPC on IL were mimicked by lysophosphatidylinositol(LPI), a negatively charged cone-shaped lipophilicmolecule; (6) the effects of LPC on IL were not mimickedby a short chain LPC (C6:0) and by phosphatidylcholine, acylindrical-shaped lipophilic molecule. In summary, our resultsshow that cone-shaped lipophilic molecules (LPC andLPI) suppress VGCC in pituitary cells and that this suppressionis independent on the polarity of the hydrophilic head.Our results also suggest that incorporation of LPC and LPIinto the phospholipid bilayer underlies this suppression, andthat molecular shape is a determinant in this suppression.Lysophospholipids (LPLs) are lipophilic molecules consistingof a hydrophilic head and a hydrophobic tail. LPLs containinga large hydrophilic head and a thin hydrophobic tailwere defined as cones. It was hypothesized that incorporationof cones into the outer leaflet of the phospholipid bilayerincreases membrane tension and it was demonstratedthat cone-shaped LPLs alter the gating of mechanosensitiveion channels. Previous studies demonstrated modulationof voltage-gated calcium channels (VGCC) by membranestretch. We therefore examined the effects of the cone-shapedmolecule, Lysophosphatidylchloline (LPC), on VGCC in pituitarycells. Our findings may be summarized as follows: (1)LPC . In the current workwe further analyze the contribution of our biological featuresto the recognition task. We demonstrate our results onthe popular problem of face recognition. We analyze colorface images  and show that recognition performanceimproves as more biological principles are incorporatedinto the model. Worst recognition results are obtainedwhen the images are processed as grayscale (intensitychannel); a significant improvement in performance isachieved by representing images in the biological color-spaceby adding two opponent-color channels  to theintensity channel. Finally, we use the complete ensemble ofbiological features—intensity and opponent-color channelsshaped by appropriate filters at various scales and orientations.On the ensemble of these features, we apply, iteratively,biologically inspired Boosting. At every iteration, the biologicalfeatures are used to construct weak (face) learners on thetraining data. The best weak learner is weighted by its accuracyand then added to the final strong learner. At the successiveiteration, the training data is reweighted: examples thatare misclassified gain weight and examples that are classifiedcorrectly lose weight. This technique results in the best recognitionperformance. A dispute exists as to whether morphology is a discrete andindependent element of lexical structure or whether it simplyreflects a fine-tuning of the system to the statistical correlationthat exists among orthographic and semantic propertiesof words. Imaging studies in English failed to show unequivocal morphologicalactivation that is independent of semanticor orthographic activation . InHebrew, Cognitive research has revealed that morphologicaldecomposition is an important component of reading, and using fMRI we identified areas inthe brain, the lMFG and lIPS, activated distinctly during explicitmorphological processing . In thisfMRI study, we aimed to replicate our results using an implicittask. This would further establish our results and showthat morphological processing is automatic in reading Hebrew.Words were presented in the mask priming paradigm and subjects perform a lexical decisiontask. Subjects were not aware of the presented prime.The manipulation was the relation between prime and target.We used primes that were morphologically related, semanticallyrelated and orthographically related to targets. Inthe morphology condition we used both words semanticallyrelated to the target and words sharing the same root buthaving quite distinct meanings. We found different patternsof activity in the different priming conditions. In the lMFGand lIPS activation was significantly reduced when the primewas morphologically related to the target. This effect wasnot found in the semantic or orthographic condition. Furthermorethis attenuation was not influenced by the semantictransparency of the morphological prime. These resultsstrongly resemble our previous results and reflect the importanceof morphological processing in Hebrew reading. Scanswere performed in Hadassah Hebrew University Hospital,Israel.Supported by Center for Complexity Science. Most psychophysical tasks assess performance around a referencestimulus. Previously , westudied which types of reference repetitions improve resolutionin auditory 2-tone frequency discrimination. We had3 conditions: no reference (NR)—no repetition across trials;reference 1st (R1st)—reference tone (1000 Hz) was presentedin the first interval; reference 1st or 2nd (R1st-2nd)—reference tone was presented in the 1st or in the 2nd interval.Surprisingly, compared to the NR, listeners' frequency resolutionwas significantly improved only in R1st, indicatingthat consistent temporal position is crucial for reference utilization.We now asked whether consistency of temporal positionis also crucial in the visual domain. We administered aspatial frequency discrimination paradigm analogous to theauditory paradigm, asking which of 2 sequentially presentedgrating stimuli is denser. We used the same conditions: NR,R1st (0.5 c/deg) and R1st–2nd. In contrast to the auditoryresults, the 2 reference conditions were performed similarly,and significantly better (7% ± 1.3) than the NR (22% ± 3.0)condition, indicating that temporal position is not crucial.We further assessed a simultaneous frequency discriminationparadigm, in which the gratings were presented simultaneouslyand subjects were asked whether the denser grating wason the upper or lower half of the screen. We administered 3equivalent conditions: NR, RU—the reference was always atthe upper half of the screen, RU or L—the reference was eitherat the upper or the lower half of the screen. In the parallelparadigm only the RU condition was better than NR,indicating that spatial consistency is crucial for reference utilizationin the visual domain. These findings show that repeatinga reference improves resolution only under specificconditions. Temporal consistency is crucial in the auditorymodality, whereas spatial consistency is crucial in the visualmodality.The study was supported by ISF Center of Excellence grant andby the Institue of Psychobiology. Disturbed sleep is a common complaint among Schizophreniapatients. Since previous studies have demonstrated treatmentresistance for sleep-medication treatment for insomniain these patients, the aim of the present study was to examinethe effects of music background as treatment for insomnia inSchizophrenia patients.Twenty four Schizophrenia patients, who had no other majorpsychiatric, sleep, or neurological disorders, participatedin the study . The study comprised one 7-day, running-in period,followed by one 7-day experimental period. The treatmentwas music background at desired bedtime. During each ofthese two experimental periods, subjects' sleep was continuouslymonitored with a wrist actigraph  and subjects were asked to fill out several questionnairesconcerned with a wide spectrum of issues, such asdepression, anxiety, and life satisfaction.t(23) =3.01, P < .006), showing shorter sleep latency when musicbackground was played (21.04 ± 14.6) than when it was not(37.01 ± 32.4). A significant difference was also found in sleepefficiency (t(23) = −3.35, P < .003), showing higher sleepefficiency when music background was played (86.0 ± 15.5)than when it was not (82.44 ± 18.3). A significant differencewas found in depression level (t(23) = 2.96, P < .007), showinglower depression level after background music was played (12.29 ± 12.1) than when it was not (15.25 ± 10.6). No significant differences were found in anxiety level (t(23) = .22,P > .05), nor in life satisfaction (t(23) = 1.28, P > .05).A paired-sample t-test was conducted, comparing objectivesleep parameters manifested by patients with music backgroundat desired bedtime and without music exposure. Asignificant difference was found in sleep latency  warfare nerve agents are highlytoxic compounds that irreversibly inhibit cholinesterases(ChE). Inhibition of ChE results in the accumulation ofacetylcholine in the synaptic cleft, leading to excessive stimulationof cholinergic receptors. Following exposure to highand lethal OP doses, signs of toxicity such as salivation,tremors, convulsions and seizures, respiratory failure and ultimatelydeath are seen. Following exposure to lower sublethalOP doses none of these severe signs are observed.Therefore, it is impossible to elucidate any significant effectfollowing exposure to sub-lethal doses using the standardtoxicity data. Comprehensive series of studies have shownto have long-term neurological and psychological disorders(namely insomnia) following sub-lethal OP doses in humans.Since the data suggested a continuous deteriorationin the circadian rhythm, it was very challenging, technologicallyand methodologically, to find a suitable marker forsuch insult in an animal model. In this study we present anapproach of measuring alterations in the circadian rhythmbody temperature and changes in ECoG activity by utilizingtelemetry following chronic, sub-lethal doses of the nerveagent VX. VX was administrated via Alzet mini osmoticpumps implanted in the rats for one month. Data was collectedcontinuously 24 h/day during the 3 days preexposureand the following 1 month of VX exposure. Fast Fouriertransform spectrum analysis was performed for 30 s period,every 3 hours of the EcoG recordings. Changes in circadianrhythm, as well as changes in individual brain wave were detected.This approach might elucidate the potential damagecaused by chronic, low-dose OP exposure. The brain localization of cognitive functions is limited toinvasive lesion or electrophysiological studies. Noninvasiveimaging techniques such as functional magnetic resonanceimaging (MRI) are less informative in rodents due to the useof anesthetics. In this work we used a novel MRI-behaviorcorrelation framework for localization of cognitive performancein rats. Thirty one rats underwent two MRI sessions(at 7T) at ages of 9 and 12 months . The MRI session included a diffusion tensor imaging(DTI) protocol from which the fractional anisotropy(FA) and apparent diffusion coefficient (ADC) maps were extracted.While the FA is more sensitive to white matter theADC represent both gray matter and white matter. Betweenthe two MRI sessions the rats performed a 6-day Morris watermaze test. From the water maze we used the latency ofthe rats to reach the platform in the first (d1), fifth (d5),and sixth day (d6) in which the platform was removed . The comparison between the two imaging sessionsrevealed a significant FA and ADC signal changes inthe hippocampus. Correlation analysis between the FA/ADCindices of MRI1 with latency of d1, d5, and d6 were localizedat the amygdala, hippocampus and caudate/putamen regions,respectively. Correlation analysis between the FA/ADCindices of MRI2 with latency of d1, d5, and d6 was not localizedto any specific region. These results manifest the differentcortical domains that affect the behavior at the differentdays of the water maze; while in d1 stress factors may controlthe performance of the rat, spatial memory skills anddecision making affect the d5 and d6 performance. In additionthe fact that between the MRI sessions the hippocampusshowed significant signal change may indicate on theplasticity changes that this region underwent following theMorris water maze. To conclude, MRI-behavioral correlationscan be used for localization of cognitive functions inrodents. It is becoming increasingly evident that organisms acting inuncertain dynamical environments employ exact or approximateBayesian statistical calculations in order to continuouslyestimate the environmental state and integrate informationfrom multiple sensory modalities. What is less clearis how these putative computations are implemented by corticalneural networks. We show how optimal real-time stateestimation based on multi-modal sensory information maybe effectively implemented by neural networks decoding sensoryspikes. We demonstrate the efficacy of the approach onstatic decision problems as well as on dynamic tracking problems,and relate the properties of optimal tuning curves tothe properties of the environment. β has been intensivelyinvestigated, only little is known regarding immunotherapytargeting tau aggregates , a major neuropathology in Alzheimer'sdisease(AD) and tauopathies. We reported recently the hazardouspotential of immunizing mice with full length recombinanttau for targeting host normal tau protein, inducingneurological deficits and NFT-pathology. Here weinvestigated the effect of immunotherapy targeting specificallypathological tau conformers  in aNFT-mouse model. The results are of special interest sincelast month it has been published that using a similar approachby immunizing with peptide tau-P-Ser396,404 reducedrobustly NFTs in NFT-mice (Asuni 2007). We immunizedNFT-mice with a mixture of P-tau peptides relatedto NFTs of AD/tauopathy patients and mice with complete Freund's adjuvant and pertussis. The micewere examined for clinical neurological deficits, and effecton NFT-burden. No neurological deficits were noted followingtau-P-immunotherapy at least for 8 months. ReducedGallyas staining relative to controls (∼20% P = .02), indicatinga reduced NFT-burden, was detected. Some similartrend, yet smaller, was noted in IHC using AT8 and AT180Abs (recognizing NFT-related P-tau), but did not reach astatistic significance. To conclude, our results suggest a decreasein NFT-burden following tau-P-immunotherapy , mostly demonstrated by Gallyasstaining, but less by NFT-related IHC. The effect seems lessrobust than that reported with tau-P396,404. This may be relatedto the different tau-P peptides and immunization protocolsused, or may point to the limited effectiveness of tau-P-immunotherapeutic approach. Moreover, the lack of clinicaldeficits points that these specific peptide immunogensare encephalitogenic, encouraging further study of their anti-NFT potential.While immunotherapy targeting amyloid- Motion-induced-blindness (MIB), Bonneh et al., Nature2001, was used to examine the accessible properties of highcontrastvisual objects which are not consciously available.Stimuli consisted of a static Gabor target embedded in a rotatinggrid. Under such conditions, the target perceptuallydisappears after few seconds. Following (100 milliseconds)Observers' report of disappearance, a high-contrast Gaborprobe was presented, and the target was removed within 200–600 milliseconds. The probe often caused the reappearanceof the invisible target within the limited trial time. Surprisingly,we found low reappearance rates when probes werenot in the proximity of the target or when orthogonal to it,even when proximal. High reappearance rates were observedwith probes proximal and similar to the target. Plaid targetsmade of superimposed orthogonal Gabor patches reappearedwhen probes included only one component, but plaidprobes were not very effective with component targets. Theresults show that subconscious objects preserve their locationand component-orientation and demonstrate that visualprocesses sensitive to proximity and feature-similarityoperate across the boundary of awareness. By controllingthe duration of target presentation we found that “reactivating”the target may take 200–400 milliseconds, dependingon the depth of suppression. The asymmetric interaction betweenvisible and invisible plaids suggests that invisible objectsbreak into their feature components. We have previously shown that the activities of the brainstructures making up the memory systems defined by Whiteand MacDonald (2002) are mainly correlated with the hippocampusin the place condition of a water escape task,whereas they are correlated with the amygdala in the cue condition.This demonstrates a rearrangement of the functionalconnectivity depending on the learning condition and suggeststhat the activation of a memory system should be describedas the focusing of functional connectivity toward thecentral structure of the system. This may explain how severalmemory systems can share the same structures while remainingindependent. Della-Maggiore and coll. (2000) showedthat age-related alteration to the system sustaining delayedvisual discrimination could be compensated by the reconfigurationof the pattern of connectivity. Indeed, whereas theperformances of young and old subjects were comparable,the activated cerebral networks were different. Although, thischange in connectivity may be due to the use of a differentstrategy, this study gives an insight into understandinghow decreasing cognitive resources due to age (or pathology)may be compensated. To support this concept, we induceddorsohippocampal lesions tomice. Sham- and hippocampallesionedrodents were submitted to the place learning conditionin the water cross-maze. Though impaired during thefirst three days, lesioned mice had the same level of performancethan the sham-mice on the fifth day. We hypothesizethat this behavioural recuperation would be coupled with achange in the pattern of connectivity. The activities of micebrain structures are evaluated by counting the number of Zif268 immunoreactive cells after training in the place conditionof the aquatic cross-maze. By using structural equationmodelling, the present study investigates how the pattern ofeffective connectivity induced by learning is changed face tothe lesion of the hippocampus. Dopamine is suggested as a prominent etiological factor inseveral neuropsychiatric disorders such as Parkinson's diseaseand schizophrenia. In such dopamine related pathologies mitochondrialdysfunction has been reported. Notably, mitochondriaare target organelles for dopamine by the virtueof the fact that MAO, the main metabolizing enzyme ofdopamine, is located on their outer membrane. We haverecently demonstrated that dopamine reversibly inhibitedcomplex I activity in isolated disrupted mitochondria. In orderto investigate whether DA-complex I interaction affectsmitochondrial function in viable cells, we studied the effectof DA on mitochondrial membrane potential as a markerfor the oxidative phosphorylation activity and mitochondrialrespiration in intact viable human neuroblastoma SHSY5Ycells. DA significantly dissipated mitochondrial membranepotential and inhibited mitochondrial respiration incells, similarly to complex I inhibitor, rotenone. ComplexI-DA interaction induced mitochondrial dysfunction as bypassingcomplex I of the respiratory system prevented theDA induced depolarization of mitochondrial membrane potentialas well as the reduction in the respiration rate. Unlikecomplex I, DA did not inhibit complexes II, IV and Vactivities in disrupted mitochondria. Abnormal interactionbetween dopamine and mitochondrial complex I was observedin schizophrenia, as in patients dopamine inhibitedcomplex I activity twice as much as that of control subjectsor of patients with affective disorders. Notably, antipsychoticdrugs but not antidepressants inhibit mitochondrial respirationthrough complex I. The present study suggests that DAaffects mitochondrial function through its interaction withcomplex I of the oxidative phosphorylation system. We furtherhypothesize that the interaction between DA and mitochondriais associated with mitochondrial dysfunction observedin DA-related neuropsychiatric disorders, such as inschizophrenia.Supported by the Chief Scientist Israel Ministry of Health. A poststreptococcal autoimmune process has been suggestedto be involved in the pathogenesis of a subgroup of childrenwith tics and obsessive compulsive disorder (OCD), identifiedby the acronym PANDAS for Pediatric AutoimmuneNeuropsychiatric Disorder Associated with Strepptococcalinfection. It has been suggested that antibodies producedagainst group A beta-hemolytic streptococci (GABHS) crossreact with neural cells, in a process involving molecularmimicry. Although PANDAS has received much attention inrecent years, no study to date assessed compulsive-like behaviorsin an animal model of GABHS-related neuropsychiatricsymptoms. The aim of the present study was thereforeto test the hypothesis that group A streptococcal infectionmay lead to the emergence of OCD. To this end, Lewis ratswere immunized with an extract prepared from GABHS, andtheir compulsive behavior was assessed using two rat modelsof OCD, namely, the signal attenuation model and theinduced-grooming assay. Sera taken from rats immunizedwith GABHS extract demonstrated stronger immuno reactivityto streptococcus A and to neural tissue compared tosera of control rats and in addition induced high levels of acalcium/calmodulin-dependent protein (CaM) kinase activityin human neuroblastoma cells. Antianibodies immunolabelingwas stronger in the striatum and thalamus of immunizedrats compared to control rats . Inparallel, rats immunized with GABHS antigens tended toshow increased compulsivity in two animal models of OCD.These preliminary results suggest that immunizing rats withGABHS extract can lead to the emergence of “compulsive”behavior. μM increase inhomocysteine is associated with a 70% higher risk forschizophrenia. Elevated homocysteine is reported to altermacromolecule methylation. We studied whether elevatedplasma homocysteine levels in schizophrenia are associatedwith altered global DNA-methylation. DNA was extractedfrom peripheral blood leukocytes of 28 schizophreniapatients versus 26 matched healthy controls. Percentof global genome DNA-methylation was measured usingthe cytosine-extension method. Homocysteine levels werehigher in schizophrenia patients than in controls . No difference in globalDNA methylation between schizophrenia patients and controlsubjects was found . A significant interaction between diagnosis and smokingon DNA methylation was obtained . Although leukocytes may be a useful cell modelto evaluate epigenetic changes such as global DNA methylationin brain, future studies are on the way to compare globalDNA methylation in peripheral tissue versus brain in laboratoryanimals.Meta-analysis recently suggested that a 5 n = 21 for trained versus−70.79 + 1.69, n = 18 for naive and −70.77 + 1.28, n = 19for pseudo trained, P < .005). We suggest that olfactorylearning is accompanied by hyper-polarization of the reversalpotential of fast inhibitory synaptic transmission. This shiftenhances the effect of such inhibitory transmission, therebycompensating for the increase in excitatory transmission.We have previously shown that olfactory-discriminationlearning results with a series of intrinsic and synaptic modificationsin layer II piriform (olfactory) cortex pyramidal neurons,which last for days after learning completion. In particular,enhanced excitatory synaptic transmission is indicatedby reduced paired-pulse facilitation, enhanced rate of riseof EPSPs and increased spine density along basal and apicaldendrites of these neurons. The purpose of the present studywas to examine whether inhibitory synaptic transmission inputinto pyramidal neurons is also modified after olfactorylearning. Intracellular recordings with sharp electrodes weremade from layer II pyramidal neurons five days after trainingcompletion, in the presence of APV and DNQX, to blockglutamatergic synaptic transmission. IPSPs were evoked byelectrical stimulations applied in layer III. The averaged fastIPSP's reversal potential was significantly lower in neuronsfrom trained rats  within the basal ganglia (BG)is a common treatment for Parkinson's disease (PD) in itsadvanced stages and is used in an exploratory manner inmultiple movement and behavioral disorders. Multiple experimentalstudies show that stimulation in globus pallidus(GP) leads to complex modulation of the neuronal activityin the stimulated nucleus. In order to investigate the basic effectof DBS on single neurons we used DBS-like protocols usingextracellular electrodes similar to those used in vivo andrecorded the cellular response in acute brain slices from ratsusing the BG whole-cell configuration of the patch-clamptechnique. We present characterization of several types ofcells in the GP using whole-cell current clamp protocols andthe effect of the stimulation on the spiking pattern of thesecells. The analysis of these cellular mechanisms of response tostimulation are crucial for developing advanced therapeuticstimulation protocols and pave the way to close loop stimulationdevices. Previous studies have shown an advantage of treadmill trainingover conventional physiotherapeutic treatments in patientswith gait disturbances after acute supratentorial stroke.Likewise, repetitive exercises like the “arm ability training” lead to an improved motor performance.The present study investigated these therapies in patientswith acute cerebellar stroke.Twelve patients with acute (<four weeks) ischemic lesions ofthe territory of the superior or of the posterior inferior cerebellarartery and twelve healthy control subjects were examined.One half of the patients received a daily half-hour treadmilltraining over two weeks. Patients with a relevant armataxia received an additional “arm ability training.” The localisationof the lesions was determined by 3D MRI. Gait disturbancesand arm ataxia were quantified by clinical scoresand by a 3D camera system. All examinations were performedin the acute phase, after two weeks and three months.No significant effect of treadmill training or “Arm AbilityTraining” could be shown. Treated as well as untreated patientsshowed a nearly complete restitution of motor symptomsafter three months. In seven patients the ischemic lesioninvolved cerebellar nuclei in the acute phase, but only in onepatient after three months. The clinical scores were worse inthose patients with involvement of cerebellar nuclei.The results of the present study suggest a relationship betweenthe extent of the initial motor deficits and the involvementof cerebellar nuclei. No effects of the rehabilitativetherapies could be shown, possibly because of the good spontaneousrecovery fromsymptoms in patients without permanentlesions of the cerebellar nuclei. The results have to becontrolled in a larger group of patients.Supported by BMBF, German-Israeli Cooperation in Neuroscience(01GA0508), and IFORES . n = 34) of the recorded mirror neuronsresponded also to filmed actions. Half of them (n = 17)preferentially responded to actions as seen from the first personview. The remaining neurons responded either to multiplepoints of view (n = 10) or showed a preference foractions as seen from the side view (n = 1) or frontal view(n = 6). Our quantitative investigations show that the responsesof mirror neurons are modulated by the point ofview from which actions are observed. Two nonmutually exclusiveexplanations can be given for this result. First, undernaturalistic conditions, monkeys as well as humans are moreoften visually exposed to their own actions . Second, the mirror neuronsystem might have originally evolved to map monkey's actionsonto own motor representations possibly for refiningobject manipulation behaviors. The same system was then,later in evolution, adapted to also understanding the manipulationbehaviors of conspecifics.Mirror neurons are a class of neurons in monkey pre-motorcortex that respond both when the monkey performs an actionand when he sees the same action performed by humansor monkeys. While many studies have shown that such neuronsare robustly activated under naturalistic conditions, ithas been difficult to elicit single-cell responses using filmedstimuli. Here we present neurophysiological evidence in onemonkey showing that mirror neurons do respond to movies.In our experiments, we first isolated mirror neurons and furthertested them with filmed actions. To keep the monkey'sattention to the movie a fixation paradigm was used. Thestimuli consisted of filmed goal-directed actions as observedfrom three different points of view: frontal view, side viewand first person view . About 40% (Supported by the Deutsche Forschungsgemeinschaft (SFB 550-C10). +current (INaP) and M-type K+ current (IM). Thus, facilitationof the ADP by low pi may be due to INaP enhancementand/or IM inhibition. We tested these two hypothesesusing intracellular sharp microelectrode recordings in CA1pyramidal cells in situ. Our data favor the second hypothesisfor the following reasons: (1) after blocking IM with 20 μMXE991, which by itself caused ADP facilitation and bursting,low pi had no further effect; (2) after blocking INaP with10 μM riluzole, which by itself caused ADP suppression, lowpi still enhanced the ADP; (3) injection of positive currentramps into neurons perfused with ACSF containing Na+ andCa2+ channel blockers, disclosed an increase in membraneconductance at voltages positive to −60mV (IM activationthreshold), which was prevented by XE991 and enhanced bythe IM enhancer retigabine (10 μM). Low pi mimicked theeffect of XE991 in reducing membrane conductance, and itseffect was occluded by XE991. These and other data suggestthat low pi facilitates the spike ADP and bursting activity byinhibiting IM. This hypothesis is currently being examinedusing voltage clamp techniques.Modest reduction in extracellular osmotic pressure (pi)causes neuronal network hyperexcitability and epileptiformseizures. It is commonly believed that this effect of low piis mediated by constriction of the extracellular space consequentto cell swelling, which enhances excitatory electricfield effects. However, we have shown previously that lowpi also increases intrinsic neuronal excitability in principalbrain neurons. Specifically, we found that low pi promotesbursting by facilitating the spike afterdepolarization (ADP)in hippocampal pyramidal cells. Such an effect undoubtedlywould contribute to low pi-induced network hyperexcitability.How does low pi facilitate the spike ADP and bursting?The waveformof the spike ADP is determined by interplay oftwo low-threshold, noninactivating currents: persistent NaSupported by BSF and SFB-TR3. Short-term saccadic adaptation (STSA) is a form ofcerebellar-dependent motor learning in which a retinal vector,defining a desired spatial location, becomes associatedwith a saccade vector, whose amplitude may differ from thatof the retinal vector by up to 30%. We have previously reportedthat STSA is based on adjusting a Purkinje cell (PC)simple spike (SS) population signal and that disturbances ofsaccadic adaptation, resulting from cerebellar disease may beaccompanied by an inability to maintain stable saccade amplitudesif long series of stereotypic saccades have to be carriedout. We have interpreted the latter as uncompensatedsaccadic fatigue, an inability of the saccade system to accountfor changes of the plant due to usage, an idea which is supportedby the comparison of the saccade kinematics of patientsand controls. Here we tested the idea that the cerebellarmechanism used to compensate saccadic fatigue is the sameas the one causing STSA. To this end, we recorded SS fromnonsaccade related vermal PC in lobuli VI and VII whilemonkeys executed several hundred stereotypic saccades. Indeed,when the animals repeated the same saccades timeand again, their kinematics changed while their accuracy wasmaintained: a decrease in peak velocity was fully compensatedby an increase in saccade duration. Parallel to the increasein saccade duration, many of the PC developed new,late saccade-related bursts, fired around the time of the endof the altered saccade. These newly arising saccade-relatedbursts were fully appropriate to extend the duration of a SSpopulation response as based on the responses of PC, alreadysaccade-related at the outset, by an extent needed in order toaccount for the increase in saccade duration. These findingsare in full accordance with the concept that the cerebellumcontrols behavior using a population code and, moreover,support the notion that STSA is the manifestation of amechanismneeded in order to compensate fatigue.Supported by the Deutschen Forschungsgemeinschaft SFB 550. The biological response to stress is concerned with themaintenance of homeostasis in the presence of real or perceivedchallenges. This process requires numerous adaptiveresponses involving changes in the central nervous and neuroendocrinesystems. When a situation is perceived as stressful,the brain activates many neuronal circuits linking centersinvolved in sensory, motor, autonomic, cognitive, andemotional functions in order to adapt to the demand. However,the details of the pathways by which the brain translatesstressful stimuli into the final, integrated biological responseare presently incompletely understood. Nevertheless,it is clear that dysregulation of these physiological responsesto stress can have severe psychological and physiological consequences,and there is much evidence to suggest that inappropriateregulation, disproportional intensity, or chronicand/or irreversible activation of the stress response is linkedto the etiology and pathophysiology of psychological andphysiological disorders. Understanding the neurobiology ofstress by focusing on the brain circuits and genes, which areassociated with, or altered by, the stress response will provideimportant insights into the brain mechanisms by whichstress affects psychological and physiological disorders. Weexamine the hypothesis that the CRF/Urocortin family ofpeptides and receptors play an important role in modulatingthe neuroendocrine and behavioral responses to challenge.Defining the contributions of the individual ligandsand receptors of the CRF/Urocortin family to the maintenanceof stress-linked homeostasis may improve our abilityto design therapeutic interventions for, and thus manage,affective and stress-related disorders. We employ integratedmolecular, biochemical, physiological and behavioral methods,focusing on the generation of mice genetic models asan in vivo tool, in order to study the central pathways andmolecular mechanisms mediating the stress response. Posttraumatic stress disorder (PTSD) develops in about 20%of those exposed to a threat to life or physical integrity.This implies the participation of dynamic biological processessuch as epigenetic modifications. This study investigatedwhether variations in DNA methylation pattern isassociated with maladaptation to traumatic event in a ratmodel of PTSD. Rats were exposed to a predator and classifiedinto “PTSD-like” and “non-PTSD” according to theirresponse in elevated plus-maze and acoustic startle responseparadigm. Hippocampal global DNA methylation patternwas assessed using amplification of inter-methylated sitesmethod (AIMS): successive digestion of genomic DNA bySmaI and Cfr9I restriction enzymes, produced a mix of originallymethylated fragments, which were amplified and radiolabeledby PCR and separated on 6% polyacrylamide denaturedsequencing gel. From the complex pattern of bands,we isolated 7 fragments displaying differential methylationpattern between the “PTSD-like” and “non-PTSD” groups.These fragments were amplified by PCR reaction, cloned andsequenced. Their location on the rat genome was establishedusing the BLAST engine. Several sequences showed a completehomology with intron or intron-exon boundaries ofknown genes. The genes identified by this procedure Dll3,PKCeta, Fstl3 and Rps6kb2 participate in synaptic formationand remodeling, differentiation of cells, protein phophorylationand other cellular regulatory processes. We are now in aprocess of validation the methylation changes using bi-sulfiteassay and examining whether these variations have functionalsignificance by quantifying mRNA expression. Ourinitial results suggest that changes in DNA methylation patternmay be associated with maladaptation to environmentalstress and the development of PTSD.Supported by The National Institute for Psychobiology, Israel. The ability to estimate temporal intervals on the scale of tensto hundreds ofmilliseconds is important for adequate motor,visual and auditory abilities. Yet, little is known about howthe brain estimates these durations. In a typical paradigm,listeners are asked which of 2 sequentially presented brieftones is longer. We now asked whether applying a consistentreference improves the accuracy of temporal estimations. Weapplied 3 paradigms: reference short—a 100-millisecond referencetone was presented either in the 1st or in the 2nd intervalin each trial, and nonreference tone was always longer; reference1st- the reference tone was always presented in the 1st interval,and the 2nd interval contained a shorter or longer tone;no reference—there was no repeated reference across trials.Sixty sixHUstudents participated in the experiment , each tested with a single paradigm, administeredin 2 sessions (1 week apart). Each session contained5 subsequent 80-trial assessments, using an adaptivestaircase procedure. The reference 1st paradigm was performedsignificantly better than the other 2 paradigms fromthe very first assessment. The small difference in protocol betweenreference 1st and reference short elicited a 2.6 fold differencein thresholds, and a 4.8 fold difference in cross subjectvariability (11% ± .06 versus 29% ± .29). This benefit remainedconstant within and across assessment sessions. Theno reference condition yielded even somewhat (though notsignificantly) poorer discriminations (36% ± .21). Musicallytrained students performed significantly better. These resultsindicate that a reference can dramatically sharpen discrimination.However, detecting a repeated duration is not immediatefor the auditory system. Temporal certainty is of crucialimportance, whereas duration certainty, even when consistentlymapped to response category  is notsufficient.The study was supportedby the ISF Center of Excellence Grant& by the Institute of Psychobiology. The induction of neural tissue represents an early and fundamentalstep in the generation of the vertebrate nervous system.During this process, pluripotent cells are directed to aneural fate. Much of the understanding of neural inductionin vertebrates is derived from studies performed in Xenopusembryos. These studies led to the “default model” of neuralinduction, which proposes that cells within the ectodermlayer of the frog gastrula have an autonomous tendency todifferentiate into neural tissue, which is inhibited by BMPswhich act as an epidermal inducers. Later works in Xenopusand chick models have shown a more complex picturein which FGFs are major players in addition to BMP inhibitionand suggested BMP signaling-dependent and or independentroles of FGF. In attempting to understand the principlesthat underlie neural induction in humans, we use thehuman embryonic stem cell (hESC) model. We establisheda simple one-step approach for derivation of neural precursors(NPs) fromhESCs in chemically defined serum-free suspensionculture conditions .This system serve as a definedin vitro model to study early neural differentiation of hESC.Here we report that bFGF promotes the expression of earlyneural genes such as Musashi1 and NeuroD1, suggesting itsrole in early neural specification. This effect is not associatedwith neural cells proliferation. Moreover, this FGF effect isprobably, at least in part, not mediated through antagonismof BMP signaling. Nevertheless, hESCs, when cultured in theabsence of FGF and BMP-signaling, differentiate towards aneural fate, suggesting a default mechanism of neural induction,similar to that which was reported in amphibian models.Our data suggest that bFGF plays a role, but is not essential,in the neural induction process of hESCs, and supportsthe “default model” of neural induction in mammals. + channel (K2P)family, is expressed in the central and peripheral nervous system,as well as in the heart, kidney and testis tissues. K2P2.1activity is regulated by a variety of physical and chemical effectorsincluding temperature, fatty acids, internal pH, mechanicalstretch and phosphorylation. Although K2P2.1 isclassified as a leak channel, it was shown to posses an exceptionalcapability to reversibly convert between leak andvoltage dependent phenotypes. Here, we report that humanK2P2.1 channel, expressed in Xenopus oocytes, is inhibitedby external acidosis within the physiological range (pKa =7.3). Mutations in two outer pore histidine residues dramaticallydecreased channel responsiveness to external acidosis.Mutation of a conserved glutamate residue (E84) known tobe fundamental to C-type gating had a similar effect. Furthermore,those three residues were found to be located inclose proximity to one another. We thus propose a novelmechanism for pH sensing in which protonation of histidineresidues destabilize hydrogen bonds, formed by E84, that arenecessary formaintaining the C-type gate at the open conformation.In accordance with this proposed mechanism, protoninduced current decrease was inhibited by external potassiumions and enhanced by a mutation (S164Y) known toaccelerate C-type gating. Moreover, proton current inhibitionis voltage-dependent being more pronounced at negativepotentials. The voltage-dependent current fraction wassignificantly decreased in the pHo insensitive mutants, presentingI-V relationship of an open rectifier channel. Thus,we suggest that voltage dependent C-type gating accelerationby protons, in physiological pHo, serves as a mechanism forthe voltage dependent mode and the outward rectificationbehavior of K2P2.1.Potassium leak currents play a critical role in determiningcell in determining cell resting membrane potential andthus control nerve and muscle excitability. K2P2.1 , a member of the 2P-domain K The inferior olive (IO), the sole provider of climbing fibersto the purkinje cells (PCs), is suspected to be centrally involvedin the etiology of the most common movement disorder,essential tremor (ET). ET is characterized by a 4–12 Hztremor of the limbs, head or jaw which is amplified duringintentional movements. Systemic application of harmaline,an alkaloid MAO inhibitor, causes tremor in animals comparableto ET, while its bath application to in-vitro preparationsincreases the occurrence of subthreshold oscillations(STOs) and their amplitude in IO neurons. These combinedfindings, contributed to the view that oscillatory activity ofIO neurons is related to ET. Hence, harmaline treated animalshave been used formany years as models for ET. The effectof harmaline on subthreshold activity of IO neurons invivo,however, has never been examined. We have recordedintracellularly IO neurons in anesthetized young adult rats.Several minutes following the injection of harmaline , in tune with muscle tremor appearance, IOneurons exhibited a remarkable transition in the oscillatoryactivity. Compared to control conditions, STOs exhibited atleast 2-fold increase in both amplitude and oscillatory epochduration. This transition was also accompanied by a significanthyperpolarization and an increased firing rate due tothe larger amplitude of STOs. Harmaline, however, did nothave a drastic effect on the average frequency of STOs relativeto control conditions, nevertheless, it significantly narrowedtheir spectral distribution. Further investigation is requiredin order to relate the neuronal activity to muscle tremor andexamine possible strategies to negate the effects of harmalineand restore normal STO activity.Supported by Nella and Leon Benozyio Center for NeurologicalDiseases. Pyramidal neurons in the piriform cortex from olfactorydiscrimination-trained rats show enhanced intrinsic neuronalexcitability that lasts for several days after learning.Such enhanced intrinsic excitability is mediated by long-termreduction of the postburst after-hyperpolarization (AHP)which is generated by repetitive spike firing. AHP reductionis due to decreased conductance of a calcium-dependentpotassium current, the sIAHP. We have previously shownthat such learning-induced AHP reduction is maintained byPKC activation. However, the sequence of protein activationwhich maintains this exceptionally long-lasting modulationof intrinsic excitability is yet to be fully described. Herewe examine whether ERKI/II, which has been implicated inlearning andmemory as well as in synaptic plasticity process,is instrumental in this process. TheMEK inhibitor, PD98059,that selectively blocks ERK, increased the AHP in neuronsfrom trained, but in neurons naїve and pseudo trained rats.Consequently, the difference in AHP amplitude and neuronaladaptation between neurons from trained rats and controlswere abolished. This effect was not mediated by modulationof basicmembrane properties. Accordingly, the level of phosphorylatedERK in the membranal fraction was significantlyhigher in pirifrom cortex samples taken of trained rats. ThePKC activator, OAG, that was shown to reduce the AHP inneurons from control rats, had no effect on these neuronsin the presence of PD98059. Our data show that ERK has akey role in maintaining persistent PKC-mediated learninginducedenhancement of neuronal excitability. In two-tone frequency discrimination tasks, participants listento sequentially presented tones and are asked to decidewhich tone is higher. Recent results from our lab  showed that if one of the tones is repeatedacross trials (reference) at a consistent temporal position, performance quickly andsignificantly improves compared to a no-reference paradigm.These findings indicate that the reference is used effectively,perhaps by eliminating the need for actual comparison betweenthe stimuli presented in each trial. In order to test thishypothesis, ERPs were measured while subjects performedthe task. Two conditions were applied: reference 1st, in whichthe reference tone was always in the first position, and thesecond tone was either higher or lower, and reference 2nd,in which the reference was always second, and the first tonewas either higher or lower. Thus, in reference 1st condition,trial-specific information, which is needed to resolve the task,is presented only at the second interval, whereas in reference2nd condition, this information is provided already bythe first interval. In the reference 1st condition both tonesinduced N1-P2-N2 waves, but only the second tone induceda P3 wave, indicating that a clear perceptual categorizationonly occurred after the second tone. In the reference 2nd condition,responses were similar, but the P3 decision wave waselicited after the first tone, and no P3 wave followed the secondtone. The switch in the temporal position of P3 indicatesthat, in the reference 2nd condition, subjects indeed reacha decision after hearing only the first tone, before the secondstimulus was presented. Taken together, we find that thepresence of a reference stimulus eliminates the need for onlinecomparisons within trials, and automatically enables theuse of a better strategy. Noticeably, participants are unawareof this switch.The study was supported by ISF Center of Excellence Grant andby the Institue of Psychobiology. Clinical studies have shown that coadministration of selectiveserotonin reuptake inhibitor (SSRI) antidepressants and typical antipsychotics can ameliorate negative symptoms in schizophrenic patients.Efficacy against negative symptoms is also seen withcertain atypical antipsychotics . The effectof the combined treatment can not be explained by pharmacokineticinteraction, implying that complex molecularmechanism might lie in the basis of the distinctive clinicaleffect of this treatment. Our previous studies indicated thatgamma-aminobutyric acid type A (GABA-A) beta3 receptorsubunit, the enzyme glutamic acid decarboxylase (GAD67),and protein kinase C (PKC) beta2, known as importantmodulatorsof GABA activity, might be distinctively regulated bythe combination of SSRIs and antipsychotics, compared toeach individual treatment alone. In the present study, wehave found that chronic coadministration  offluvoxamine (10 mg/kg) and haloperidol (1 mg/kg), as wellas atypical antipsychotic clozapine (10 mg/kg), significantlydecreased GABA-A beta3 receptor subunit protein levels andinduced receptor endocytosis in rat frontal cortex. Individualtreatment of fluvoxamine or haloperidol did not producechanges in GABA-A beta3 receptor subunit expression or endocytosis.In addition, we have shown that the combinedtreatment and clozapine similarly regulated molecular signalingpathways that modulate GABA-A receptor function,such as, PKC and ERK1/2. Furthermore, acute treatment(30minute and 1 hour) with fluvoxamine and haloperidolgiven together, or clozapine, altered ERK1/2 and PKC phosphorylationlevels, and time-dependent dynamics of ERKphosphorylation were observed. Together, our findings suggestthat the combined treatment may downregulate GABAsystem in rat frontal cortex, and alter the PKC and MAPKmolecular signaling pathways. μM, 20 μM) induced the phosphorylationof NR2A(Y1325)  but did notmodulate the levels of NR2A protein itself. Moreover, applicationof the D2 and D1 dopamine antagonists, Etic (60 μM)and SCH23390 (40 μM) were sufficient to reduce basal phosphorylationof NR2A, suggesting thatintrinsic dopaminergic activity maintains tyrosine phosphorylationof the NR2A in the mature hippocampus. In contrastto dopamine, NMDA application, which induces ERK2phosphorylation, did not induce NR2A(Y1325) phosphorylation(n = 8). Overall, our results suggest that dopamineinteracts with the NMDA receptor via tyrosine phosphorylationof NR2A(Y1325). We currently are analyzing the differentialeffect of the different dopamine receptors on othertyrosine residues and NR subunits.Dopamine and NMDA receptor are playing a major role inmature brain function and learning processes. Previous researchin our laboratory identified convergence of NMDAand dopamine on the levels of ERK2 activation and rsk2 expressionin the hippocampus. Furthermore, it was shownthat the dopamine activation of ERK2 is NMDA receptordependent . The molecular basisfor this functional interaction between dopamine and theNMDA receptors is not clear. However, its relevance for differentbrain functions is highly important. We hypothesizethat dopamine interacts with the NMDA receptor via modulationof its tyrosine phosphorylation in the mature hippocampus.Using pharmacological set-up for mature hippocampalslices and phospho-specific antibodies, we foundthat application of both high and low doses of dopamine forten minutes , a cage in which the animal receives food/ad libitum/ but access to water is contingent upon a correctnosepoke within a specialized drinking apparatus at a singlecorner of the cage. The behavior of the mice is continuouslymonitored using “transponders” (reporting chips) implantedsubcutaneously. As a result, training can be achievedin the home cage, totally avoiding human handling. To attributebehavioral significance to a tone, half the visits tothe drinking corner were accompanied by the presentationof a warning tone at a fixed frequency that was immediatelyfollowed by an aversive airpuff. Electrophysiological recordingsin auditory cortex were carried out in anaesthetized animalstaken out of the cage at various time points before andduring the behavioral training. Stimuli consisted of tone sequencesin which the warning tone was embedded with varyingprobabilities. Preliminary results indicate that during behaviouraltraining animals learned to avoid the airpuff. Furthermore,the local field potentials in response to the warningfrequency, when it was presented at a low probability as partof an oddball sequence, were more salient than the responsesto other frequencies under the same conditions.This research is supported by an FP6 grant. Based on evidence on abnormalities in nitric oxide (NO)function in schizophrenia, we have developed a neurodevelopmentalmodel of negative symptoms based on neonatal inhibitionof NO synthase (NOS) during postnatal days 3–5.In this model, neonatal NOS inhibition led in adulthood toa cognitive deficit that is central to negative symptomatology,namely, attentional perseveration/inflexibility, as manifestedin abnormally persistent latent inhibition. In supportof its relevance to negative symptoms, this abnormality wasresistant to the typical antipsychotic drug haloperidol but alleviatedby the atypical APD clozapine. Here we aimed todemonstrate neonatal NOS inhibition-induced attentionalperseveration and its alleviation by clozapine using an additionalselective attention task, discrimination reversal. Ratswere required to learn left-right discrimination in a T-mazewith the choice of one of the arms reinforced, and then thetwo reinforcement contingencies were reversed so that thechoice of the opposite arm was reinforced. Typically, thetransfer of behavioral control to the current contingencies isimpeded by the previously acquired contingencies. We foundthat neonatal NOS inhibition did not hinder rats' capacityto learn discrimination task or to retrieve the previously acquiredstimulus-response contingency, but rather impairedtheir ability to shift behavioral strategy, that is, to choose thepreviously unrewarded arm. Thus, attentional perseverationseen in abnormally persistent LI was paralleled by increasedperseveration in reversal. Furthermore, as seen in LI, this perseverativebehavior was alleviated by clozapine. These resultssupport the notion that neonatal NOS inhibition provides amodel of negative symptoms with construct and predictivevalidity. 2 stimulatingprobes, on the forearm. Subjects also underwent measurementof pain threshold (PT), with one cooling and oneheating probes (9 cm2 each) activated simultaneously to producethe TGI. The stimuli were separated by 0–30 cm, distanceswhich encompass one or two dermatomes. Simultaneouscold and warm stimuli produced burning pain at allseparation distances. PT values (∼26 and 38°C) were significantlylower than CPT and HPT, respectively, and were relativelyfixed across all distances except for 30 cm at which PTincreased towards CPT and HPT values. In conclusion, innocuouscold and warm stimuli can spatially summate, bothwithin and between dermatomes and evoke a painful TGI.Most likely, nonnociceptive cold and warm channels integrateonto 2nd or 3rd order nociceptive neurons which, inturn induce a unique painful burning resulting from thisblend.Interlaced hot and cold stimuli administered simultaneouslyon the skin induce a paradoxical heat sensation; a phenomenontermed the thermal grill illusion (TGI). Studies onthe grill illusion have yielded contradictory results regardingits quality and intensity, which in turn led to controversiesconcerning the underlying mechanism. The controversiesmay result from testing the TGI with absolute stimulationtemperatures thereby disregarding inter-subjects' variationin temperature sensitivity. Therefore, the first aim wasto measure the individual threshold of the TGI. Another aimwas to measure the spatial boundaries of the TGI by spatiallyseparating between the cooling and warming stimuli,in order to explore possible mechanisms. Subjects  underwent measurements of heat-pain (HPT)and cold-pain thresholds (CPT) with 9 and 18 cm, Stimulation at a constant intensity and location usually inducea gradual decrease in receptors' output leading to weakeningof subjective sensation, a phenomenon termed habituation.Habituation to pain was not studied in depth and resultsare controversial. The aim was to investigate the stimulationparameters allowing for pain habituation, that is, toassess the role of absolute versus relative stimulation intensity.Subjects were administered with cold and hot stimuliof either various absolute temperatures or at intensities setindividually to induce an initial visual analog scale (VAS)scores of 2, 4, and 6 . Subjects rated their perceived pain during stimulation(3–5 minutes). Absolute temperature, initial VAS scoresand time significantly affected pain ratings. Temperatures of43–45°C always induced reduction in pain ratings with timewhereas 47-48°C always induced elevation in pain ratingswith time, regardless of initial VAS scores. Stimuli equivalentto VAS 2 always induced reduction in pain ratings and thoseequivalent to VAS 4 and 6 induced elevation in pain ratingswith time, regardless of absolute temperatures. Nevertheless,absolute temperature and initial VAS scores cointeracted inthat they strengthened the patterns induced by one another.Sex affected the value of pain ratings but not their changewith time. Habituation to pain occurs only for relativelyweak temperatures or at low VAS levels. With strong stimulationtemperatures and/or temperatures inducing moderatestrongpain, pain sensation gradually increases to unbearableintensities. It is hypothesized that the lack of pain habituationat those circumstances serves as a protective mechanismagainst potential and actual tissue damage. It also appearsfrom the results that individual variations in pain thresholdand responsiveness are less influential than stimulation parameterson pain habituation and excitation. α = 0.05. A significant decrease in Hippocampus/skulland hippocampus/brain ratios was found when the RRMS,but not the PMS, groups were compared to controls . Furthermore, there was a significant correlationbetween the hippocampus/brain ratio and disease duration among the MS patients. To the best of ourknowledge this is the first report of a disease-related atrophyin hippocampus of RRMS. Considering the key role playedby the hippocampal formation in memory processes, it islikely that preferential hippocampal atrophy is a significantcontributor to the mechanism underlying cognitive deficitsin MS.Multiple sclerosis (MS) is an autoimmune disease characterizedby inflammation and demyelination. A significant proportionof MS patients also exhibit cognitive deficits. Thehippocampus is a brain region implicated in memory formation,and hippocampal volume decline has been demonstratedin conditions associated with cognitive deficits suchas Alzheimer, depression and aging. The aim of the presentstudy was to test the hypothesis that hippocampal volumedeclines as a function of disease duration in MS; using quantitativeMRI. Twenty five women (age range 23–58) who underwenta brain MRI scan were included in the study. 9 subjects(age 23–50) with disease duration of less than 1 yearhad early (probable) MS (PMS) at the time of the scans. 10additional subjects (age 29–58), with disease duration 3–24years, had an established remitting-relapsing disease (RRMS)and 6 healthy women (age 30–54) served as controls. Hippocampalvolumes were measured off T2 weighted images using quantitativeimage analysis software (Image J), and normalizedto skull and whole brain volumes. ANOVA, t-tests and simpleregression were used for statistical analysis as appropriate,Supported by J. Sagol doctoral fellowship to YaelDeri. Several recent studies have shown that fMRI response patternsfrom early visual areas enable accurate decoding of orientedgratings and motion directions . Accurate classification is evidence of underlyingneural selectivity for the changing dimension of the stimulusin the area tested. We used the same classification methodologyto decode executed movement responses in several corticalareas including primary motor and somatosensory cortex.Twelve subjects played the common game rock-paperscissorsagainst a video taped virtual opponent whose movementswere randomized. Subjects chose their movementsfreely with the objective of winning the game. We definedseveral cortical regions of interest (ROIs) including primarymotor and somatosensory cortex and extracted the spatialpattern of fMRI responses in each ROI associated with eachtrial in the game. We then used Fisher linear discriminantanalysis to classify responses fromthe three movement types.We tested the accuracy of the classification by decoding theexecuted movements on independent trials not included inthose used to train the classifier .Executed movements were decoded from the fMRI responsepatterns in primary motor and somatosensory areas withaccuracy of ∼65%, significantly better than chance performance(33% because there were three possible movements).Neural activity in human primary motor and somatosensorycortex is selective for executed movements. Classification canbe successfully used to decode executed movements, evenwhen using a fast event related fMRI protocol, with sufficientreliability to distinguish small differences in handmovement.This methodology may, therefore, enable assessment of underlyingneural selectivity in the study ofmotor control .Supported by the HFSP and Seaver Foundation. Most receptor tyrosine kinases (RTKs) and G-protein coupledreceptors (GPCRs) activate MAPK cascades but still exertdiverse functions and therefore signal specificity remainsan enigma. Also, most GPCR ligands utilize families of receptorsfor mediation of diverse biological actions; howeverthe type I GnRH receptor (GnRHR) seems to be the sole receptormediating GnRH-induced gonadotropin release. Signalingcomplexes associated with GPCRs may provide themeans for signal specificity. Here we describe a signalingcomplex associated with GnRHR, a unique GPCR lackinga C-carboxy tail. Unlike in cases of other GPCRs this signalingcomplex is preformed and exposure of LbetaT2 gonadotropesto GnRH induces dynamic rearrangement of thecomplex. The signaling complex core is c-Src and its bindingpartners include PKC delta, epsilon and alpha, Ras, MEK1/2,ERK1/2, tubulin, FAK, paxillin, vinculin, caveolin-1, KSR-1 and the GnRHR. A short exposure to GnRH (5 minutes)causes MEK1/2, ERK1/2, tubulin, vinculin, and the Gn-RHR to detach from c-Src followed by reassociation withthe complex by 30minutes. On the other hand, FAK, paxillin,the PKCs and caveolin-1 stay bound to c-Src and KSRappears in the complex only after 30 min of GnRH stimulus.GnRH stimulated ERK1/2 activity in the complex in ac-Src-dependent manner. The GnRH activated ERK1/2 thenphosphorylates FAK and paxillin, while caveolin-1 is phosphorylatedon Tyr14 apparently by the activated c-Src. RTKsand GPCRs translocate ERK1/2 to the nucleus to phosphorylateand activate transcription factors. Therefore the role ofthe multiprotein signaling complex seems to sequester a cytosolicpool of activated ERK1/2 to phosphorylate FAK andpaxillin at focal adhesions apparently for cell migration andspreading.Supported by ISF and GIF. 2. The subjects were healthy young men (17–35), with corrected-to-normal vision acuity (6:6 or better),with color blinded individuals (n = 9) or controls (n =7). The results show a significant advantage of the colorblindedpersons in the perceptual functions: better visualacuity, higher CS , and better stereopsis (53%). Thus, the results indicatethat the processing of monochromatic perceptual functionsin color-blinded persons is superior to that of peoplewith normal color vision. This suggests that the advantagesof monochromatic vision lie in the consequence ofan adaptation process throughout development in order tocompensate for the loss of the important dimension of colorvision.Color vision enables discrimination and segmentation betweenvery similar objects, thus adding an important dimensionto visual processing. One out of eight men has a lackscones function in the retinal fovea, and as color blind, reliesonly on monochromatic information. In this study weexplored the possibility that the visual system has adaptedto the loss of information provided by the color system byachieving superior performance in the monochromatic systemto compensate for the missing information. We measuredbasic functions of the visual system such as visualacuity, stereopsis, day contrast sensitivity (CS), and fovealmesopic CS. The mesopic CS was measured under conditionsof full darkness, and with natural density filters thatcovered the monitor, transmitting background luminanceof 0.03 cd/m Conditioned taste aversion (CTA) may be acquired when ananimal consumes a novel taste and then experiences the symptoms of poisoning . Animals will later avoid the taste thatwas previously associated with malaise. Several molecularchanges were found to be correlated with novel taste learningand CTA in the insular cortex (IC). However, very littleis known on the circuit level within the insular cortex subservingtaste learning . Previous studies,that used the immediate early gene (IEG) c-fos proteinas a functional marker of neuronal activity in the IC, haveshown that c-fos expression is elevated in the IC followingtaste aversion learning. In the current study we used confocalmicroscopy along with c-fos, the GABAergic GAD67and nuclear immmunofluorescence markers, in order to determinewhether the change in c-fos expression is localizedto GABAergic interneurons in the IC following novel tastetraining and CTA. Our results indicate that although total cfosexpression is not changed following novel taste only, it isspecifically higher in GABAergic neurons in layers I-IV of thedysgranular IC (DI). Moreover, in accordance with previousresults, total c-fos expression is elevated in the IC followingCTA, but also specifically in GABAergic neurons in layers IIVand layers IV-VI. In contrast, no layer specific elevation ofc-fos expression in GABAergic neurons can be detected followingLiCl injection only, although the total c-fos expressionis higher following LiCl i.p. administration. We proposethat novel taste learning is mediated through GABAergiclayer specific activation in the DI, while CTA learning isinvolved in more sparse activation of neurons in the insularcortex. A basic attribute of the neocortex is its organization intofunctional, vertically oriented columns, which is particularlyprominent in the “barrel” field of the somatosensory cortexof the rat. Though the barrels in layer 4 have been extensivelyinvestigated, there is disagreement regarding direct interactionsbetween layer 4 neurons of neighboring barrels.Whether or not these interactions exist is fundamental toour understanding of sensory integration of thalamic inputsand the origin of multiwhiskers response of layer 4 cells. Onetheory claims that direct interbarrel synaptic connections influenceneighboring barrels. An opposing theory states thatinteractions between barrels are negligible and subcorticalmechanisms are responsible for multiwhisker responses. Totest for monosynaptic interbarrel connections, we made invitrointracellular current-clamp recordings in layer 4 of thalamocorticalslices. Dissected slices connected only throughlayer 4 showed that electrical stimulation in one barrel triggersboth antidromic and orthodromic responses in neuronsof neighboring barrels, although these responses did not necessarilyalways appear together. Although EPSPs evoked bystimulation of a neighboring barrel were smaller than thoseevoked by direct barrel stimulation, this experiment providesan indication of a direct flow of information between barrelsand suggests it can play a significant role in cortical gain controland determination of the cortical receptive fields.This work was supported by ISF grants. Activity-dependent neuroprotective protein (ADNP) wasfirst discovered as a protein associated with neuroprotection.The gene is highly conserved, and contains zinc fingers anda homeobox domain. ADNP is essential for brain formationand ADNP knockout mice exhibit failure of neural tubeclosure and death on E8.5-9.5. Upregulation of transcriptsassociated with lipid metabolism, and down regulation oftranscripts associated with neurogenesis and organogenesiswas observed in the knockout embryos. Recently, ADNP wasfound to interact with members of the mating type switching/sucrose nonfermenting (SWI/SNF) chromatin remodelingcomplex. ADNP2 (KIAA0863) is a new protein, paralogto ADNP, with a very similar structure and expression pattern.Our research aim is to further understand the functionof these proteins and their counter-relationship. Our findingsindicatemutual regulation between ADNP and ADNP2.A reduction in ADNP2 expression was seen in the ADNPknock-out mice, and a reduction in ADNP was seen in knockdown of ADNP2. As a first step, several research tools wereconstructed. First, ADNP and ADNP2 knock down systemsusing siRNA technology were established in P19 cells. Thesetools enable the examination and comparison of the phenotypiceffect of ADNP and ADNP2 down regulation inboth pluripotent and neouro-differentiated P19 cells. In addition,in order to trace the cellular localization of ADNP2,green fluorescent protein was attached to ADNP2 to form achimeric protein, which was expressed in HEK293 cells. Finally,antibodies against two peptide sequences in ADNP2were produced and affinity purified to identify the ADNP2protein. Taken together, these tools will enable further investigationsinto the counter-relationship of the essential proteinADNP and its family member ADNP2.Support by BSF, ISF, Lily, and Avraham Gildor Chair, AdamsSuper Center, and Allon Therapeutics Inc. Thiamine deficiency (TD) is a model of chronic impairmentof oxidative metabolism leading to neuronal loss. Rats are feda thiamine-deficient diet accompanied by injections of thecentral thiamine antagonist, pyrithiamine. They exhibit neurologicalimpairments, cognitive deficits as well well-definedneuropathological lesions. Neurodegeneration develops overa period of 12 to 14 days and can be reversed by thiamineadministration. Use of this model can help elucidate mechanismsof neuronal degeneration as well as important pathsof neuronal rescue. Furthermore, since TD is partially reversibleafter thiamine administration, the effect of neuroprotectivedrugs on recovery can also be studied. In this studywe investigated the neuroprotective effects of rasagiline, aMAO-B inhibitor, in TD rats, using neurological score, cognitivetesting and histopathology. Magnetic resonance imaging(MRI) was used to study the pathology and brain changesin the rasagiline-treated and untreated-TD rats. Magneticresonance spectroscopy (MRS) was used measure metabolicchanges. We found that rasagiline significantly delayed theinduction of the TD syndrome and decreased the severity ofthe associated neuropathology. Rasagiline improved cognitionin the Morris water maze. The severity of both the cognitiveand histopathological changes was significantly less inrasagiline-TD rats. T2-weightedMR imaging revealed severetime-dependent damages, mainly in the thalami and the inferiorcolliculi which were diminished with rasagiline treatment.We found that rasagiline both ameliorated and delayedneuronal injury. MRS showed an increase in lactate levels inthe thalamus of untreated-TD rats which was postponed anddecreased in the thalami of the rasagiline-TD group. Our resultsdemonstrated significant neuroprotection by rasagilinein this model which could have implications for clinical neurodegenerativedisorders. Themain challenge in constructing conductance-based compartmentalconductance-based compartmental models thatcapture the firing pattern of neurons is constraining the densityof the various membrane ion channels that determinethese firing patterns. Presently, quantitative data on the densityof a certain ion channel along a specific dendritic regionis by and large lacking. The dominant method to date is torecord the in vitro experimental response of the cell to a setof current stimuli and then attempt to replicate the responsein a detailed compartmental model of that cell. Yet, in experiments,intrinsic noise gives rise to a large variability inthe voltage responses to repetitions of the exact same input.Thus, the common approach of fitting models by attemptingto perfectly replicate, point by point, a single chosen traceout of the spectrum of variable responses does not seem to dojustice to the data. In addition, finding a single error functionthat faithfully characterizes the distance between two spikingtraces is not a trivial pursuit. To address these issues, we proposeto adopt a multiple objective optimization (MOO) approachthat allows the use of several error functions jointly.When more than one error function is available, the comparisonbetween experimental voltage traces and model responsecan be performed on the basis of individual featuresof interest . Each feature can becompared between model and experimental mean, in unitsof its experimental variability, thereby incorporating into thefitting a measure of this variability. We demonstrate the successof MOO when used in conjunction with genetic algorithmoptimization, in generating an excellent fit betweenmodel behavior and the firing pattern of two distinct electricalclasses of cortical interneurons, accommodating andfast-spiking. We argue that the multiple, diverse models generatedby this method could serve as the building blocks forrealistic simulation of large neural networks. Postpubertal dystrophin-deficient mutant (mdx) mouse hasbeen reported to exhibit both muscular dystrophy and raisedserum acetylcholinesterase (AChE) concentrations . InthisSupported by MDA (LA). Recently, it was shown that neurons bursting in culture havea tendency to fire according to some order (Van Pelt 2005).Specifically, a subpopulation of the culture fires earlier thanaverage (Eytan and Marom 2006). The role of these early-tofireneurons in the population bursting is not clear, as theymay be only probes of the ongoing population activity onone hand, or lead the recruitment of activity in the burst onthe other hand. In the light of this question, we have analyzedthe spontaneous bursting activity data of dissociated rat hippocampaland cortical neuron cultures that were recordedover a few weeks using multi-electrodes. The cultures wereprepared and grown in three labs using different protocols.Most of the bursts were preceded by a preburst activity, indicatinga slow recruitment of activity in the neurons sampledby the electrodes, and therefore, in the whole culture.Still, surprisingly, we find that the locality of the electrodefiring occurs in the preburst but is diminished in the burst.Leader electrodes were defined as those few electrodes thatconsistently fired first in prebursts. We observed that theseleaders are stable over a few tens of hours, and that their distributioncan only be temporarily disturbed using externalstimulation. We show that the identity of the leader initiatingthe preburst of a given burst determines, statistically, theelectrode firing statistics during the following burst. Basedon these results, we suggest that the leaders belong to a subnetworkof neurons in the cultures and serve as nucleationcenters for the recruitment of neural activity.JPE, CZ were supported by the Fonds National Suisse, SM bythe ISF, EM and SJ by the ISF and Minerva. β-neurexins, and SHANK3 have all been linked byboth linkage and association studies to autism spectrum disorder(ASD), however, PSD95 has not yet been studied in thiscontext. We identified and genotyped all six tagging SNPs(htSNPs) across the DLG4 gene region using HapMap andthe Haploview program. PBAT-Helix tree was used to testassociation by family-based methods, in 152 probands from133 families for htSNPs with DSM IV autistic disorder as wellas IQ and vineland adaptive behavior scales (VABSs) scores.The results were also verified using UNPHASED. Nominalassociation was observed between1htSNP (rs17203281) anddiagnosis , and 3 htSNPs were associatedwith IQ and VABS scores . Multivariate and haplotypeanalysis showed significant association between DLG4 and allthree phenotypes . The FBAT-GEEmultivariate statistic was significant for all four SNPs and forall three phenotypes (P = .0098). A common (25%) fourlocushaplotype (rs17203281-rs3826408-rs929229-rs507506:G-C-A-A) was significantly associated with all three phenotypes. Importantly, the current investigation,by demonstrating association of common taggingSNPS with ASD, VABS and IQ across the DLG4 generegion, suggests that dysfunction of synaptic complex scaffoldingproteins such as PSD-95 may be a general risk factorin this disorder. The finding that IQ and VABS scores arealso associated with DLG4 suggests that other disorders withIsrael Society for Neuroscience 31cognitive and social function deficits exhibited in daily livingskills might be profitably investigated for association withPSD-95 and related scaffolding proteins.PDZ-domain scaffolding proteins such as PSD-95 (DLG4)along with neurexins, neuroligins, and SHANK3 comprisethe elements of trans-synaptic cell-adhesion complexes thatare thought to bridge pre- and postsynaptic division. Neuroligins, Spatial learning and memory deficits in rodents have largelybeen studied using the Morris water maze (MWM). Althoughoriginally the water maze task was designed for rats,it has also been applied to mice. However, learning in theMWM relies on swimming abilities, which evolutionary arenot well developed in mice. It is thus not surprising thatmicewhen compared with rats show an impairment. We havetherefore assessed spatial learning and memory in mice usinga dry maze. The dry maze is a paradigm for measuringspatial learning and memory in mice. In the present study,evaluation of cognitive function was performed in ICR micefollowing minimal traumatic brain-injury (mTBI) or shaminjury.Mice were tested 7 days or 30 days post injury. Thedry maze is a circular plastic arena which comprises 20 smallwells arranged in a circular manner. The maze paradigm involvesthree parts: (1) training part, which lasts 2 days duringwhich all 20 wells are baited with drinking water; (2)learning part which lasts 7 days and only one of the wellsis baited (the same well for the entire week); (3) probe partwhich lasts 2 days during which a different well was baited.The mice were kept on water depravation (1 hour of waterper day) during the entire experiment. Each animal's pathwas tracked and its latency to reach the well was recorded.In addition, the percentage of success in reaching the wellwas calculated. Significant differences were observed betweenthe injured mice in comparison with the sham group followingboth time intervals. Seven days post mTBI the miceshowed learning deficits in the learning part as well as inthe probe part. Thirty days post mTBI, there were no significantdifferences in the learning part, but deficits were evidentin the probe part. These results demonstrate that thereare long term deficits in cognitive learning abilities in mTBImice which are measurable in the highly sensitive paradigmof the dry maze. A concept and methodology derived from animal studieswas utilized as a framework for studying rituals in obsessivecompulsive disorder (OCD) patients and deriving objectiveand observable criteria for compulsive rituals across patients.OCD rituals performed by patients in their own home werevideotaped and compared with the behavior of healthy individualsinstructed to perform the same rituals. The videotapedrituals were deconstructed into visits to specific locationsor objects , and to the acts performed ateach location/object . Quantitativeanalyses revealed that compulsiveness emanates from the expansionof repeats for some acts and visits, and from the additionof superfluous act types. Best discrimination betweenOCDand control rituals (90.9% success) was provided by theparameter “maximum of act repeats in a ritual” (R2 = 0.77).It is suggested that the identified properties of compulsivebehavior are consistent with a recent hypothesis that ritualizedbehavior shifts the individual's attention from a normalfocus on structured actions to a pathological attraction ontothe processing of basic acts, a shift that invariably overtaxesmemory. Characteristics and mechanisms of compulsive ritualsmay prove useful in objective assessment of psychiatricdisorders, behavioral therapy, and OCD nosology.Supported by Adams Super Center for Brain Studies, Tel-AvivUniversity, Israel. 2+ -release from intracellularstores via the ryanodine receptor (RyR), and that theenhanced Ca2+ -release is directly responsible for neuronalcell dysfunction and death. Moreover, in in vitro studies, wehave shown that GlcCer directly interacts with and modulatesthe activity of the RyaR, the major Ca2+ -release channelin the ER, and that this also occurs in human brain tissueobtained post-mortem from Gaucher disease patients.These findings suggest that defective Ca2+ -homeostasis maybe a mechanism responsible for neuropathophysiology inacute neuronopathic Gaucher disease. However, it is still notclear how accumulated GlcCer leads to neuronal cell death.Thus, we are performing comprehensive gene arrays studiesof cultured hippocampal neurons. We compared untreatedneurons to Gaucher disease biochemical model neurons usingconduritol-B-epoxide (CBE), an active site-directed inhibitorof GlcCerase. Our data suggest significant alterationsin gene expression in this model. Among the genes thatwere transcriptionally regulated are genes related to nervoussystem development and genes involved in mitochondriafunction. These results will hopefully shed light onthe pathways activated in neurons upon GlcCer accumulation,and will thus lead to a clearer picture of the cellularmechanisms involved in neuronal cell dysfunction anddeath.Gaucher disease is the most common lysosomal storage disorder(LSD). This metabolic disorder is caused by mutationsin the gene encoding glucocerebrosidase (GlcCerase), andas a result, glucosylceramide (GlcCer) accumulates withinthe cell. Types 2 and 3, the most severe forms of the disease,are characterized by neurological impairment and neuronalcell death. Over the past few years, our laboratoryhas shown in neuronal models of Gaucher disease that Glc-Cer enhances agonist-induced Ca Neurons in the motor cortex are typically tuned to the directionof limb movements. There's also evidence for similartuning of the local field potential (LFP), representingthe pooled neural activity (at roughly 1mm). But it is currentlyunclear if the different directions of movements arerepresented in clusters within the limb areas of the humanbrain. To that end, we conducted a functional MRI studyin which subjects performed a reaching task towards 4 targetsusing an MRI-compatible joystick. Regions of interest(ROIs) were selected on the basis of their activation duringthe various reaching conditions. In each ROI, we studied thedegree to which the spatial patterns of the fMRI activation were correlated across trials.The correlation coefficient was computed for trials repeatingthe same motion (“same” condition) and for trialswith different directions of movement (“different condition”).We found that in the primary motor cortex, premotorcortex, supplementary motor area, and various regionsalong the intraparietal sulcus, the spatial pattern of fMRIactivation was positively correlated across repetitions in the“same” condition, whereas the correlation between trials indifferent directions was slightly negative. The results indicatethat a non homogenous representation of directional movementsis present in the human motor areas. While, clearly,important information may be lost due to the low spatialresolution of fMRI and its inherent noise, one can still predictthe direction of hand movement on a single trial fromthe fMRI signal at a level better than chance. This methodmay be a useful tool for investigating interactions and hierarchiesof brain areas involved in sensorimotor action andperception.The first two authors contributed equally to this work. Functional neuroimaging studies of aphasic stroke patientsoffer the prospect of a better understanding of the neuronalmechanisms that underlie language recovery. There is ongoingdebate concerning the capacity of the right hemisphere(RH) to takeover language abilities after a focal brain lesionto the left hemisphere (LH).In this study, we investigate systematicpatterns of brain language organization as a functionof linguistic performance following recovery from childhoodinsults to the language-dominant hemisphere.We present preliminary data of 7 children with a historyof single, left hemisphere CVAs, who were diagnosed withnonfluent aphasia at onset (ages 6–17) and subsequently recovered.Twelve age- and sex-matched healthy right handersserved as controls. All underwent fMRI scanning duringthree linguistic activation tasks, during the chronic stage (atleast 2 years postonset).Outcomes yielded predominant tendency of RH Lateralizationin patients versus LH lateralization in the healthy controlgroup. The patterns of activation in the RH in patientswere in brain areas homologous to LH regions involvedin language functioning under normal circumstances.However, correlation analyses with linguistic performancedemonstrated that better linguistic performance is associatedwith greater involvment of the left hemisphere. This findingheld true for patients' linguistic performance inside the MRIscanner (for Rhyming and Comprehension tasks), as well asfor behavioral linguistic mesurments which were carried outoutside the scanner .These findings imply that the left hemisphere becomes moreinvolved as the patient becomes more proficient at the linguistictask. Hence, it appears that better recoverymay reflectmore involvement of perilesional regions of the damaged LH.Funded by the Israel Science Foundation (ISF). Taste learning is correlative with phosphorylation of proteinsregulating translation, in the brain area underlying its function.In addition, inhibition of protein synthesis in the gustatorycortex attenuates long but not short term taste memory.we employed two parallel different proteomic approachesto identify modulation on the protein expression levels inthe gustatory cortex in correlation with novel taste learning.Both screening and additional direct methods identified andverified the synaptic protein, PSD-95 as an induced protein.The correlative induction of PSD-95 with learning is MAPKdependent and is also induced at synapses of the taste cortex.Moreover, the time window of PSD-95 increased expressionis narrow and learning novel but not familiar taste inducedits expression. This learning-related induction of PSD-95 wasMAPK dependent, and was expressed locally at synapses ofthe taste cortex. To examine whether PSD-95 induction inthe cortex was necessary for the taste memory trace formation,we attenuated PSD-95 expression in the gustatory cortexin vivo, by temporally and spatially restricted lentiviralmediated RNAi. Indeed, PSD-95 levels in the gustatory cortexwere necessary for learning novel taste in thesiRNA injectedrats. Lithium salts (Li) are the standard treatment for bipolar disorder.The “inositol depletion” hypothesis proposes that Liacts by depletion of brain inositol, based on the uncompetitiveinhibition of inositol monophosphatase (IMPase) by Li,resulting in decreased inositol, and subsequent down regulationof the phosphoinositide cycle (PI). Berridge proposedthat depletion of brain inositol levels and the consequent reducedrate of resynthesis of phosphatidilinositol and of secondmessenger signal generation leads to a decreased responseto neurotransmission through this pathway. It has recentlybeen shown that IMPase is an activation target for calbindinD28k. Purified calbindin attaches to a specific aminoacid sequence on purified IMPase enhancing its activity byseveral fold. The effect of calbindin on IMPase activity ismost meaningful at conditions that otherwise lead to lowIMPase activity such as low substrate concentration. Thissuggests that calbindin could be a key endogenous regulatorof the phosphatidylinositol cycle.Find out whether short oligopeptides comprised from theIMPase sequence to which calbindin was shown to attach interferewith the interaction and abolish IMPase activation bycalbindin.μM recombinant calbindinand with or without 10 μM specific peptides was quantifiedspectrophotometrically bymeasuring Pi release fromthesubstrate inositol-1-phosphate.IMPase activity in brain homogenates in the presence orabsence of 60 mM Li (to discriminate between IMPase andnonspecific phosphatases), 20 Calbindin's activation of IMPase by 1.66 fold was abolishedby specific peptides derived from the sequence of the interactionsite of the IMPase protein with calbindin but not bya scrambled peptide. This finding may lead to the developmentof molecules capable of inhibiting endogenous IMPaseactivity as an alternative mood stabilizing drugs.Supported by a Stanley Foundation grant to O. A. and G. A. Spastic myoclonus produced in spinal cord injury patientswith incomplete thoracic lesions was studied using simultaneousvideo monitoring and surface EMG (s-EMG) recordingsfrom the ankle joint antagonistic muscles tibialis anterior(TA) and lateral gastrocnemius (LG). Myoclonic activityhas been revealed in the recorded muscles following dorsiflexionof the ankle joint, during body weight supported(BWS) treadmill locomotion, and after BWS locomotion.Statistical analysis of the myoclonic activity using Wavelettransform and coherence, showed that the myoclonus wascharacterized by a typical ∼6–8 Hz tremor and that the flexoractivity (TA) was slightly led by the activity of the extensor(LG) during the dorsiflexion-induced myoclonus, but notduring or following BWS treadmill locomotion. The myoclonusproduced by dorsiflexion of the ankle could be attenuatedin four out of the six patients by dorsiflexion ofthe contralateral ankle. We suggest that the myoclonus is notnecessarily due to a repeated activation of stretch reflex andthat it involves activation of spinal central pattern generators(CPGs). We also propose that activation of intact crossed inhibitorycommissural pathways is capable of suppressing thecontralateral myoclonus. The long axonal process of a neuron poses a problem wheninformation on damage to the axon must be conveyed to thedistant cell soma. It is known that injured peripheral nerveaxons can signal to their cell bodies, and cause a “reprogramming”of the cell body for long range elongating outgrowth.We have recently discovered that the mechanism forthis process is based on local synthesis of nuclear import proteinsin the axon at the injury site. These proteins can thenbind signaling proteins tagged with nuclear import signals,and transport them back to the cell body where they inducechanges in the regenerative properties of the nerve. Our currentefforts are focused on understanding how the system isregulated, what signals it transports, and what is the transcriptionalresponse at the cell body. The presentation willfocus on new data on regulation of the importins system inaxons, initial identification of candidate signaling proteins,and characterization of the transcriptional response in neuronalcell bodies. Depression is a multifactorial disease caused by both geneticand environmental factors and the prevalence of depressivedisorders appears to be increasing in modern society. Themajor tools in the quest to reveal the molecular basis of depressionand discover new antidepressants are animal models.Since depression in humans develops gradually and theeffect of antidepressant treatment in clinics is effective onlyafter chronic administration, development of animal modelsof chronic depression is essential. To meet this challenge, aDominant Submissive Relationship (DSR) model was developedfor mood stabilizing and antidepressant drug testing.In the DSR model pairs of animals compete during daily 5-min interactions for limited amounts of food. Under theseconditions, about 30–40% of the pairs develop dominantsubmissiverelationships that are characteristic of normal socialbehavior. Treatment of submissive animals with knownantidepressants significantly reduced submissive behavior ina dose-dependent manner. Therapeutic efficacy was delayedin concordance with the delay of therapeutic efficacy of antidepressantsroutinely seen in clinic. These characteristicsmake the DSR model a valuable tool for study etiology of depressionand for the testing of antidepressants. The purposeof this study is to evaluate ability of outbreed Sabra mice todevelop dominant submissive relationships. Two month oldmale Sabra mice were subjected to the DSR test. The datashow that about half of the animals developed strong andstable D-S relationships during second week of experimentthat remain stable during third week of experiment. Thisstudy revealed that Sabra outbred mice are able to developstrong D-S relationships and may serve as a potential modelfor screening antidepressants and investigation of genetic elementsthat are responsible for dominant and/or submissivebehavior. P < .01 at each time point,n = 4−6).Daily administration of L-Dopa (6 mg/kg) and carbidopa(1.5 mg/kg) caused a gradual increase in dyskineticmovements in sham-operated rats, which reached a peak at3 weeks after commencing treatment. The intensity of dyskineticmovements was reduced in rats which had been transplantedwith fibroblasts in STN or EP. In histopathologicalanalysis performed 7 months following transplantationthe transplanted cells were located at the site of transplantationwithout signs of significant inflammation. We suggestthat this technology can serve as a broad platform forthe treatment of various neurological disorders in which localareas of inappropriately high neuronal activity exist, andspecifically for Parkinson's disease.Motor dysfunction in Parkinson's disease results from decreasedstriatal dopaminergic input, leading to increasedneuronal activity in striatal output pathways, primarily GPi,SNr and STN. We are developing autologous fibroblast transplantationin these areas of neuronal hyperactivity as a potentialtreatment for Parkinson's disease, based on our observationthat addition of dissociated fibroblasts to a primaryculture of cerebral cortical neurons reduces synchronizationof neuronal discharge. Primary cultures of rat corticalneurons were prepared and plated on multi-electrodearrays. Mature fibroblasts were added to the cultures andelectrical recording was taken 3-4 days later. Discharge rateof cortical neurons cultured on multielectrode array was reducedto 32±5% control at 3 days following fibroblasts seeding.Unilateral 6-OHDA lesion in medial forebrain bundlewas carried out in Fischer rats. Syngeneic dermal fibroblasts(200 000) were transplanted at entopeduncular nucleus  and SNr. Apomorphine-inducedrotational behavior (0.25 mg/kg) was reduced 2, 4, 8, and 26weeks following transplantation, to 22 ± 9, 28 ± 12, 30 ± 11,and 24 ± 7% control respectively  in the regulation of prostaglandin E2(PGE2) and nitric oxide (NO) synthesis, which are importantmediators of inflammatory responses. This was studiedboth under basal conditions and in lipopolysaccharideinduced neonatal rat glial cells. Under basal conditions, allthree endothelins, given at concentrations of 10nM and100 nM, increase PGE2 and NO release by about 2-3 fold ina dose dependent manner. However, in LPS induced cells,all endothelins decrease the production of PGE2 and NOto about one half. BQ123 and BQ788, antagonists of ETAand ETB receptors, respectively, completely blocked both thestimulatory and inhibitory endothein actions. These resultsdemonstrate for the first time the dual ability of endothelins,acting via ETA and ETB receptors, to influence the productionof inflammatory mediators in glial cells under basal andinflammatory conditions. Targeting the ET system may be apromising approach in modifying the course of inflammationduring AD.This research was supported by the Israel Science Foundation(Grant no. 500/04). Stimulation of sacrocaudal afferents (SCA) has been foundto induce a locomotor-like and body-axis stabilizing rhythmin the isolated spinal cord of the neonatal rat and mouse.The SCA-induced rhythm depended on synaptic activationof sacral interneurons whose axons cross the cord and ascendrostrally mainly through the contralateral ventral funiculus(VF). In the present work we have used fluorescentlabeling techniques and confocal microscopy to identifythese interneurons and characterize their association withthe cholinergic system that has been shown to produce locomotorlike episodes in the isolated spinal cord. Retrogradefluorescent labeling of the cut VF at the lumbosacral junctionrevealed several groups of S1–S4 interneurons contralateralto the fill. Labeled interneurons were mostly located in theintermediate gray, a few in the dorsal horn, and some in theventral horn. The laminar locations and trajectories of theseneurons are similar to those of projection neurons of thespinothalamic, spinoreticular, and spinocerebellar tracts orof ascending propriospinal pathways. Immunocytochemicallabeling of the cholinergic transmission components, cholineacetyltransferase (ChAT), vesicular ACh-transporter, acetylcholinesteraseand muscarinic AChRs, revealed that subpopulationsof these sacral interneurons produced and/or receivedcholinergic innervation. Further studies are requiredto clarify the contribution of these cholinergic elements topattern generation and inter-segmental communication inthe mammalian spinal cord. Chronic mild stress (CMS) in rats is a widely used modelof depression, which is linked to stress-induced decreasesof neurogenesis in the hippocampus. Antidepressant treatmentsappear to protect against hippocampal volume loss.Moreover, antidepressants administration reverses the behaviorof stressed animals such as anhedonia (decreased sucrosepreference) and increased immobility in the forcedswim test. Our goals were to evaluate the effect of chronicmild stress and fluoxetine (5 mg/kg/day i.p.) therapy on theIGF1 system in the rat brain and on behavioral and cognitiveparameters. Male rats were exposed sequentially, over a periodof 3 weeks, to a variety of mild stressors (Wilner 1997),and another control groups of rats received the same treatmentwithout stress. Body weight gain of fluoxetine treatedrats did not differ from the control group. After 3 weeks ofCMS animals were exposed to the open field (OF) test followedby a Morris water maze (MWM). In the OF fluoxetinetreated stressed rats showed decreased immobility, andincreased frequency and duration time spent in the innerzones of the arena, suggesting anxiolytic and more motivatedbehavior. However, in the MWM we observed a significantfacilitating effect of fluoxetine in the acquisition phasein the nonstressed animals only. After autopsy we dissectedbrains and separated the cortex and hippocampus. IGF-1 receptor (IGF-1R) expression was determined by Westernblot analysis. We found that CMS significantly reducedthe IGF-1R levels in the cortex and the hippocampus, and fluoxetine treatment reversed the expression to normal levels.We suggest that decreased IGF-1R in the brain followingCMS may contribute to depression and anxiety, which arereversed by fluoxetine therapy. However, fluoxetine therapyslightly improved performance in the MWM in normal butnot in stressed rats suggesting that more factors are involvedin the process of improving cognition. Backward masking—where visual images are briefly (10–100 milliseconds) flashed and followed by a mask, often renderingthem unrecognizable—offers an opportunity to studyneural correlates of object recognition. Previous fMRI studiesof this phenomenon have revealed that recognition istightly correlated to high BOLD activity in ventral streamvisual areas. Here, we used intracranial EEG (iEEG) recordings,which offer good localization and a msec temporal resolution,to investigate in more detail the neuronal eventswhich correlate to recognition in this paradigm. Recordingswere done using subdural intracranial electrodes, implantedin epilepsy patients strictly for clinical purposes.Patients viewed a briefly (16 milliseconds) presented targetimage belonging to one of three categories—faces, houses,and tools—followed by a fixed mask image. Interposed betweentarget and mask was a blank period of variable duration,resulting in a total time difference (SOA) of 16–200 milliseconds between target and mask onset. The subjecthad to overtly name the target's category. Speech utteranceswere recorded. Working at threshold SOA, where imagerecognition was successful in only about half the trials,allowed comparison between trials identical in terms of objectiveparameters  but differingin the subject's state of recognition. Our results showeda drastic recognition-associated increase in LFP parameters.The amplitude of gamma activity was highly correlated tothe state of recognition in a number of electrodes. Interestingly,the duration of these gamma power increases oftenoutlasted the image exposure duration. In other electrodesites, recognition-related changes were more prominentin the shape and amplitude of the N170 evoked potentialrecorded. These effects were only found in electrodes thatshowed a clear object selectivity. The results point to the potentialpower of intracranial recordings to uncover neuronalcorrelates of perceptual awareness.Supported by ISF grant to R. Malach and US-Israel BSF grantto Malach and Fried. When deprived of spontaneous network activity by chronicexposure to tetrodotoxin (TTX), cultured cortical and striatalneurons die over a period of one to two weeks. Priorto their death neurons retract their dendrites, lose dendriticspines yet express a two fold increase in miniature excitatorypostsynaptic currents (mEPSCs). Unlike TTX treatment,chronic blockage of glutamate receptors does not havea toxic effect of its own. Moreover, blocking the AMPA subtypeof the glutamate receptor protects TTX-silenced neuronsfrom degenerating, indicating that mEPSCs becomestoxic to chronically silenced neurons. Further investigationrevealed that chronically silenced neurons are impaired alsoin their ability to clear out calcium from the cytoplasm,which may explain their vulnerability to relatively small calciumchanges. The molecular mechanism of TTX-inducedneuronal death exhibited some apoptotic characteristics suchas the upregulation of the Bax and Bak genes, mitochondrialfission and DNA fragmentation. On the other hand, itlacked caspase-3 activation, indicating that a caspase independentform of apoptosis is activated once action potentialsare blocked. We conclude that neuronal activity is beneficialto neuronal survival only when it involves spontaneous trainsof action potential, and that in the absence of network activity,subthreshold synaptic currents are in fact toxic and mayset in motion mechanisms of programmed cell death. Tempotron learning rule [1] for a leaky integrate-and-fire(LIF) neuron provides a powerful method for learning anddecoding time- and synchrony-based neuronal code. Tempotronlearning rule is supervised, that is, the modificationof LIF input synaptic strengths is governed by the externalteaching signal which specifies the correct spiking behaviorfor each given input. However, in biological systemsthe learning of temporal code is not necessarily supervised.In present work we design architecture and learningrules for a small LIF network capable of unsupervised(self-supervised) learning of temporal neuronal code. Thelearning rule for every LIF is based on the tempotron learningrule with additional long-term synaptic depression. Recurrentconnectivity and signaling rules provide for selfsupervisionin the network. As an example, we demonstratethe capability of this “network of tempotrons” to distinguishbetween Poisson-spiking representations of two or more differentspatio-temporal sequences with identical average spikecounts in each channel. Our objective is to develop a model of sporadic PD by selectivelysilencing genes identified in our transcriptomic andprotein profiling of human SNpc from sporadic PD brains,while enforcing the expression of others. The mouse substantianigra-derived cell-line SN4741 was employed as a modelto study the involvement of the identified proteins intimatelyconnected to the neurotoxic cascade  and the response to cell injury induced bythe dopaminergic neurotoxin MPP+, serum deprivation andH2O2. SN4741 cells were infected with small-hairpin RNA(shRNA)-encoding lentiviruses targeting the selected transcriptsor with nontarget shRNA control (scramble). Thepercentage of silencing was evaluated using real-time PCRand Western blot analysis with specific antibodies. Parametersof cell survival were assessed. Alterations in cell cyclewere analyzed by flow cytometry. MPP+ andH2O2 induced atime and dose-dependent alteration in the protein expressionof the oxygen and iron-regulated proteins transferrin receptorand prolyl hydroxylase (PHD2/EGLN1) and decreases inSKP1A, HSC-70 and ALDH1A. ShRNA-mediated silencingof Skp1A, a component of the SCF ubiquitin (E3) ligase complex,showed a significant delay in completion of the cell cycleand an increased susceptibility to MPP+ and serum starvation.The approach to develop an “ultimate model” of PD bysilencing or over expressing single genes that were identifiedasmutated in the familial cases has notmet with the expectedsuccess. We have reproduced to a significant extent the geneand protein alterations initially described in our studies withSNpc from Parkinsonian subjects, in a dopaminergic cell linefrom mice SNpc. The successful results obtained with thepresent study will help us to develop an experimental micemodel of sporadic PD based on viral-mediated RNAi deliverywhich will be of help for developing novel neuroprotectivedrugs with possible disease modifying activity. The NMDA-type of glutamate receptors play major roles inexcitatory neurotransmission, synaptic plasticity and memoryformation. Data from several laboratories have shownthat the unusual D-amino acid, D-serine, is a physiologicalregulator of NMDA receptors by binding to the “glycine site”at the NR1 subunit. Brain D-serine is synthesized from Lserineby the serine racemase enzyme. Serine racemase wasshown to be expressed in astrocytes and recently demonstratedin neurons as well, but little is known on its regulation.We now explored mechanisms regulating serineracemase enzyme and D-serine synthesis in the brain. Despitethe fact that serine racemase lacks transmembrane domains,a significant portion of the enzyme is tightly boundto detergent-resistant membranes from brain. Immunocytochemicalexperiments revealed highest levels of membraneboundserine racemase at the plasma membrane of neuronalprocesses. We found that membrane association of serineracemase is mediated by palmitoylation, which leads to almostcomplete inactivation of the enzyme. Treatment of primarycultures with NMDA increased several fold the levelsof membrane-bound serine racemase by enhancing thepalmitoylation of the serine racemase enzyme. Our data indicatesthat NMDA receptor activation promotes feedbackinhibition of serine racemase to downregulate D-serine levels.Palmitoylation of serine racemase provides a novel mechanismregulating D-serine synthesis, with implications forNMDA receptor transmission. Cannabinoid  receptors are activated by delta-9-tetrahydrocannabinol (THC), the major biologically activeingredient of the Cannabis sativa plant, or by endogenous(endo)cannabinoids such as anandamide and 2-arachidonoyl glycerol (2AG). The“endocannabinoids” andtheir synthesizing and degrading enzymes as well as theCB receptors form the“endocannabinoid” system (ECS)which appears to be an important regulator of many(neuro)physiological functions including feeding, appetite,motor functions and inflammation. The ECS has also beenshown to play an essential role in several developmentalfunctions. Thus high levels of anandamide degradation enableuterine implantation of the embryo. Further it has beenshown that the endocannabinoids and their receptors play afundamental role in axon guidance and synaptogenesis duringmid gestation. During postnatal life, CB1 receptor activationin the newborn is essential for the initiation of milksuckling. Thus we have shown that two different CB1 receptorantagonists (SR141716 and VCHSR1) impair mouse pupdevelopment and suckling, when administered within 24 hof birth. Further, intracerebral injections of SR141716 alsoimpair pup development but only if injected at the base ofthe brain, suggesting a role for hypothalamic or basal gangliareceptor activation in pup suckling. Finally, prenatal marihuana,THC or anandamide exposure have been shown toaffectmidgestational weight and the development of the prefrontalcortex, dopamine system and CB1 receptors in themature offspring. In conclusion, the ECS fulfills many physiologicalfunctions in the mature organism. However, only atseveral junctions during development, seems the ECS to playa critical role. Therefore, the repercussions of pre- or postnatalexposure to (endo)cannabinoids should be studied moreextensively. The role of fixational eye-movements (FeyeMs), which arecomposed of drifts, tremors and microsaccades (MSs), in visualperception is controversial. There is a long-standing debateabout MSs whether they contribute to vision. A recentdebate is whether MSs and the so-called saccadic-intrusions(SI) are different names to the same phenomenon. We haverecorded systematically FeyeM at high resolution from 4naїve human subjects under various conditions. We reporthere that (i) in all subjects spontaneous MSs are primarily inthe horizontal plane ; (ii) voluntary saccadesare often accompanied by an overshooting component whichis larger in the horizontal direction. This overshooting componentis independent of the size and duration of the saccade,but has the same size and duration distributions as thespontaneous MSs, and thus might be generated by the samemechanism generating spontaneous MSs; (iii) moving elementsin the background reduce the amount of spontaneousMSs, in a direction specificmanner, suggesting thatMSs havea role in vision thatmight be related to the sensed image; (iv)the kinematics of MSs and SIs are similar. These results supportthe claim that while a single MS changes the position ofthe eye, SI is composed of a sequence of two or more MSswhich eventually return the eye to the original position. This work was supported by the German Federal MinistryofEducation and Research, Israeli Ministry of Science and TechnologyFoundation. P <.01. Performance in females is improvedby treatment with the membrane activated chelators (MACs)DP-109 and DP-460, resulting in significant learning within3days (P < .01). P-tau immunoreactivity in female mice,following treatment with MACs, was significantly reducedin the same areas that GFAP staining was reduced. Synaptophysinstaining was increased, indicating increased synapticdensities, particularly in the cingulate cortex of females(P < .05) in response to treatment, possibly explaining theimprovement inMWMbehavior. Our data suggest that ameliorationof cognitive deficits in aged 3xTgAD mice treatedwith MACs is associated with a multifaceted effect of MACson the pathologies characteristic of AD, that is, reducing thetoxic ABeta species, inhibition of astrocyte activation and tauhyperphosphorylation.Transition metals such as zinc and copper contribute to thepathologies inherent in Alzheimer's disease (AD). This includesnot only zinc-dependent amyloid-beta aggregationand precipitation but also astrocyte activation, release of inflammatorycytokines and tau hyperphosphorylation. Treatmentwith lipophilic chelators  has been shown to reduce theplaque load and level of insoluble ABeta. Lee et al. haveshown  in Tg2576 mice that synapticzinc is gender dependent, being greater in females, andis correlated with significantly higher levels of ABeta plaquesand insoluble ABeta. 18-month-old 3xTgAD mice that expressmutations in presenilin-1, APP and tau, demonstratesevere memory deficits when tested in the Morris water maze(MWM). We have found that female 18 month-old 3xTgADmice have greater deficits than do males, never achieving asignificant improvement in performance over an 8-day period.This correlates with higher levels, in females, of p-tau-2.8-fold on immunoblots from cortical extracts and higherastrocyte activation (GFAP immunostaining) than do similarlyaged males,JEF, YD, and AK are employees of D-Pharm. Perhaps the most severe constraint on the nature of neuralrepresentation is the multiplicity and wide range oftimescales that are characteristic of processes underlyingneuronal excitability and synaptic communication. Wesuggest that under this constraint, the order in whichneurons are recruited following a stimulus is an invariant,information-carrying statistic of response features. Wedemonstrate experimentally that in spontaneously formednetworks of cortical neurons in vitro, the information thatthe response carries about the stimulation source is preservedwhen precise times to first-spikes are reduced to recruitmentorder. We looked into the nature of order coding by consideringits dependence upon precise firing times of individualneurons and correlations between pairs of neurons. The parasitoid wasp A. compressa manipulates cockroachesto serve as live food supply for its offspring. To do so, thewasp injects a venom cocktail specifically into two ganglialocated in the head of the cockroach prey. This sting evokestwo unique behavioral effects on the stung cockroach: first,the cockroach grooms spontaneously and excessively for 30minutes. Second, the cockroach enters a long-lasting hypokineticstate during which it does not initiate spontaneous locomotionand is less responsive to aversive stimuli. The goalof the present study was to identify which of the two cockroachhead ganglia, namely the supra- and subesophagealganglia, is responsible for which of the two venom effects.To achieve this goal we manually injected crude venom into either ganglion  and quantified the behavioral outcomein an open-field arena. Venom injected directly intothe supraesophageal ganglion significantly increased spontaneousgrooming and general locomotion without affectingresponsiveness to aversive stimuli. In contrast, venom injecteddirectly into the subesophageal ganglion significantlydecreased general locomotion and responsiveness to aversivestimuli but did not initiate grooming. We therefore concludethat the two distinct venom-induced behavioral effects observedin cockroaches stung by A. compressa can be traced,at least in part, to specific ganglia in the cockroach head. Ourresults suggest that the venom induces excessive groomingby manipulating neuronal circuits in the supra-esophagealganglion and the hypokinetic state by manipulating neuronalcircuits in the subesophageal ganglion. Standard short term synaptic plasticity models  predict that higher probability of releasewill entail more rapid adaptation. In layer 4 of thesomatosensory cortex adaptation is believed to result fromshort term synaptic depression of thalamocortical synapses.We observed in vivo that both excitatory and inhibitory inputs(estimated using intracellular recordings) evoked bystrong whisker stimulation adaptmore than the input evokedby weaker stimulation. Assuming that stronger whisker stimuliincrease presynaptic firing rate and are associated withhigher probability of release in the synapses of the sensorypathway, these results cannot be explained by synaptic depressionmechanisms. In an attempt to explain this observationwe recorded from single units in the ventro posteriormedial thalamic nucleus (VPM) and applied the same stimuli.Although VPM firing adapted profoundly less than corticalsynaptic inputs, PSTH of VPM cells showed similar stimulusstrength dependent adaptation rate providing an explanationto the results observed in the cortex. This, nevertheless,raised the question of how the phenomenon occurs inthe VPM. Next we investigated a possible role for the reticularthalamic nucleus (RT), which provides feedback inhibitionto VPM cells, in the observed stimulus strength dependentadaptation rate. Paired recordings of single VPM unitsand multiunit activity in the RT before and after electrolyticlesion of the RT show that the RT plays a major role in shapingthe adaptation of VPM cells as previously shown . The ability to extinguish emotional responses in the face ofa no-longer relevant conditioned cue is an essential part ofa healthy emotional memory system. Despite the efficacy ofbehavior therapy for anxiety disorders, extinction-like treatmentsrequire repeated cue exposures and are vulnerable toreversal by a number of environmental factors, particularlystress. The endocannabinoid system and CB1 receptors inparticular, has recently emerged as considerably importantin the regulation of emotionality and stress, and in extinctionof fear-related learning. CB1 receptors are highly expressedin the amygdala, which is known to be importantfor anxiety and emotional learning. The main purpose ofthis study is to examine the effects of exposure to a stressfulexperience on inhibitory fear avoidance extinction, andthe potential involvement of CB1 receptors in these memoryprocesses in the amygdala. We found that exposure toa stressful experience of placing rats on an elevated platformfor 30 min impaired consolidation of extinction of inhibitoryavoidance. Injecting rats with a low dose of theCB1 agonist WIN55,212-2 (0.25 mg/kg) prior to exposingthem to the stressor, resulted in intact extinction. Thus,the CB1 agonist reversed the impairing effects of the stressoron extinction learning. Importantly, we were able to localizethe blocking effect of the CB1 agonist to the amygdala;accordingly, WIN55,212-2 (6 ng/0.5 ml) reversed theimpairing effects of the stressor on extinction when microinjectedto the amygdala before placing rats on the elevatedplatform. These results may support a wide therapeuticapplication of cannabinoids in the facilitation of extinctiontherapy that is often accompanied by stressful lifeevents. μm deep in the tissue. We find that the spatiotemporalpattern of activation was critically dependent on the natureof the stimulation delivered.One of the major challenges in studying the function of sensorycircuits is to understand how the representation of complex,natural stimuli arises fromthe basic response propertiesof neurons. Rodents in their natural environment use theirwhiskers to distinguish between surfaces having subtly differenttextures and shapes. They do so by actively sweeping theirwhiskers across surfaces in a rhythmic forward and backwardmotion. While it is widely accepted that the brain “reconstructs”these complex sensory stimuli from the informationcontained in the concerted activity of ensembles of neurons,the nature and mechanisms underlying this sensory informationprocessing remains largely unknown. To determinethe role of neuronal interaction in coding of tactile informationwe employed two-photon laser ScanningMicroscopyin combination with loading of the cortex with membranepermeable calcium sensitive indicators (AM dyes) which isloaded in a large fraction of the neurons in the layer 2/3 network.This new method enabled us to simultaneously measurefrom many cells in the activated network. Upon effectivetactile stimulation the electrical activity of neurons inthe network were monitored via the calcium signal evokedby the action potentials. To measure from large number ofneurons and yet keeping good temporal resolution we developeda new scanning methods that scans a random line scanpath that was defined a priori by the user. We have been ableto record calcium transient signals from tens of neurons upto 400  Experimental recordings have demonstrated that neurons inthe primary visual cortex are able to learn to express temporalintervals as a function of reward timing . The form of this expression is a stimulus evokedperiod of transient activity that persists until the expectedreward time. It is not known how biological networks areable to learn temporal representations with time scales thatare orders of magnitude larger than the intrinsic excitabilitytime constants of individual neurons. We have previouslydeveloped a synaptic plasticity rule that allows a networkwith recurrent lateral connections to learn synaptic weightssufficient to set network decay times that correspond withtrained temporal intervals by expressing novel plasticity eligibilitytraces, called protoweights, as permanent lateral recurrentsynaptic weights. We demonstrate that our rule is ableto encode multiple intervals in both deterministic networksof passive integrator neurons and noisy stochastic networksof nonlinear integrate and fire neurons. An extension to nonorthogonal inputs is examined. Synaptic expression in ourmodel is modulated by an external reward signal that is inhibitedby activity at the network or single neuron level, thisdistinction has implications for possible biological mechanismsand possible consequences under different experimentalconditions. We examine the temporal structure of bothnoise and stimulus evoked correlations, in order to make experimentallytestable predictions for key elements of our encodingand learning paradigms. Cockroaches stung in the brain by the parasitoid wasp Ampulexcompressa enter a long-lasting hypokinetic state. Thisstate is characterized by decreased responsiveness to aversivestimuli, suggesting a manipulation of a neuromodulatorysystem in the cockroach brain. A likely candidate is theopioid system, which is known to affect responsiveness tostimuli in insects. The aim of the present study was to explorethis possibility. To achieve this goal we injected differentopioid-receptor antagonists  to cockroachesprior to stinging by A. compressa. We then tested the responsivenessof these cockroaches to electric foot shocks in ashuttle box. All opioid-receptor antagonists significantly decreasedthe avoidance threshold of stung cockroaches to footshocks. The most profound effect, however, was achievedwith the kappa-specific antagonist Nor-BNI. These resultssuggest that the venom of A. compressa might manipulateresponsiveness in stung cockroaches by affecting the opioidsystem predominantly via kappa-opioid receptors. If true, toour knowledge, this would be the first evidence of a behavioralmanipulation of one insect by another mediated via theopioid system. BL-1020 is a novel compound composed of the dopamine-2 (D2) antagonist Perphenazine and the inhibitory neurotransmitterGABA (gamma-amino-butyric acid), indicatedfor the treatment of schizophrenia. Preclinical studies showthat BL-1020 delivers GABA to the brain, increases corticaldopamine, binds to GABA-A receptors and effectively reducespsychotic behavior with significantly fewer side effectsthan Perphenazine. A single dose escalating, double blind,placebo controlled Phase 1 trial, in 48 healthy volunteersindicated that BL-1020 is safe, well tolerated with a widetherapeutic window, an MTD phase IIa, 6 weeks, study inschizophrenic patients is ongoing.n = 4)that received a single oral administration of BL-1020 . PET scans were done at baseline, 6 hours, and24 hours post dosing. The volunteers were also monitored forsafety, PK and changes in plasma prolactin levels.A PET study to assess the degree of D2 receptor occupancyin the human brain was conducted in healthy male volunteers,following administration of BL-1020, using [11C]raclopride as PET tracer. The trial ,consisted of 12 healthy volunteers  resulted in occupancy of 50% at 6 hours.PK modeling suggests that this dose is sufficient to obtain D2occupancy greater than 70% in a multiple dosing scenario,and thus should be within the therapeutic window. Therewas a linear correlation between plasma prolactin levels andestimated striatal D2 occupancy. There were no significantchanges in ECG, vital signs, physical examination or laboratoryvalues.These results are consistent with BL-1020 product profile ofa safe, well tolerated, and provide the opportunity to test thehypothesis that GABA-enhanced D2 blockade may offer enhancedantipsychotic activity with minimal side effects.This work has been supported by BioLinRx. The process that leads to the moment of free recollectionis still a major puzzle in human memory research. We directlyinvestigated the involvement of the medial temporallobe (MTL) in this process by recording from single neuronsin neurosurgical epilepsy patients while they were watchingshort movie clips and later were freely recalling them. Patientsprovided written informed consent to participate inthe experiment and the study conformed to the guidelinesof the Medical Institutional Review Board at UCLA. Eachrecording session was composed of two parts. In the firstpart, (viewing session) patients were exposed to a sequenceof short (5–10 seconds) audio-visual clips with well knowncontent such as famous movie scenes, people, locations orevents. Each clip was presented 6 times in a pseudo-randomorder. Interleaved blanks of 0–5 seconds were used after eachclip. A typical session contained 10–16 different clips andlasted about 10min. In the second part of the experiment, following a short (1–5 minutes) break,patients were asked to name the clips they remembered regardlessof order. Performance on this task was 90.7% onaverage. Recordings were obtained from 332 MTL single ormultiunits in 16 recording sessions with 9 patients. Of these,30 neurons (9%) exhibited strikingly selective firing in responseto a specific clip, which persists throughout clip durationas long as 10 seconds and even following clip offset.Importantly, we found that verbal reports of memories ofthese specific clips at the time of free recall were precededand accompanied by highly selective firing of these sameneurons. This phenomenon was manifested mainly in hippocampusand entorhinal cortex neurons and rarely in otherMTL structures. These results suggest that a subset of neuronsin MTL participates in both perceiving and retrievingof specific items, and hint to a possible role of these neuronsin initiating the process of recollection.NINDS grant to I. Fried ISF to R. Malach Binational US-Isrealgrant to R. Malach and I. Fried. Exposing humans to several specific steroidal compounds inducescompounds induces pheromonal like responses, suchas alterations in mood, hormonal state, and psychophysiology.However, it is not yet clear whether these compoundsaffect through chemical sensing or through alternative pharmacologicalroutes such as transdermal diffusion. In orderto address this, we set out to replicate previous experiments,but here include a group of anosmic (without a sense ofsmell) women. We hypothesized that if the effect is throughtransduction in the main olfactory system, then these womenshould not show the effects. The putative pheromone 4, 16-Androstadiene (AND) or placebo (yeast) were sniffed 10times at the beginning of a ∼2 hour recording session wherewe measured psychophysiological parameters , mood , and salivaryhormones (testosterone and cortisol), while subjects viewedmood-inducing video clips. To date, 3 subjects have beenstudied. Consistent with previous reports, this experimentalarrangement modulated mood states and physiologicalarousal in the intended manner in all 3 subjects. Data froman intended cohort of 30 subjects will be presented. Electroconvulsive therapy (ECT) is the most effective treatmentformajor depression. Our aim was to test whether subconvulsiveelectrical stimulation (SCES) of specific rewardrelatedbrain regions such as the prelimbic cortex (PLC)or nucleus accumbens (NAC) can induce an antidepressanteffect in a widely used rat model for depressive behavior.We have utilized a battery of behavioral tests including sucrosepreference, forced swimming test, home-cage locomotion,exploration of a novel environment and the Morriswater maze. Also, we measured the levels of brain-derivedneurotrophic factor (BDNF). We found that repeated SCEStreatment of either the NAC or the ventral PLC reversed the main behavioral deficit and the reductionof BDNF levels in the dorsal hippocampus induced byCMS, much like ECT did, but without causing cognitive sideeffects. These results suggest that SCES treatment of ventralPLC and NAC can induce an antidepressant effect similarto ECT, but without causing a cognitive deficit, implicatingthese areas in the pathophysiology of depression. Classical supervised learning algorithms  implicitly use the contribution of an inputsynapse to the firing output by changing the synaptic weightin proportion to its correlation with the output. In the biologicalcontext, however, the contribution of a specific inputto the final neuronal output might be difficult to calculateand, in particular, it might not be available as an explicit parameterfor plasticity. Here we propose a novel idea for therole of the inherent probabilistic nature of synaptic release for learning. We present an algorithm that utilizessynaptic stochasticity in order to sample the input space andto implicitly estimate the contribution of each synapse forthe “success” of the desired target output. The algorithm isbased on the positive correlation between the contributionof a synapse and the “achievement” in attaining the desiredoutput of randomly sampled input subgroups in which itparticipates  . We further examine theperformance of this learning rule in terms of memory capacityand convergence time and in terms of its robustness to ahigh variability in the synaptic weights. Finally we demonstratehow this abstract idea can simplify a complex learningtask of mapping temporal input pattern to an arbitrary outputpattern in a realistic model neuron. Microglia play a critical role in the innate immune responseof the CNS to injury and disease by removing degeneratingmyelin through phagocytosis. Phagocytosis of C3biopsonizedmyelin is mediated by complement receptor-3(CR3) and phagocytosis of nonopsonized myelin by CR3and scavenger receptor-A (SRA). Small GTPases of the Rhofamily play a central role in motile responses that involveactin and/or microtubule networks, from neurite extensionto phagocytosis. Among these, Rho, Rac and CdC42 regulateactin. C3 transferase toxin (Clostridium botulinum) that selectivelyinhibits Rho, enables studying rho-dependent signalling.Rho activates ROCK  that phosphorylatesmyosin light chain phosphatase,increasing thereby myosin II activity and the formationof stress-fibers (bundles of F-actin and myosin). In thepresent study we examined the role of Rho/ROCK signallingon myelin phagocytosis and stress-fiber formation in microglia.Rho-inhibitor C3 augmented phagocytosis of C3biopsonizedand nonopsonized myelin in microglia that expressCR3 and SRA combined and separately, suggesting thatRho down-regulates CR3 and SRA mediated myelin phagocytosis.Phagocytosis of C3bi-opsonized and nonopsonizedmyelin was further augmented by ROCK-inhibitor Y-27632,suggesting that ROCK also downregulates myelin phagocytosis.F-actin, visualized by phalloidin staining, formed anetwork of stress-fibers throughout the cytoplasm of normalmicroglia, and was further present at the perimeterof cells. F-actin fibers became disassembled in ROCK inhibitedmicroglia that further displayed many more filopodiathan normal, suggesting that Rho/ROCK signalling upregulatesstress-fibers and downregulates filopodia. Notably,filopodia engulf myelin in the course of phagocytosis. ThusRho/ROCK may downregulate myelin phagocytosis by upregulatingstress-fibers and downregulating filopodia.Supported by Israel Science Foundation 11/06. Recent neuropsychological and neuroimaging evidence suggeststhat the cerebral language system may be described asa distributed functional network, rather than the traditionalview of two localized centers. Within this network, the classicallanguage sites (Broca's andWernicke's areas) may processsuch word attributes as morphology, phonology and syntax,whereas the network of sensory-motor properties may processspecific semantic information. This sensory-motor semanticnetwork may engage various nonlinguistic areas thatare close to the related sensory or motor processors. UsingfMRI, we identified two separate centers in the sensorymotornetwork that process two aspects of word semantics,one related to motor and one to somatosensory propertiesof words. Twelve right-handed, native Hebrew speakers participatedin this study. Stimuli words were divided into differentcategories according to their semantic properties: motor,somatosensory and control . Words werepresented in category blocks and, for each word, subjectsperformed a semantic decision (is the word pleasant or unpleasant?)or a phonological decision (does the word havetwo syllables). Compared to control, the semantic processingof motor words yielded activation in left MTG and bilaterallyin the fusiform gyrus. Previous studies  found that these areas are activated when contrastingthe naming of tools with the naming of animals. Additionally,the semantic processing of somatosensory words,compared to control, yielded activation in left inferior parietallobule (ba40), an area which is part of the secondary somatosensorycortex (Eickhof 2006). By contrast, the phonologicalprocessing of the stimuli did not exhibit differentialactivations according to the semantic properties of the words.We concluded that the processing of motor and somatosensorysemantic properties of words are subserved by distinctcortical sites.This study was supported by the Levie-Edersheim-Gitter InstituteFor Functional Brain Imaging. Temporal lobe epilepsy (TLE) is the most common form ofpartial epilepsy and is associated with significant morbidity.TLE patients often show hippocampus histopathology characterizedby cell loss in the CA3 and CA1 subfields and in thedentate hilus. In experimental animals injection of the muscarinicagonist, pilocarpine, induces status epilepticus (SE),followed 2-3 weeks later by the appearance of spontaneousseizures and hippocampal damage similar to that observedin human TLE patients. Temporal lobe structures, includingthe hippocampus, are enriched with cholinergic innervationand dysfunction of the cholinergic system is well known inseveral neurological disorders. However, it is not known whatrole cholinergic dysfunctionmay have in TLE. The aim of thepresent study was to explore changes in cholinergic transmissionand their role in the pathogenesis of TLE. To thisend we have established the pilocarpine model in mice andsearched for changes in expression of key cholinergic genesduring epileptogenesis. 97 FVB/N mice were injected withpilocarpine (280–340 mg/Kg). Continuous video recordingsmade in 11 mice showed high rate of spontaneous seizures(82%) 4–8 weeks after SE. RT-PCR demonstrated increasedmRNA levels in both the synaptic (S) and readthrough (R)alternatively spliced transcripts of the ACHE gene. ACHEupregulation was noticed already at 48 hours following SEand correlated with an increase in the enzyme activity as wasshown in activity gel and Karnovski staining. Increased expressionlasted for two weeks and were found to be significantlyincreased in both the hippocampus and temporal cortex.In situ hybridizations confirmed the expression of ACHEin all regions of the hippocampus, and immunostainingsconfirmed its expression in principal pyramidal neurons,GABAergic interneurons, but only rarely in astrocytes. Theupregulation of ACHE during the latent period of epileptogenesissuggest a role for cholinergic dysfunction in epileptogenesis. 4. Maternal hypoxia at embryonic day17 (E17) failed to trigger inflammation or cell death in fetalbrain at 24 hours after hypoxia. However, maternal hypoxiadecreased in the hippocampus levels of neuronal migrationsignaling: Reelin , Disable 1 , and amyloid precursor protein 2 hours after the insult. Thesechanges persisted for 24 hours. At later times, Reelin levelsin hippocampi of newborns in the maternal hypoxia treatedgroup increased compared to controls .Full protection from maternal hypoxia effects on hippocampalReelin levels resulted from maternal pretreatment withMgSO4. In the newborn cortex, there was a higher sensitivitytoMgSO4 treatment. Taken together, the long-termneurodevelopmentaloutcome of prenatal and perinatal hypoxia maydepend on perturbation of developmental signals that affectneuronal migration.Prenatal hypoxia ischemia is a major cause of neurodevelopmentalimpairment in the newborn, associated with riskfor motor, behavioral and cognitive impaired outcomes. Wehave previously shown, in a mousemodel, thatmaternal pretreatmentwith magnesium sulfate (Mg) partially preventedthe behavioral consequences of maternal hypoxia in the adultoffspring. We now used this mouse model of maternal hypoxiato examine the immediate molecular responses of signalingpathways associated with both cell death and neurogenesis.We also characterized responses to maternal pretreatmentwith MgSOSupported by BSF Grant no. 2003166. The floor plate is one of the key organizers of the centralnervous system in vertebrates and plays important roles inboth ventral patterning and axonal guidance in the neuralThe floor plate is one of the key organizers of the centralnervous system in vertebrates and plays important roles inboth ventral patterning and axonal guidance in the neuraltube. The floor plate is induced at the ventral midline ofthe neural tube through the action of Sonic hedgehog (Shh),which in turn activates the transcription of target genes.Nato3 is a member of the basic Helix-Loop-Helix (bHLH)family of transcription factors, which regulate the specification/differentiation of specific cell lineages during neurogenesis.We found that within the developing spinal cordMNato3 and CNato3 expression is restricted to the floorplate in mouse and chick, respectively. However, the signalingpathway through which MNato3 acts is currently unknown.Here, we aimed at identifying cis control elementsand molecular mechanisms that target MNato3 expressionto the floor plate. To identify the DNA regions that directMNato3 expression to the floor plate we applied a reportergene assay in chick embryos using in ovo electroporation.Our results reveal a short genomic DNA region upstream ofMNato3, which is necessary and sufficient to derive mouseNato3 expression in the chick floor plate. We next looked forevolutionarily conserved transcription factor binding siteswithin this region, which may regulate the expression ofMNato3. In vitro studies confirmed that the putative conservedbinding sites identified in vivo and in silico are indeedfunctional, and relate MNato3 to the Shh signaling pathway.Our results provide the first linkage between MNato3 andthe signaling pathway these factors regulate, and suggest thatMNato3 may have an important role in spinal cord development. GABAergic interneurons are a diverse population with animportant role in network function. Distinct GABAergic circuitswere shown to differentially process information dynamics–4). This. This4])Supported by Marie Curie grant. Pregestational adversity impacts offspring affective behavior. To discover whether preconceptionstressmight exert its effects by altering the dam'smaternalbehavior, in turn influencing the development of offspringbehavior, we investigated the effects of cross-fosteringoffspring of preconception stressed dams to control damsand vice versa. Virgin rats were undisturbed (controls), orexposed to varied, unpredictable, stressors for 7 days, ending1 week prior to mating. Pregestational stress did not affectconception rates, duration of pregnancy, litter size, or genderratio of offspring, but offspring of stressed dams weremarginally lighter at birth as well as at 2 months, whereasfostering increased body weight. Two hundred and eightyeight offspring in 6 experimental groups were tested in a varietyof tasks to evaluate affective and social behavior. Therewere complex interactions due to influence of preconceptionstress, gender, and fostering, which suggested that preconceptionstressed mothers contribute partially to the alterationsin offspring behavior. However, some of the variancewas also explained by offspring differences—that is,even if raised by control mothers, offspring of preconceptionstressed dams showed behavioral changes.Supported by the BSF to ML and JS. A novel, comprehensive theory of the neural correlates ofconsciousness is presented. It states that two types of neuralnetworks, namely feedforward networks and Hopfield-likefeedback loops, compose three levels of consciousness: a low,unconscious processing level, amiddle, conscious perceptionlevel, and a high level, integrating consciousness. We claimthat only stable firing patterns of complexHopfield-like feedbackneural networks give rise to conscious perception. Thus,low-level feedforward networks of sensory processing do notinvolve conscious perception, whereas the high-level feedbackloops of many middle-level areas give rise to one, cohesiveconsciousness. Examples from visual and auditory systemsare presented, as well as a thorough discussion on therole of attention and subcortical areas within this framework.Several new conjectures arise from this theory and new experimentaldesigns are suggested. Amblyopia is a reduction of best-corrected visual acuitycaused by abnormal visual experience during the “critical period,”which prevents normal development of the visual perceptualfunctions, usually in one eye. The cognitive functionsare not affected, probably due to normal visual input fromthe other eye. Does abnormal binocular visual experiencelimit the development of normal visual cognition? Here wereport the case of LG, a 20-year-old male, with reduced visualacuity in both eyes, which does not result from a known opticaldeficiency and could not be corrected by spectacles. Hehas been diagnosed as congenital associative visual agnosiawith severely impaired face identification; he does not recognizevery familiar faces including his own and his parents',and has dificulies identifying distant objects. He has no otherneurological disorders, he can read, his IQ is above average,and he functions normally in any other aspect. His early andhigh-level visual areas displayed robust fMRI activation byvisual stimuli, whereas intermediate visual areas displayedprofound ihibition during visual processing. We employeda treatment of amblyopia tailored to LG, training him twice aweek, monocularly and binicularly. After sixmonths of training,a remakable improvement in all visual parameters wasnoted: Distance VA (LogMar) from 0.66 to 0.4 and 0.5 to0.46 , near VA from 0.48 to 0.36 and 0.4 to 0.32, Lateralinteractions, from 0.08  to −0.35(facilitation) and from −0.1 to −0.36. The crowding effectwas reduced from 0.233 to 0.06 and from 0.17 to 0.02. Stereopsisimproved from 30 to 20 arcsec. Very importantly, wenoticed a subjective improvement in his processing time forrecognition and the ability to identify objects and shapes requiringglobal integration. Thus, improvement of the visualfunctions may be transferred to improvement—perhaps ona slower time scale—of cognitive functions and brain areasthat were impaired.Supported by a grant from the Israel Science Foundation. www.allontherapeutics.com) in a phase II program inAlzheimer's disease.Complete deficiency of activity-dependent neuroprotectiveprotein (ADNP) is embryonic lethal, hence, the outcomeof partial ADNP deficiency was examined. ADNP+/− miceexhibited cognitive deficits, significant increases in phosphorylatedtau, tangle-like structures and neurodegenerationas compared to ADNP+/+ mice. Increased tau hyperphosphorylationis known to cause memory impairmentsin neurodegenerative diseases associated with tauopathies,including the most prevalent Alzheimer's disease. The currentstudy suggested that ADNP is an essential protein forbrain function and plays a role in normal cognitive performanceand social interactions. ADNP-deficient mice offer anideal paradigm for evaluation of cognitive enhancers. NAP(NAPVSIPQ) is a peptide derived from ADNP that interactswith microtubules and provides potent neuroprotection.NAP treatment partially ameliorated cognitive deficits andreduced tau hyperphosphorylation in the ADNP+/− mice. NAP isSupported by BSF, ISF, Lily, and Avraham Gildor Chair, AdamsSuper Center and Allon Therapeutics Inc. Common analysis of neuronal data involves averaging of activityacross many trials or events ignoring possible effectsof trial-by-trial variability. The objective of this study is toexamine representations of behavioral parameters with singletrial resolution. We simultaneously recorded, single unitactivities using 32 independently moveable microelectrodesfrom primary motor (M1) and pre-motor areas of the monkeyduring performance of “center-out” reaching movementsand during visuomotor learning. We computed the relationsbetween firing rate of single cells in single trials to severalbehavioral parameters . We found that firingrate variability of single cells could be significantly correlatedwith behavioral events, and in many cases with morethan one behavioral parameter. The correlation was highestduring movements towards the cell's preferred direction. Interestingly,the degree of correlation could change at differenttime windows and was not restricted to the time of increasedmean firing rate. Further, the trial-by-trial analysis revealedrelations that could not be observed in the averaged evokedresponse of the cell. These findings show a useful tool for observingrelations between the activities of single cells at thelevel of single trials and may explain variability in behavioralperformance. These correlates may improve inference of behavioron the basis of neural activity.Supported by BSF, J and J Fund for Innovative Science, FIF byRosetrees Trust, Abraham and Ida Baruch Foundation. Visual context plays a prominent role in every day perception.Contextual information can facilitate recognition of objectswithin scenes by providing predictions about objectsthat are most likely to appear in a specific setting, alongwith the locations that are most likely to contain objects inthe scene. Is such identity-related (semantic) and locationrelated contextual knowledge represented separatelyor jointly as a bound representation? We conducted an fMRIpriming experiment whereby semantic and spatial relationsbetween prime and target object pictures were independentlymanipulated. This method allowed us to determine whetherthe two contextual factors affect object recognition with orwithout interacting, supporting a unified versus independentrepresentations, respectively. Results revealed a semantic byspatial interaction in reaction times for target object recognition.Namely, significant semantic priming was obtainedwhen targets were positioned in expected (congruent), butnot in unexpected (incongruent) locations. fMRI resultsshowed corresponding interactive effects in brain regions associatedwith semantic processing ,visual contextual processing ,and object-related processing . Inaddition, activation in frontoparietal areas suggests that attentionand memory-related processes might also contributeto the contextual effects observed. These findings indicatethat object recognition benefits from associative representationsthat integrate information about objects' identities andtheir locations, and directly modulate activation in objectprocessingcortical regions. Such contextual schemas are usefulin maintaining a coherent and meaningful representationof the visual world, and in providing a platform from whichpredictions can be generated to facilitate perception and action. During neural crest (NC) ontogeny, an epithelial to mesenchymaltransition is necessary for cell emigration fromthe dorsal neural tube. This process is likely to involvea network of gene activites which remain largely unexplored.We demonstrate that Rho signaling, via Rock, inhibitsthe onset of NC delamination. In vivo loss-of-functionof RhoA or RhoB or of general Rho signaling by C3 transferaseenhanced NC delamination. Consistently, treatmentof neural primordia with C3 or with the Rock inhibitorY27632 both accelerated and enhanced NC emigration. Reciprocally,Rho activation by LPA inhibited the process.Next, we analyzed the responsible mechanisms. Inhibitionof Rho/Rock profoundly affected the morphology of NCcells by disrupting actin stress fibers and vinculin focal adhesions.Moreover, it stimulated a premature downregulationof N-cadherin and of cell-cell adhesions. Reciprocally,retention of stress fibers, focal adhesions and N-cadherinwere monitored upon treatment with LPA. Possible interactionsbetween Rho and the BMP-dependent pathway leadingto NC delamination were addressed. Blocking Rho orRock function rescued NC delamination in explants treatedwith noggin or with the cell-cycle inhibitor mimosine. Inthe latter case, NC cells emigrated while arrested at G1.Hence, Rho signaling negatively regulates NC delaminationthrough modification of cytoskeleton assembly and cellcelladhesions by acting downstream of BMP and of G1/Stransition. The human tendency to think spontaneously in the absenceof cognitive load is one aspect of the “self ” challenging neuroscienceresearch. This tendency was suggested to be relatedto the “default-mode” brain network, which shows increasedactivity at rest. Support for this notion stems fromstudies indicating that the medial prefrontal cortex (MPFC),a main component of this network, is associated with selfrelatedfunctioning. The current study examined a directmanipulation of MPFC, an important addition to prior researchwhich used only correlative imaging techniques. Themanipulation of MPFC in conscious participants was performedby means of deep transcranial magnetic stimulation(dTMS) administered with the H-coil, a novel TMS coil fordeep brain stimulation. The effect of a “temporary lesion” inthe MPFC was assessed using inhibitory dTMS, followed by a2-minute “rest” period. This “lesion” was expected to attenuate“default-mode” activity during rest, resulting in an alteredsense of “self ” and induced sense of dissociation. Fortysubjects are planned to participate in this study, which willinclude real versus sham dTMS conditions and “rest” versus“no-rest” conditions. Here we present preliminary resultsobtained from the first ten participants, five in the “dTMS +rest” condition and five in the “dTMS + no-rest” condition.Senses of self and of dissociation were examined using situationalself-awareness questionnaires and a situational senseof dissociation questionnaire. Results show that whereas subjectsin the “dTMS + no-rest” condition did not experiencea noticeable change, subjects in the “dTMS + rest” experienceda dissociative sensation, accompanied by alterations inthe level of self-awareness. Subjects' free reporting supportthis data, and include describing a temporary feeling of detachmentand numbness. These preliminary results supportthe notion that MPFC activity during rest might be significantfor an integrative, on-going sense of self in humans.This study was supported by the Adams Super-Center for Brain Studies, Tel-Aviv University, Israel. In many natural tasks auditory systems must satisfy twoseemingly conflicting requirements: on one hand, informationprocessing often relies on exquisite sensitivity to finetemporal features of the incoming signal. On the other hand,the overall time scale of these input signals can be subjectto substantial variability. For instance in speech, variationsin speaking rate can readily introduce a time warp rangingfrom two fold compression to two fold dilation. Howdoes the neural system overcome this challenge? To addressthis question we study a neural model of spike-based learningof an auditory discrimination task, extending our recenttempotron model. In our present model, synaptic inputs aremodeled as conductances rather than current pulses. In theconductance-based tempotron the time scale of the voltagedynamics strongly depends on the total synaptic conductancerather than being a fixed parameter. As a result, thestatistics of inputs as well as the synaptic learning rule, interactwith the time scale of neural information processing bychanging the effective integration time constant of the cell.Importantly, since the effective membrane time constant ofthe neuron scales inversely with its total conductance, theneuron exhibits a high degree of time warp invariance. Wehave applied our model to speech recognition problems. Usinga simple model of the auditory periphery, sound signalsare converted into spike patterns by thresholding theirpower-spectral densities, and fed into a small populationof conductance-based Integrate and Fire neurons. Surprisingly,using our tempotron learning rule, the system achievednearly perfect word recognition accuracy on a standardizeddigit recognition task. Our results show that simple biologicallyplausible mechanisms of spatio-temporal integrationand synaptic plasticity, can endow the neural system withpowerful time warp invariant auditory processing capabilities.Supported by Minerva Foundation, ISF (Center of Excellenceno. 8006/00), MAFAT. Research on multisensory integration has expanded rapidlyin recent years attracting scientists from a variety of fields includingpsychophysics, MRI, robotics and single cell studies.In my presentation I will highlight the potential of the barnowl as a unique animal model for research on visual auditoryintegration. Barn owls are highly efficient nocturnal predatorsthat have evolved precise and sensitive visual and auditorysystems. Barn owls operate in noisy and dim lightedenvironments, environments where the benefit of merginginformation from different modalities is substantial. Thus,the ability to integrate visual and auditory signals may becritical to the survival of this species. I will describe recent resultsfrom my lab on the properties of multisensory neuronsin the forebrain and midbrain of the barn owl and will comparethese findings with results obtained from cats .This work was supported by an ISF BIKURA grant. Octopuses depend on the high flexibility of their arms tocarry their arms to carry out a large variety of task like hunting,swimming and mating. Thus far only the motor primitivereaching for a target movement has been shown to be visuallyguided. Other movements that do utilize the high flexibilityof the arms, like those used for searching and probing,have been hypothesized to be largely autonomous and not directlycontrolled by the central nervous system. We designeda behavioral task allowing us to define a relationship betweenthe CNS and the peripheral nervous system that enables directedarm movement. Eye-arm coordination was tested usinga transparent Plexiglas maze. 9 adult Octopus vulgariswere trained to insert a single arm through a tube for a foodreward. Initially, food was presented inside a tube for severaldays, and animals learned to reach in to collect a foodreward. Next, the transparent three armed maze was introducedfully baited. These introductory phases accustomedthe subjects to reach through a tube, out of the water andinto a goal box in order to retrieve food. In the experimentalphase a food reward was placed in only one of the three compartmentsthat was visually cued, octopuses were required toguide their arms towards the rewarded compartment. Criteriafor successful learning were the completion of 5 correcttrials in a row. 6 of the 9 animals completed the experiment,reaching criterion within 22 to 208 trials. After criterionwas reached 20 control trials were preformed usingan opaque maze. During control trials the animals' performancesfell back to chance level. This study is the first behavioraltest showing that octopuses can learn to visually controlarm movements that are not restricted to the control of fewdegrees of freedom (like reaching). Our findings suggest thatoctopuses are capable of central control of arm movementsand perhaps cross reference between different sensory inputsand motor outputs. Lithium has been the standard pharmacological treatmentfor bipolar disorder over the last 50 years, however themolecular targets through which lithium exerts its therapeuticeffects are still not defined. Inhibition of the activity ofthe enzyme inositolmonophosphatase by therapeutically relevantlithium concentrations raised the possibility that thisenzyme is the primary target of this drug. Mammalian inositolmonophosphatase is coded by two genes, IMPA1 andIMPA2. IMPase activity levels were found to be reduced (upto 65% in hippocampus) however inositol levels were notfound to be altered and animals survived during two weekson inositol deficiency food. We characterized the behavioralphenotype of mice with a knockout IMPA1 gene (IMPA1−/−) to study the in vivo physiological functions of IMPA1, ingeneral, and more specifically its potential role as a moleculartarget in mediating lithium-dependent physiological effects.In brains of adult IMPA1−/− mice Behavioral analysis ofthe IMPA1−/− mice indicated an increased motor activity inthe open-field test, the forced-swim test and the tail suspensiontest. In conclusion the IMPA1−/− mouse indicates thatgenetic inactivation of IMPA1 can mimic some actions oflithium. The dI1, dI2, and dI3 classes of interneurons originate atthe dorsal spinal cord, from a group of progenitors definedby the expression of bHLH transcription factors: Math1,Ngn1+Ngn2, and Mash1, respectively. The expression of thebHLH transcription factors is followed by the expression ofLim-HD transcription factors Lhx2 + Lhx9, Lim1 and Isl1,respectively. In all postmitotic dI neurons sequential activationof other transcription factors leads to the expression ofreceptors for floor plate derived guidance molecules  which enable the commissural interneuron toreach the floor plate. Ectopic expression in the chick neuraltube was used in order to investigate the role of differenttranscription factors in the determination of dI neuronsand the segregation of dI neurons to different dI subclass. Wefound that a bHLH gene, NSCL1 transiently induce expressionof the commissural neuron receptors TAG1 and Rig1but does not induce the expression of Lim-HD proteins. Ectopicexpression also demonstrated corepression between thelim-homeodomain proteins: Lhx9 inhibits the expression ofLim1 and Isl1, Lim1 inhibits the expression of Lhx2/9 andIsl1 inhibits the expression of Lhx2\9 and Lim1. Thus, twoparallel differentiation pathways may regulate commissuralinterneuron fate. The initial commissural axonal trajectorymight be governed by the activation of TAG1/Rig-1/DCC expressionby the bHLH proteinNSCL1. Subsequently, subtypespecification is determined by the expression of Lim-HDproteins. Microglia play a critical role in the innate immune responseof the CNS to injury and disease by removing, throughphagocytosis, tissue debris (degenerating myelin in injuryand demyelinating diseases) and pathogens (yeast). Phagocytosisof C3bi-opsonized myelin is mediated by ComplementReceptor-3 (CR3) and phagocytosis of nonopsonizedmyelin by CR3 and Scavenger Receptor-A (SRA). Phagocytosisof C3bi-opsonized Zymosan (yeast derived particle) ismediated by CR3, and phagocytosis of nonopsonized Zymosanby Dectin-1 (beta-glucan receptor) and mannose receptor. The protein tyrosinekinase spleen tyrosine kinase (Syk) is critical for immuneresponses. In the present study, we tested the role of Sykin regulating phagocytosis of myelin and Zymosan in microglia.Syk inhibitors, Syk-Inhibitor and R406, augmentedphagocytosis of C3bi-opsonized and nonopsonizedmyelin inmicroglia expressing CR3 and SRA combined or separately.Syk thus downregulates phagocytosis of C3bi-opsonized andnonopsonized myelin by CR3 and SRA. Syk-Inhibitor didnot modulate phagocytosis of C3bi-opsonized Zymosan butinhibited phagocytosis of nonopsonized Zymosan. Syk thusupregulates Dectin-1 and/or MR mediated phagocytosis ofnonopsonized Zymosan and down-regulates CR3 mediatedphagocytosis of C3bi-opsonized Zymosan. Syk-Inhibitor inhibitedphagocytosis of C3bi-opsonized and nonopsonizedZymosan in microglia lacking CR3, thus no CR3 mediatedphagocytosis, supporting the suggestion that Syk upregulatesDectin-1 and/or MR mediated phagocytosis of nonopsonizedZymosan. Syk-Inhibitor augmented phagocytosis ofC3bi-opsonized Zymosan in HL60 cell line that express CR3but neither Dectin-1 nor MR, thus CR3 mediated phagocytosisonly, supporting the suggestion that Syk downregulatesCR3 mediated phagocytosis of nonopsonized Zymosan.Thus altogether, Syk downregulates CR3 and SRA mediatedphagocytosis and upregulates Dectin-1 and/or MR mediatedphagocytosis.Supported by Nider Sachsen Israeli Cooperation. In order to study a sensory system, one needs to quantify theresponse to stimuli that vary systematically. Whereas in visionand audition one can vary the stimuli by wavelength andfrequency, respectively, there is no equivalent metric in olfaction,and the rules linking neural responses to odorant featuresremain unknown. Several studies have linked responsepatterns to restricted odorant features, such as number ofcarbons, and type/position of functional group. These metrics,however, fail to account for response patterns to odorantsvarying along other structural dimensions. To generatea multidimensional odor metric, we obtained 1664 molecularodorant features, and generated a metric where eachmolecule was represented as a vector of descriptor values. Revisitingnumerous studies, we found that this novel olfactorymetric was always better at accounting for neural responsesthan the specificmetric used in each study. Critically, this singlemetric was equally applicable across studies in differentanimals, and olfactory neurons that used odorants varyingalong different feature types and different neuronal responsemeasurement methods, where it explained previous anomaliesin odorant response profiles. Thus, we propose an olfactorymetric that provides a unified account of independentlyobtained results, and offers a quantitative measure for odorantcomparison. Finally, we recommend on sets of odorantsthat are best in terms of spanning the physicochemical spacefor use in olfactory neuronal response experiments. Integration of neurons with microelectronic devices has beena subject of intense studies over the last decade. One of themajor problems in assembling efficient neuroelectronic hybridsystems is the weak electrical coupling between the components.This is mainly due to the fundamental property ofliving cells to form and maintain an extracellular cleft betweenthe plasma membrane and any substrate to which theyadhere. This cleft shunts the current generated by the neuronand the device and thus reduces the signal-to-noise ratio. Increasingthe seal resistance formed between the neurons andthe gate surface is thus a challenge which could improve thecoupling coefficient. Here we report a new approach to improvethe physical and electrical coupling between neuronsand the surface of electronic chip by harnessing a basic propertyof cells namely, the internalization of particles by phagocytosis.To that end we fabricate gold micro-structures in theform of dendritic spines that protrude from the transistorgate surface . The protruding structureswere functionalized by poly-l-lysine. Using on line confocalmicroscope imaging of neurons expressing GFP-actin we observedthat cultured Aplysia neurons readily engulf the goldspinesforming tight physical contact between the cells andthe surface of the device. Electron micrographs of the contactarea confirm that the plasma membrane of the neuronsengulfs the gold-spines and that the gap formed between theplasma membrane and the artificial spine is 30—70 nm. Measurementsof the extracellular field potentials by passive goldspines indicate that the neuron-gold spine junction may improvethe electrical coupling of neuro electronic hybrids significantly. Primary insomnia (PI) is the difficulty initiating and/ormaintaining sleep, or experiencing nonrestorative sleep inthe absence of another sleep disorder, psychiatric or physicalcause. The hyperarousal hypothesis is the leading theoryfor the aetiology of PI. The model poses that due to cognitiveand physiological hyperarousal, individuals with PI failto experience the full deactivation of sensory and cognitiveprocessing which normally occurs during sleep. A potentialimplication of this hypothesis is that processing of informationduring sleep would differ between people with PI andhealthy sleepers. In this study we tested whether participantswith PI exhibit impaired gating of external sensory stimulationduring sleep. The markers of sensory processing includedevoked K-complexes and changes in event-related potentials(ERPs). 15 participants meeting DSM criteria for insomnia,for a minimum of six months, and 15 controls sleptin the lab for polysomnography and ERP testing. The ERPstimulus consisted of pairs of clicks . This stimuluswas presented during wake, while watching a silentmovie,and then during subsequent sleep. Polysomnography datawas staged, and blocks of stimuli that occurred during stageII were used for ERP analysis. The number of evoked K complexeswas quantified by comparing number of K complexeswithout stimuli, to an equivalent period when stimuli werepresented. Participants with insomnia had significantly increasedP300 during wake and sleep, with a smaller attenuationto the second stimulus. During sleep, both groupsshowed an equivalent amount of evoked in K complexes inresponse to stimulation. However, overall participants withinsomnia had more K complexes. These findings indicatethat PI is associated with altered gating mechanisms in bothsleep and wake, and is the first objective measure for sleepdisorder known in this population.Supported by NARSAD, APA postdoctoral fellowship, andUNCF-Merck postdoctoral fellowship. Category learning is a fundamental cognitive capacity thatenables meaningful and economical representations of objectsand events. Recent studies, both in the field of machinelearning and in the field of cognitive development, stressedthe importance of objects comparison for the process of categorylearning. We claim that although theoretically categoriescan be learned and refined by either identifying attributesshared by objects within specific categories as wellas identifying the attributes discriminating objects from differentcategories, there is a difference in the usability of thesetwo types of comparison by humans. In a recent study wecompared adults' performance with that of children in a categorylearning task. We discovered that when presented onlywith objects known to be from the same category, childrenlearned the categorization rules as well as adults. However,when presented only with objects from different categories,unlike adults, most children failed to learn the categorizationrules. This difference between learning from pairs of the sameversus different categories may explain known phenomenain cognitive development, such as the common difficulty ofyoung children in learning subordinate-level categories, andthe late emergence of expertise. We suggest that such difficultiesresults from cognitive, not perceptual, immaturity–mainly poor logico-inferential capacity for extracting informationfrom exemplars identified as belong to different categories.This study was supported by a “Center of Excellence” grant fromthe Israel Science Foundation, a grant from the US-Israel BinationalScience Foundation, anda grant by the EU under theDIRAC integrated project IST-027787. 2+ in SGCs in TG inresponse to ATP using Fluo-3 or Fura-2 as Ca2+ indicators.The effects of submandibular inflammation weretested in short term cultures (20 h), and that of axotomyin intact ganglia. In controls the threshold of SGC responseto ATP concentration was 5 microM (>20% of thecells responded), and reached maximum at 100 microM;at least 25 cells were examined at each concentration. InSGCs from treated mice the threshold for ATP effect was0.01 microM  and reachedmaximum at 10 microM. These results apply for both treatments.In this work we showed for the first time thatthe sensitivity of SGCs in TG to the inflammatory mediatorATP greatly increased after axotomy and inflammation.We conclude that SGCs are likely to be involvedin pathological changes in TG and might contribute tothe abnormal signaling that takes place in chronic painstates.Satellite glial cells (SGCs) are the main type of glial cells insensory ganglia. The morphology of these cells has been describedin detail, but little is known about the physiologicaland pharmacological properties. We have shown previouslythat SGCs in trigeminal ganglia (TG) are endowed withfunctional P2Y purinergic receptors, and the objective of thepresent work was to find out whether these receptors are alteredunder pathological states–axotomy of the infraorbitalnerve or complete Freund's adjuvant (CFA) injection in thesubmandibular region of mice. Trigeminal ganglia were removed4–7 days after treatments and were tested in vitro. Weexamined changes in intracellular CaSupported by BSF and ISF. 4 (Mg),although the exact mechanism is unknown. Our primarygoal was to find gene networks that were modulated by hypoxiaand elucidate the mechanisms involved in Mg prophylacticaction. Pregnant mice were treated i.p. at 17 daysgestation with Mg/PBS every 20minutes (4 hours) followedby 2-hour hypoxic  or normoxic conditions.The mice divided for 3 groups: SA (PBS+normoxia),SH (PBS+hypoxia) and MgH (Mg+hypoxia). Fetus cerebelliwere isolated 2 hours, 24 hours, and 20 days after insult.mRNA was extracted and gene expression was analyzedby affymetrix DNA chips (mouse 430 2.0). Mixedmodel2-Way ANOVA (Partek) was used to compare effectof treatment (SH-SA and MgH-SA). SH modified the expressionof 7, 3 and 1127 genes, at 2 h, 24 h and 20 daysafter hypoxia, respectively (at least 1.5 folds change comparedto SA group (FC) P < .05), while pretreatment withMg followed by hypoxia changed the expression of 10, 10and 832 genes at parallel times. Among the genes changed20 days after insult 74 were modified more than 2.5 FCby SH and only 15 when Mg was applied (14 appeared inboth comparisons). To identify signaling pathways modulatedby the treatments, the Gene Set Enrichment Analysiswas used. Three gene sets were modulated in at least2 time points (FDR < 0.05). Cell cycle gene set was upregulated2 h after hypoxia followed by down-regulation atlater time points. Mg induced opposite influence upregulatingcell cycle genes 24 hours and 20 days after the insult.Mitochondria gene set was downregulated at all times followedSH. Mg caused downregulation at 2 h and 20 days, incontrast to upregulation at 24 hours after the insult. Overall,prenatal hypoxia effect is most noticeable 20 days afterthe injury. Opposite change due to Mg pretreatment wasobserved in some times, suggesting interference in similarmechanism.Prenatal hypoxia is related to a variety of motor dysfunctionsand behavioral problems in the adult life. One ofthe treatments used for prenatal hypoxia is MgSOSupported by BSF Grant no. 2003166. Expertise in object recognition requires knowledge of the diagnosticvisual features of the object. The nature of the diagnosticinformation and the stage in the visual processinghierarchy at which it is utilized are still unknown. We comparedperformance and event-related potentials (ERPs) of15 car experts and 15 novices performing a category verificationtask. The objects categorized were from categorieswith which the two groups had different levels of experience and were categorized at the basicand subordinate levels. The information contained in theimages was manipulated by filtering them at different spatialfrequencies (SF). Experts and novices showed equivalentperformance for faces and airplanes. Face subordinatecategorization relied more on low SFs than on high SFs,while subordinate categorization of airplanes relied moreon high SFs. Subordinate categorization of cars, however,differed between experts and novices. Experts relied moreon high SFs than on low SFs while novices performed atchance level irrespective of SF. Electrophysiologically, N170,an early face-selective ERP component, was modulated byexpertise but this effect did not interact with SF or categorizationlevel. In the experts' left hemisphere N170 amplitudein response to cars was equivalent to N170 amplitudeto faces, both higher than to airplanes. In novicesthe N170 in response to cars was equivalent in response toairplanes, both being smaller in amplitude than the N170to faces. Our findings suggest that the diagnostic informationneeded for expert object recognition is quantitativelyand not qualitatively different from everyday objectrecognition, as similarly to airplane subordinate categorizationin novices, expert subordinate car categorization reliedon high SFs. Furthermore, the expert use of specific SFscales does not occur at the early perceptual stages reflectedby the N170 and may be related to later post-perceptualprocesses. The Attentional Blink (AB) is a well-explored phenomenonduring which a first target within a rapid sequence of stimuliis successfully detected yet a second target fails to be reported.The question whether the AB deficit is of merely visualnature or affects severalmodalities, such as auditory andtactile, has been extensively debated. Previous studies useddual task paradigms to address this question. Themain problemwith this approach is that the dual tasking effect couldnot be separated from the blink effect. In the current study,we bypassed this obstacle by registering Event-Related Potentials(ERPs) to an unattended deviant stimulus within an auditorystream while participants are engaged in a visual ABparadigm as their only behavioral task. The mismatch negativity(MMN) ERP signature of involuntary change detectionis the difference between the response to auditory standardsand deviants. Surprisingly, we find that when conditionalidentification of the second visual target fails (at lag3), the MMN significantly increases. We suggest that whenthe visual system blinks, attentional resources are freed up foruse by the auditory modality, resulting in facilitated changedetection processes as reflected in the augmented MMN response. Supported by the Israel Science Foundation and the US-IsraelBinational Science Foundation. Activation of endogenous neural stem cells (eNSCs) has beenproposed as a novel form of therapy in a variety of neurologicaldisorders, including stroke. Previous data suggest thatapplication of external factors can boost a long-termendogenousrepair mechanism. Upon activation platelets shed microparticles(PMPs) which contain a variety of growth factorsthat are central to angiogenesis and neurogenesis. Becauseinterrelations between newborn neural and endothelialcells are essential to eNSC survival, maturation and differentiationwe evaluated the effects of PMP after brain ischemia.Spontaneously hypertensive rats underwent permanentmiddlecerebral artery occlusion (PMCAO) and were given BrdUto label newborn cells. Animals were treated with vehicle orwith PMPs delivered via a biodegradable polymer appliedto the brain surface immediately following injury. Animalswere tested with a reproducible motor and sensory scorefor 90 days after PMCAO. Infarct volumes were measuredat 90 days post—PMCAO. We used immunohistochemistryto evaluate the fate of newborn cells in the ischemic brain.Newly formed blood vessels were counted in the brains toevaluate angiogenesis.Our results demonstrate a dose dependent increase in thenumber of newborn cells in animals treated with PMPs anda significant increase in the number of blood vessels observedat the infarct boundary zone. Treatment with PMPsignificantly improved behavioral deficits in a dose dependentmanner and there were no significant differences in infarctvolumes between the different treatment groups.PMPs significantly induce neurogenesis and angiogenesis afterPMCAO in a dose-dependent manner and these effectsare correlated with better functional outcome and reduceddisability in the long term after stroke despite the lack of aneuroprotective effect. This strategy can be used in subsequentstudies to further improve functional gain after braininjury.Supported by Peritz and Chantel Scheinberg. It is thought that adaptation in the barrel cortex resultsfrom short term synaptic depression of thalamocortical inputs.The probabilistic nature of synaptic transmission andits modulation by short term depression should contributeto cell-specific trial to trial variability during repetitive stimulation.Here we compared the trial to trial variability ofsubthreshold synaptic adaptation in vivo, during periodicwhisker deflection in couples of simultaneously recordedcells. Additionally, we compared the adaptation exhibited bya large population of neurons, which was detected using fastoptical imaging based on voltage sensitive dyes (VSDs), withthe adaptation of intracellularly recorded cells. Because theVSDs signal reflects primarily the average synaptic potentialsof the neuronal population, rather than spiking activity, thisallowed us to extend the comparison of adaptation of synapticinputs to the population level. Considerable trial to trialvariability in adaptation was reveled by measuring the responsivenessof the cell to repetitive stimulation. These experimentsshowed a high correlation of the adaptation betweennearby neurons recorded simultaneously as well as betweena single cell and the optically monitored large populationof responsive neurons in its vicinity. These results suggestthat adaptation of cortical neurons depends not only onshort term synaptic depression, but also on a coordinatedprocess that homogenize adaptation among nearby neuronseither at the thalamic or cortical level.This work was supported by ISF—The Charles H. Revson Foundationand the Goldsmith foundation. Hering's law of equal innervation implies that eye movementsare accomplished by two independent subsystems: onefor purely conjugate movements (version) and one for purelydisconjugate movements (vergence). Thus, in order to fixatea certain point in space, the oculomotor system does notmove each eye separately, but, rather, sends the extra-ocularmuscles a combination of version and vergence signals to directthe eyes to the sought for fixation point. Experimentsdevised to test Hering's law have indeed verified the existenceof two types of eye movement, each with its own characteristics:versional movements are either extremely fast (hundredsof degrees/sec) preprogrammed saccadic movementsor slow smooth pursuit movements, whereas vergencemovementsare slow (tens of degrees/sec) smooth eye movementsthat are evoked by retinal disparity and rely on visual feedback.The clear discrepancy between the two types of eyemovements has usually been taken as a confirmation of Hering'ssuggested law. However, more precise measurements ofeye movements have shown seeming deviations from Hering'slaw in accommodative vergence experiments. In lightof these apparent deviations from Hering's law, some researchershave completely abandoned the concept of equalinnervation to the two eyes. Others retained the basic law,but hypothesized a “holding reflex,” which needs to be addedto the other known types of eye movements. In contradistinction,we argue that Hering's law of equal innervation isactually demanded by the existence of the ancient (in evolutionaryterms) conjugate system in the visual system. Wethen explain the “deviations” from Hering's law both qualitativelyand quantitatively within the paradigm of equalinnervation using the well-known mechanism of smoothpursuit. Sounds in natural settings always appear over a noisy background,and the way the auditory system extracts soundsfrom such backgrounds is of extreme importance both theoreticallyand practically. The theory of masking of tones bynoise drove human psychoacoustic research and resulted inarguably the most important concept in hearing, that of thecritical band. In the mouse, the critical band is wide relativeto other mammals. As a result, the mouse is a useful modelfor discriminating between peripheral and central processingmechanisms in masking. We are using intracellular andextracellular recordings in vivo in mice to study neuronal responsesin the auditory cortex to tones masked by broadbandnoise or by slowly fluctuating broadband noise maskers. Themasked threshold  increases with noise level. Such results can beexplained by energy masking in the peripheral auditory system:once the signal-to-noise ratio within the critical bandcentered at the target tone frequency is high enough, thetone is detected. However, when Additional information issupplied to the auditory system by slowly modulating themasker, masking can be reduced substantially below the valuesexpected from pure energy masking.Supported by a grant from the Joint Niedersachsen–Israel program. Visual self-recognition in humans is thought to dependupon activity in a number of frontal brain regions, particularlyin the right hemisphere. Behaviourally, self-recognitiontasks elicit a number of response-related biases. For example,in previous experiments investigating hand-responsepreferences in self-face-recognition, groups of participantswho responded “self ” (or “mine”) with the left hand and“other” (or “not mine”) with the right hand, performedbetter than other groups of participants responding withthe opposite stimulus-response mapping. It was suggestedthat such hand-response differences implicated a right hemispherespecialisation for self-recognition. We report experimentsexploring an alternative hypothesis: that improvedperformance when using the left hand to respond“self ” may reflect the interaction of two different responsetendencies. Our results showed that, when uncertain aboutthe correct response, participants tended to press the leftbutton, regardless of the stimulus-response mapping, andalso tended to press the “not mine” button, reflecting a failureto recognise the stimulus. When “self ” responses weremade with the left hand, these two tendencies worked in oppositedirections, equalising the proportions of “self ” and“other” responses. When the reverse stimulus-responsemappingwas used, however, both tendencies resulted in more‘other’ than “self ” responses, decreasing self-recognition performance.In order to dissociate the neural mechanisms ofself-recognition fromthose of decision-making, we also usedslow event-related functional magnetic resonance imaging(ER-fMRI) and analysed blood-oxygenation level dependent(BOLD) activity in a number of right hemisphere regions ofinterest. It has been shown that rats use an active sensing processto discriminate offsets in horizontal (antero-posterior) locationwith their whiskers. The rats were trained to locatethe position of two objects using their whiskers alone and toassociate between the position of the objects and the positionof a reward. Our goal here is to identify motor strategiesthat underlie this association. Kinematic variables ofhead and whiskers trajectories were compared between sequentialcontacts made with the objects in each trial, in ratsthat were trained to associate (Trained) and in rats that weretrained to sense the objects but received the reward constantly(Naїve). Out of 12 variables tested, 3 showed significantchanges between sequential contacts. These variableswere whisker's angle relative to the head, head velocity, andtouch duration. These dependencies were observed in bothTrained and Naїve rats, however values differed significantlybetween the groups. We also observed that the variance of 3variables: whisker angle velocity, whisker curvature and headvelocity was significantly lower in Trained rats. Another variable,the distance between the eyes, was significantly higherin Trained rats. This parameter is highest when the headof the rat is parallel to the ground; therefore we concludethat in this task Trained rats tilt their head less than Naїverats. Our results indicate that the behavior of Trained ratsis more stereotyped than the behavior of Naїve rats. Meaningthat in order to associate between the positions of thepoles and the reward, these rats learned to control specificaspects of their behavior. Variables with reduced variancein trained rats are candidates to be controlled by the rats.The relations between these variables and more refined temporaland spatial variables which might encode spatial offsetsfor these rats during task performance will be studiednext. Epidemiological studies associate early life stress (ELS) withincreased risk to develop PTSD and depression . While most ELS animal models concentrate on theperinatal to pre-weaning period  recentstudies indicated “juvenility” in rats (∼28 days of age)as an ELS sensitive age .Sex and individual differences in novel setting explorationwere associated with trait anxiety and stress responsivenessin both humans and animals . Therefore,the current study assessed the rats' novel setting explorationas an index of stress responsiveness and evaluatedhow it affects the consequences of juvenile stress on copingwith stressful challenges in adulthood by utilizing the twoway shuttle avoidance task and Saccharine preference. Comparedwith controls, adult juvenile stressed rats exhibitedpoor avoidance learning and a lower Saccharin preferencefollowing the avoidance task; No differences in Saccharinepreference were evident prior to the avoidance task. Furthermore,“Low explorer” Controls exhibited a higher Saccharinepreference than “High explorer” Controls, while an oppositetrend was evident among adult juvenile stressed rats. Theseresults lend further support for the juvenile stress as a modelof induction of predisposition to develop mood and anxietydisorders following subsequent stress exposure in adulthood. Patients with lesions of the cerebellum are often impaired inperforming tasks involving motion perception, but the criticallocus for such lesions remains vague. In order to studythe nature of the deficit and to identify the region of thecerebellum that may be involved, we trained monkeys intasks of visual acuity, spatial attention, luminance change detection,and the detection of coherent motion in a subsetof dots moving within a random dot field. Two regions ofthe cerebellar cortex, namely, the oculomotor vermis (lobuliVI to VIII) and the dorsal paraflocculus, are likely candidates,since they receive visual inputs and hence may beinvolved in the motion perception. As a first step towardsanalyzing the critical locus we made vermal lesions includinglobulus VI through VIII in three monkeys and testedthem postoperatively on visually guided saccades and theperceptual tasks described before. All the monkeys showedthe expected saccadic dysmetria immediately after the lesion,which subsided after a few days. Two monkeys tested for visualacuity showed opposite effects, one improved postlesionand another had deteriorated visual acuity, but boththese monkeys showed preserved improvement in allocatingcovert visuo-spatial attention upon cueing. The third monkeywas tested on luminance change detection task and hadno impairment after the lesion. Overall, there were no generalvisual deficits in these monkeys after the lesion. Twoout of the three monkeys tested for coherent motion detectiontask were impaired after the lesion. The third monkeywhich did not show any deficits after the lesion had arelatively small lesion. One of the impaired monkeys neverrecovered for a particular spatial location where the effect of lesion was most profound. We concludethat the vermis plays a critical role in motion perceptionalthough other cerebellar areas might contribute aswell. Recent evidence support the hypothesis that exposure tostress or trauma during early childhood may disturb theformation of functional brain pathways, in particular, ofthe limbic circuits. Previous findings from our lab indicatethat an exposure of rats to a relatively brief stressful experienceduring juvenility (27–29 days of age) has profoundand long-lasting behavioral effects . The importance of the environmentin the regulation of brain, behavior and physiologyhas long been recognized in biological, social and medicalsciences. Animals maintained under enriched conditionshave clearly been shown to have better learning abilities thanthose maintained under standard conditions. We set out toinvestigate the long-term effects of Juvenile stress and effectsof enriched environment (EE) on the ability of animalsto cope with subsequent learning tasks and on the expressionof the cell adhesion molecule L1, suggested to beinvolved in environment-induced neuronal re-organization.Three groups were tested: Juvenile Stress–subjected to Juvenilestress; Enriched Environment–subjected to Juvenilestress and then, from day 30 on to EE; and Naїves. In adulthood,coping and stress responses were examined using theelevated plus-maze, open field, exploration and avoidancelearning. In adulthood, “juvenile” stressed rats exhibited reducedexploration in a novel setting, and poor avoidancelearning, with learned helplessness-like behaviors, while exposureto EE impede these long lasting effects of juvenilestress. Preliminary findings suggest that these where associatedalso with lasting alterations in the expression of L1.This work was supported by the EU's PROMEMORIA Grantno. 512012 to G.R-L. It has been shown that patterns of neuronal activity in motorcortices and tuning curves might change during sensorimotorlearning . In this study, we examine co-variation of responsepatterns and temporal cross-correlation to study dynamicsof interactions between cells during performance andadaptation to different visuomotor tasks. Neuronal activityfrom monkeys' motor cortices was recorded in each sessionby a multimicroelectrode array. Each recording session wascomprised of the following blocks of trials: (1) standard 8-direction center-out task (a well-known task); (2) adaptationto visuomotor-rotation; and/or (3) adaptation to arbitraryassociation(two colors associated with two different movementdirections); (4) repetition of the standard center-outtask. This poster presents patterns of correlation found inthese different behavioral states. First, we demonstrate thatcorrelation patterns between neighboring cells in M1 andPremotor cortices may change and examine if and how thesechanges are related to behavior. Pairs of cells with correlatedfiring patterns during performance of standard task, tendto change correlation strength or pattern during adaptation.This change may last during the repetition of the standardcenter-out task that ends the session. Second, the strengthand pattern correlation between pairs of cells at the beginningof the trials might imply the responsiveness of these cellsto behavioral events that follow. These results may suggestthat the cortical network can reorganize during performanceof visuomotor associations to generate correct behavior.Supported by a Center of Excellence grant (1564/04) by the IsraelScience foundation (ISF), by Bundesministerium fr Bildungund Forschung (BMBF-DIP), and by the US-Israel BinationalScience Foundation (BSF). Mated female mouse learns the individual identity of themale during the mating and critical period of 4–6 hrours afterthe mating, subsequent exposure to another mouse orto his bedding during the 3-4 following days cause pregnancyblock. This pregnancy failure is named “Bruce effect.”The neural changes underlying this associative memory tostud male occur in the accessory olfactory bulb at the firststage of sensory processing system, but it do not exclude therole of the main olfactory bulb in processing of olfactory cuesin different social relationships, including in the case of female'smemory formation to stud male. We are investigatingthe changes in both protein expression and protein posttranslation modifications induced in the olfactory bulb of femalemice by mating. We found that there is an increase inGABAAReceptor-alpha 1 subunit level in days 1, 3 aftermating,followed by a return to basal levels (control group) inday 6. These changes occur in parallel to an increase in p-ERK levels in days 1, 3 and return to basal levels in day 6.We hypothesize that these changes are part of the molecularmechanism mediating the female's memory formation tostud male. We used event-related fMRI to investigate whetherrecollection- and familiarity-based memory judgmentsare modulated by the degree of visual similarity betweenold and new art paintings. During the study phase, subjectsperformed a flower detection task, followed by a Remember/Know/New surprise memory test. The old paintingswere randomly presented with new paintings, which wereeither visually similar or visually different fromthe old items.Consistent with our prediction, subjects were significantlyfaster and more accurate to reject new, visually differentpaintings than new, visually similar ones. The proportionof false alarms, namely Remember and Know responsesto new paintings, significantly decreased with decreasedvisual similarity. Moreover, Know responses were associatedwith significantly longer latencies. The retrieval task evokedactivation within multiple visual, parietal and prefrontalregions, within which Remember responses elicited strongeractivation than Know responses. New, visually differentpaintings evoked weaker activation than new, visually similaritems in the intraparietal sulcus. Contrasting Recollectionwith Familiarity revealed activation predominantly withinthe precuneus, where the hemodynamic response elicitedby Recollection peaked earlier than the hemodynamicresponse evoked by Familiarity. Our results suggest thatsuccessful memory retrieval of complex pictures is mediatedby a distributed cortical network with differential hemodynamicprofiles during Recollection- and Familiarity-basedjudgments, and support the “mnemonic accumulator” hypothesis,according to which recognition memory decisionsare based on the integration of sensory signals.Supported by the Swiss National Science Foundation Grant3200B0-105278 and Swiss NCCR: Plasticity and Repair. P = .0504) and rs2268494 (P = .0218) as wellas in Social Value Orientations (PBAT) for SNP rs2268494(P = .0009). Notably, these two SNPs also conferred riskfor autism in our recently published study. In summary, ourlaboratory has shown association for two social neuropeptidereceptors OXTR and AVPR1a with both autism and prosocialbehavior as measured in economic games. Acknowledgements:Hebrew University BINCA grant , the IsraelNational Institute for Psychobiology (AK), theIsrael Science Foundation (GB) and Phillip Morris International(RPE)Animal models demonstrate the role of oxytocin in modulatingaffiliative behaviors. Oxytocin (OXT) is linked to maternaland psychosexual behaviors in lower mammals andpair-bond formation in prairie voles. Moreover, recent investigationsshow that OXT facilitates social cognitive abilities:for example, OXT knockout mice show deficits in socialmemory. Recent research suggests that OXT is involvedin prosocial behavior in healthy humans; intranasal OXT increasestrust, recognition of emotion in faces, and reducessocial anxiety. Importantly, three recent investigations provideconvergent evidence for association between oxytocinreceptor (OXTR) single nucleotide polymorphisms (SNPs)and autism. Our own study, shows that association withautism is mediated by acquisition of adaptive social skills.In two independent studies, we have recently demonstratedthat a related nonapeptide receptor, arginine vasopressin 1a(AVPR1a), is associated with both autism and pro-social givingbehavior in economic tasks. In the current investigation,we demonstrate that OXTR SNPs and haplotypes predictpro-social allocation of funds in two economic games,Dictator and Social Value Orientations. Using a family basedmethod, we observed preferential transmission of individualalleles in the Dictator Game (UNPHASED) for SNPsrs1042778  and a novel Identity Search task, designedto contain detected and comparable un-detectedstimuli, and a division into distinct search-fixation regions.In addition, it is easy to generate numerous displays for eithertask, and they require several seconds of search, but resultin momentary recognition. Cards in the Identity Searchtask contain a square array of scrambled mixtures of blackand white square units. Card number, array size and choiceof number of black square units are under experimenter control.Within each display, all cards are different, except fortwo pairs of identical cards. Subject task is to find one ofthese pairs, indicating the cards with mouse clicks. The entiredisplay is replaced for each trial. We compared fixationson cards belonging to the detected pair with those on theundetected pair in the same display. We find that detectedpair cards are fixated more frequently than undetected paircards, and that within the search sequence, there are fewerintervening fixations on other cards between fixations on detectedthan on undetected pair cards. These findings raise thequestion of what comes first: does observing certain cardsmore frequently and more closely lead to finding the pair, ordoes an implicit sense of the presence of a pair lead to thesefeatures and ultimately to the explicit “aha” discovery of thepair? Analysis of the break point between selective fixationson detected cards, as found for the Set game, may provide ananswer to this question.Supported by the Israel Science Foundation(ISF) and the USIsraelBinational Science Foundation(BSF). Previous studies indicate that childhood emotional traumaserves as a major predisposing factor for the emergence ofaffective disorders later in life. It is not clear thoughwhetherchildhood stressful experiences serve as a predisposing factoror perhaps they prompt the onset of the disorder itself. Methods:the current study utilized the “juvenile-stress” model toexamine its effects on anxiety indices and exploratory behaviorin the open field and elevated plus maze, as well as oncirculating corticosterone levels. These effects were evaluatedboth soon after the exposure and in adulthood, compared tocontrols. Additionally, the effects of acute corticosterone administrationon anxiety indices and exploratory behavior ofjuvenile and adult rats were also examined compared to controls.Results: soon after the exposure, juvenile stressed ratsexhibited increased levels of activity and spent more time inthe “unsafe” regions of the arenas compared with unexposedrats. A reverse pattern of effects was evident when testedin adulthood. Similar results were obtained when juvenileand adult rats were injected with corticosterone thirty minutesbefore tested. Nevertheless, in comparison with naïverats, rats that were exposed to “juvenile stress” and challengedin the open field and elevated plus maze exhibitedincreased CORT levels both soon after the exposure and inadulthood.Opposite pattern of effects was found in juvenility and inadulthood, but increased levels of CORT seems to be involvedin both. Taken together, this differential outcome maycorrespond with different age-dependent reactivity to stresshormones.This work was supported by the EU's PROMEMORIA Grantno. 512012 to GRL. Obsessive-compulsive disorder (OCD) represents one of themost common psychiatric disorders. Functional and structuralimaging studies implicate the involvement of basalganglia-thalamo-cortical circuits in the pathophysiology ofthis disorder. In patients remaining resistant to pharmacoandbehavioral therapy, ablative lesions of structures andpathways within these circuits have been shown to reverseclinical symptoms. Following the finding that high frequencystimulation (HFS) can replace lesion in the treatment ofParkinson's disease and other motor disorders, there havebeen attempts to establish HFS also for the treatment ofOCD. To date there have been several case reports on the effectsofHFS of the anterior limb of the internal capsule and ofthe ventral striatum in OCD patients, and of the subthalamicnucleus in patients with comorbid Parkinson's disease andOCD. The results of these studies are encouraging in showingthat HFS may be effective in the treatment of OCD. Yetthe variety of targeted brain areas, the inconsistency in thedemonstration of beneficial effect and the variability in thetime needed to obtain a therapeutic effect, highlight the needfor better mapping of brain regions whose stimulation mayproduce beneficial effects in OCD patients. We have recentlyaddressed this issue by assessing the effects of HFS of the subthalamicnucleus, nucleus accumbens and globus pallidus intwo rat models of OCD, the signal attenuationmodel and thequinpirolemodel. These models differ in terms of the manipulationused to induce compulsive-like behavior, the natureof the compulsive-like behavior, and the response to pharmacologicaltreatment. These differences make it more likelythat a demonstration in the two models of an anticompulsiveeffect, reflects a genuine anticompulsive effect of HFS ofthe brain region assessed, rather than being specific to someparameter of a particular model that is not necessarily relatedto the modeled disorder. The hippocampus plays an integral role in learning andmemory processes via its multiple intra and extra neuronalconnections. Hippocampal long-term potentiation (LTP) ofexcitatory synaptic transmission was extensively examinedand was proven to be accompanied by lasting modificationsof GABAergic interneurons. However, several studies suggestthat these two seemingly analogous forms of plasticitymight exhibit dissociated pharmacological sensitivity and diversesusceptibility to modulation. In the present study, weexamined the in vivo effect of a week titanic stimulation(WTS), ineffective in producing efficient LTP, to the perforantpath (PP) on GABAergic interneurons activity andplasticity in the hippocampal dentate gyrus (DG) of theanesthetized rat. Frequency-dependent inhibition (FDI), aGABA mediated feed-forward inhibition, and paired-pulseinhibition (PPI), a form of feed-back inhibition were usedto reflect the activity of GABAergic interneurons in theDG. We report here that although the application of WTSdid not induce long-lasting modifications of the populationexcitatory post-synaptic potential in the granule cellsof the dentate gyrus, it succeed to induce lasting reducebaseline inhibition as indicated by FDI and PPI. These resultsdemonstrate a potential involvement of interneuronalplasticity in conditions where electrically induced principalcells plasticity is not apparent or fails to be maintained. Current understandings of the mechanisms that underliesuccess or failure of neurons to regenerate after axotomyemphasize two classes of factors: the intrinsic capacity ofthe neuron to regenerate, and the presence of extrinsicfactors that either inhibits or support regrowth. A criticalstep in regeneration of transected axon is the transformationof the cut axonal end into a specialized compartmentwhich orchestrates in time and space the use ofcell resources for growth processes, and integrates extracellularsignals into growth patterns, target recognition andsynaptogenesis. The failure of a cut axonal end to transforminto a competent GC apparatus and it's transformationinto an endbulb (retraction bulb) was recognized asa factor which critically interferes with regeneration by thepioneering studies of Ramon y Cajal (1928). Nevertheless,whereas the mechanisms that transform the cut axonal endinto a competent GC have been investigated, the mechanismsunderlying endbulb formation and preventing regenerativeprocesses still remain elusive. In the symposium Iwill (a) describe the self-assembly mechanisms that underliethe transformation of a differentiated axon into a functionalgrowth cone after axotomy ; (b)analyze recent experimental results that relate improper restructuringof cytoskeletal elements at the cut axonal endto the failure to assemble a competent GC by neurons withhigh capacity to regenerate; finally (c), I will discuss pharmacologicaland molecular approaches to overcoming thesubcellular barriers that impede regrowth from the endbulbs. Following three days in culture, the morphology and dimensionsof cultured Aplysia neurons reach stead state (SS). Wefound that under these conditions transection of one axonalbranch is followed by its regrowth while other noninjuredbranches maintain their morphology unchanged. Twomechanisms can account for this differential regrowth: axonalinjury “label” the microtubule (MT) tracks that connectthe site of injury with the cell body. Thereby, recruitedcellular components are preferentially transported to thesite of injury. Alternatively, the recruited cellular resourcesare equally transported to all branches but are preferentially“captured” and utilized at the site of injury by a newlyformed growth cone. The termination of the preferentialgrowth process should involve timely down regulation ofthe preferential supply or the “capture” of the cellular resources.Using on line confocal imaging of the cytoskeletalelements and organelles we suggest that simple principalsgovern the phenomenon of preferential growth. Non growingneurons maintain SS dimensions by the equal rates ofmembrane retrieval and membrane fusion within any axonalsegments. Axonal transaction reduces the rate of membraneretrieval in proportion to the removed surface area ofthe distal branch(s), while the rate of transport of Golgi derivedvesicles to the site of injury remains unchanged andis proportional to the number of MT tracks leading fromthe somata to the site of injury. The anterogradely transportedvesicles fuse with the plasma membrane at the newlyformed GC. We suggest that since the rate of membrane retrievalis proportional to the surface area, while the regeneratingbranch grow to its original dimensions the rate ofmembrane retrieval increases until it equals the rate of membranesupply. At this point the regrowth processes will beterminated. Extensive evidence indicates that administration of theadrenocortical hormone corticosterone (CORT) facilitatesthe consolidation of emotional experience. Nevertheless,high release of CORT, which can occur in extreme stressfulsituation, can result in memory deficits. This suggeststhat beyond a certain level of stress, the influence of CORTon memory consolidation may switch from a facilitating effectto a deleterious effect, leading to maladaptive emotionalresponses with regards to the aversive learning experience.Nevertheless, the boundary conditions under which such aswitch can be observed are still elusive. In order to specifythese conditions, we used in mice two fear conditioningprocedures known to result in a preferential conditionedfear response either (i) to a discrete tone or (ii) to contextual cues . First, we show that increasing theintensity of footshock from a very low (0.3 mA) to a relativelyhigh (1 mA) level gradually enhances conditioned fearresponses in an adaptive manner, i.e., as a function of thetone-shock contingency. However, beyond the critical footshockintensity of 1mA, fear responses become maladaptive,i.e., independent on the conditioning procedure. Second,preliminary results indicate that under mild footshockintensity (0.5 mA), post-training intra-hippocampal infusionsof CORT dose-dependently enhance adaptive conditionedfear responses. However, beyond a critical dose maladaptiveconditioned fear responses are again observed. Finally,we also assessed whether the CORT-dependent switchfrom adaptive to maladaptive fear responses was associatedwith changes in ERK1/2 activation-related recruitment ofthe hippocampal-amygdalar circuit. Altogether, these resultsthrow light on boundary conditions of CORT-dependentnormal and pathological fear learning.This study was supported by the CNRS, the FRC, and a PICSNo. 3939. Ribosomal S6 kinase2 (RSK2) is known to take partin several signal transduction cascades including MitogenActivated Protein Kinase/Extracellular Regulated Kinase(MAPK/ERK). Following our recent observation that ERKcan serve as a coincidence detector for fast and slow neurotransmissionin the hippocampus, we analyzed the statusof RSK2 phosphorylation subsequent to application ofNMDA, dopamine, or both to preparations of mature hippocampalslices in Sprague–Dawley rats. RSK2 was indeedphosphorylated; however, in addition, the amount of RSK2protein (60%) was induced within 10min following stimulation.Moreover, the induced expression of RSK2 could bedetected in both the cell body layer and the dendrites of hippocampalCA1 cells. Pharmacological analysis showed thatRSK2 induction was MAPK ERK Kinase (MEK)-ERK independent,but mammalian Target of Rapamycin (mTOR) andtranslation dependent. We suggest that the fast kinetics ofRSK2 translation that follows physiological stimulations, togetherwith recent observations that its overexpression is vitalfor the attenuation of major signal transduction cascades,indicate an expanded physiological function of RSK2 in neurons,and sheds new light on the role of RSK2 in the Coffin–Lowry syndrome. 2+ has long been considered theprinciple challenge necessitating the impressive array of zinchomeostatic proteins present in mammalian cells. We andothers have begun to focus on another, separate pool of Zn2+,associated with zinc homeostatic proteins (ZHP) and mitochondriawhich is dynamically regulated. These proteinsbind zinc with a relatively high affinity but release it in responseto oxidative stimuli, for example, reactive oxygenspecies, hypoxia or nitric oxide (NO). By virtue of its abilityto damage mitochondria and activate apoptoptic signalingcascades, Zn2+ released in this way could play an importantrole in cell death in the developing and ischemic CNS.To establish an association between developmental cell deathand intracellular zinc (Zni), we have adopted a flow cytometrystrategy designed to analyze large numbers of developingcells from two brain regions: the olfactory bulb (OB) andcerebellum (CB). After isolating the cells in suspension, theyare loaded with a zinc-sensitive dye, Zinpyr-1, and brieflyexposed to a cell death marker, e.g., propidium iodide orAnnexin-V prior to analysis in a FACSCanto flow cytometer.Induction of Zn2+ release from metallothioneins, e.g., byaddition of a nitric oxide donor, or cell death in an identifiedneuronal population, e.g., by fetal ethanol exposure, allowsus to correlate the specific challenge to observed levels of Zniin dying or surviving cells. Through these experiments, andtogether with in vitro studies we are conducting, we hope togain insight into the role of intracellular zinc in basic physiologicalprocesses such as cell death.A rise in intracellular ZnSupported by Israel Science Foundation (572/04) WS. The concept of receptive field (RF), the set of external stimuliexternal stimuli that will significantly alter the firing patternof a neuron, is fundamental to sensory processing. WhetherRF structure and size depends on the state of wakefulness orthe physiology of the animal or not, is controversial. Corticalneurons of the somatosensory cortex (S1) of the ratrespond to several whiskers. The origin of large RF of S1neurons remains unclear. In a previous study we suggestedthat large RF emerged by cortical integration and that theRF of cells in the ventral posterior medial thalamic nucleus(VPM) are confined mostly to a single whisker. Other studiessuggested that large RF of cortical cells reflect large RFin the VPM. In particular, large RF was demonstrated underlight anesthesia or when a state of wakefulness is mimickedby stimulation of the brainstem reticular formation.In contrast, we found that under very light anesthesia RF inthe VPM is mostly confined to one whisker. Hence, varyingthe level of anesthesia does not have a significant effecton their RF size. In these experiments, however, tracheotomizedrats were artificially respirated. In self breathingrats, showing similar reflexes and fast EEG spectrum asin respirated rats, RF size was larger (2.1 ± 0.4 comparedto 1.2 ± 0.1 in respirated rats). Despite the larger thalamicRF in self breathing rats, the number of whiskers that evokeresponse falls short of the size that was reported in severalother studies. Further study is required in order to revealthe physiological factors which determine the RF of thalamiccells.This work was supported by The Israel Science FoundationGrant 1037/03. Constraining compartmental models of neurons usingstochastic algorithms has become a critical task in the studyand understanding of neuronal behaviour. We have recentlysuggested that measurements from multiple different locationsalong the dendrite and the axon facilitate in fitting aset of model parameters. However, practical data recordingsfrom L5 pyramidal rat neurons are feasible from two locationssimultaneously (soma + dendrite). Moreover, the commonsimulative model assumes axonal physiology which hasseveral erroneous assumptions such as high channels concentrationsthat try to overcome the high potential neededfor generating an action potential at the axon hillock. In orderto estimate the parameters of a compartmental model describingonly the somato dendritic section of the neuron wehave developed a progressive process that fits the data usinga parameter pealing procedure. In this procedure we assumerecorded experimental data from both the soma and dendrite.We use a voltage-clamp placed at the soma to inject thevoltage read from experimental data, and a current-clampelectrode at the dendrite to fit by the experimental data. Thismethod allows us to disregard complexities arising from axonalphysiology. In addition, in each step we constrain onlypart of the parameters thus making sure that we do not fallinto local minima. Our results show accurate parameters fitand propose a protocol for constraining a model for a segmentof a complex neuron. Intensive efforts are made to integrate EEG and fMRI data inorder to benefit both from the high temporal resolution ofthe first and from the good spatial localization of the latter.Here we propose a platform based on structural and functionalMRI, where established as well as novel estimationmethods can be applied in order to estimate the sources ofEvent Related Potentials (ERP). The extraction of anatomicaland functional constraints is accomplished by incorporationof imaging, experimental and computational tools:Both fMRI and ERP data are collected from the same subjectin similar paradigms. The cortical surface of the subjectis extracted from the structural MRI and representedas tiled triangles or linked nodes. On each node marked asactive by a relevant fMRI contrast a dipole is seeded, orientedorthogonally to the cortical mesh. An electric modelof the head is used to estimate the projection of the dipoleat each node on each scalp electrode. Based on the resultantprojection or “ lead filed” matrix, linear estimation methodssuch as Weighted Minimum Norm and Weighted MinimumLaplacian (AKA LORETA) can be applied with proper adjustmentsto surface geometry. The linear framework can begeneralized to incorporate spatiotemporal constraints andfilters, which capture richer physiological mechanisms. Theproposed platform is demonstrated on real data from a humansubject. Pheromones regulate aspects of social and sexual behaviorsthroughout the animal kingdom. In mice, pheromone detectionis mediated by the vomeronasal organ (VNO) andthe main olfactory epithelium (MOE). Male mice deficientfor TRPC2 (TRPC2−/−), an ion channel essential for VNOsensory transduction, are impaired in sex discriminationand male-male aggression. We report here that TRPC2−/−female mice show loss of sex discrimination and reductionin female-specific behavior, which includes maternalaggression and lactating behavior. Most strikingly, mutantfemales display unique characteristics of male sexual andcourtship behaviors such as mounting, pelvic thrust, solicitation,anogenital olfactory investigation, and emission ofcomplex ultrasonic vocalizations. The same behavioral phenotypeis observed after VNO surgical removal in adultanimals, and is not accompanied by disruption of the estrouscycle and sex hormone levels. These findings suggestthat VNO-mediated pheromone inputs act in wild-type femalesto repress male behavior and activate female behaviors.Moreover, they imply that functional neuronal circuitsunderlying male-specific behaviors exist in the normal femalemouse brain. Last, we have preliminary evidence thatthe neuronal switch that regulates sex-specific mating behaviormight be related to dopaminergic cell population in thehypothalamus. Thermoregulation like other sensory mechanisms developsduring a critical period. Neuroanatomically, the body temperatureis balanced by the preoptic anterior hypothalamus(PO/AH) and controlled by thermo-sensitive neurons.Thermal-input during the critical period of thermal controlestablishment causes a plastic change in the ratio betweenthermo-sensitive neurons and innate PO/AH cells andcan modulate temperature tolerance. Here we describe epigeneticchanges associated with thermal-control establishmentin chicks. During thermal conditioning  there is atransient induction in both histone H3 dimethylation at lysine9 (H3-K9) and at lysine 27 (H3-K27) in the PO/AH.The peak of dimethylation occurred at 2 h for H3-K9 andat 6 h for H3-K27. These chromatin modifications are limitedto the critical period of thermal control establishment.When chicks that had passed the critical age (10-day-old)were exposed to similar thermal treatment there were no significantchanges in histone H3 methylation. The enzymesthat catalyze these modifications, G9a and EZH2 respectivelyare induced during similar time windows. Co-localization ofH3-K27 and EZH2, during heat conditioning was verified bydouble immunofluorescence staining. Furthermore, attenuationof EZH2 expression using antisense inhibition altersthermal responses both during heat conditioning and duringheat challenge later in life. To correlate the histone covalentmodification with thermal regulation and neuronal plasticity,the feasibility of BDNF for transcription during heatconditioning was analyzed using the chromatin immunoprecipitationtechnology (ChIP). It was established that H3-K9 and H3-K27 exert different effects on the DNA-histoneproximity in the promoter area of BDNF. Taken together,these results correlate epigenetic chromatinmethylation withthermal- adaptation-related hypothalamic plasticity.Supported by ISF. Obsessive-compulsive disorder (OCD) is a common psychiatricdisorder. Functional and structural imaging studiesimplicate the basal ganglia-thalamo-cortical circuits inthe pathophysiology of this disorder. In patients remainingresistant to pharmaco- and behavioral therapy, ablative lesionswithin these circuits have been shown to reverse clinicalsymptoms. Following the finding that high frequencystimulation (HFS) can replace lesion in the treatment ofParkinson's disease and other motor disorders, there havebeen some encouraging attempts to establishHFS also for thetreatment of OCD. Yet the variety of targeted brain areas, theinconsistency in the demonstration of beneficial effect andthe variability in the time needed to obtain a therapeutic effect,highlight the need for better mapping of brain regionswhose stimulation may produce beneficial effects in OCDpatients. We are attempting to address this issue by mappingregions for HFS for the treatment of OCD, using the signalattenuation rat model of this disorder. In this model, theattenuation of an external feedback for lever-press respondingleads, in a subsequent extinction test, to excessive leverpressingthat is not accompanied by an attempt to collecta reward. This behavior, which has been named “compulsive”lever-pressing, has been shown to have face, predictiveand construct validity as a model of compulsive behavior inOCD patients. We have recently found that HFS of the subthalamicnucleus (STN) reduces compulsive lever-pressing.The present study tested the effect of HFS of the globus pallidus(GP), which is interconnected with the STN, on compulsivelever-pressing. In addition, in order to better understandthe mechanism of action of HFS, we have also testedthe effect of temporary inactivation of the GP. Adult neurogenesis is restricted to a few regions in the mammalianbrain. One of these regions is the olfactory bulb (OB),the first station in olfactory processing pathway. In the OB,newborn neurons integrate into the circuitry as fully functionallocal interneurons (INs). These INs formthe local networkof granule cells and periglomerular neurons (PGNs),both of which are thought to modulate incoming and outgoingolfactory input, respectively. However, the contributionof the newborn cells to the activity of the existing networks,if any, remains unknown. The long-term goal of this study isto reveal the functional role of PGNs within their local networks.To address this issue, we first developed an experimentalsystem to record sensory-evoked physiological activityfrom PGNs, in vivo. Here we report preliminary data ofPGNs physiological responses based on imaging of calciumtransients and describe our experimental protocol for targetingadult-born PGNs. We imaged PGNs located at the dorsalsurface of the OB using bolus loading of the calcium indicatororegon green bapta-1 AM (OGB) into the glomerularlayer. OGB loading resulted in labeling of hundreds of neuronsthat showed strong calcium responses (upto 30% dF/F)to electrical stimuli. In order to characterize the sensory responseprofiles of the PGNs we are currently mapping theactivated regions of the OB in response to specific olfactorystimuli using intrinsic-signal imaging (ISI). IS maps are thenused to identify the activated glomeruli that are subsequentlyimaged with two-photon calcium imaging. In addition, todirectly study the newborn neurons, we are using lentivirusmediatedlabeling of the progenitor stem cells (using red fluorescentproteins) together with the calcium imaging technique.This experimental strategy now allows us to examinethe functional contribution of the newborn cells to the existingnetwork and may reveal the role of newborn neurons inolfactory coding and plasticity. Acute stroke to the human cerebellum involves glutamatergicexcitotoxicity and causes variable degrees of motor impairment.The present study focuses on the contributionof genetic background to the variability in stroke outcome.Kainate, a glutamate analog, wasmicroinjected to cerebellumin two inbred strains of mice–FVB/N and C57BL. One and14 days post injection, C57BL mice displayed more severeneurological outcome compared to FVB/N mice. Damage tothe Purkinje layer and electrophysiological response of Purkinjecells (PC) to kainate in a slice preparation were similar inboth strains. However immunohistochemical staining of calciumbinding proteins calbindin and parvalbumin revealedgreater morphological pathology in PC axons of C57BL thanof FVB/N mice, suggesting that the more severe neurologicalimpairment in C57BL mice was due to greater impairmentof axonal output from the cerebellar cortex. Towardunderstanding axonal pathology in this model, we focusedon a structure formed by basket cell fibers around the PCaxon initial segment called the “pinceau”. The results indicatethat higher basal expression of certain pinceau elements,including the voltage gated potassium channel Kvbeta2 andpotassium hyperpolarization-activated channel, HCN1, predictgreater resistance to glutamatergic neurotoxicity in thecerebellum.Supported by Israeli MOST and German BMBF. Scorpion venoms are a rich source of varies potassium channelblocking peptides. To identify novel toxins with uniqueselectivities we studied the polypeptide content of the Israeliscorpion Buthus occitanus israelis (Boi). Seventy threenovel putative toxins were discovered following analysis of400 randomly chosen venom gland-derived cDNA clones.Twenty toxins were predicted to block potassium channels.Accordingly, we identified more than 20 distinct peptidesfrom Boi crude venom which are active against differentpotassium channels, for example, Shaker, Kv1.3 and RomK1.Here we describe the isolation, cloning and genomic organizationof BoiTx1, the first toxin from the Israeli scorpionButhus occitanus israelis. BoiTx1 is a 37 amino acid-longpeptide with six conserved cysteines. BoiTx1 shows 82%–75% homology to members of the alpha-KTx3 toxin family,thus classified as an alpha-KTx3.10. The pharmacologicaleffects of BoiTx1 were studied on various cloned potassiumchannels expressed in Xenopus laevis oocytes. BoiTx1inhibited currents through Drosophila Shaker channels withan IC50 value of 3.5 ± 0.5 nM. In contrast to its structurallyrelated toxins, BoiTx1 is at least hundred-fold more potentagainst the fly, Shaker channel, then towards its mammalianhomologs, Kv1.1 and Kv1.3. Thus, BoiTx1 is the first memberof the alpha-KTx3 family that preferentially affects insectpotassium channels. This finding could lead to better understandingof the structural basis of channel selectivity inpotassium channel blocking peptides. Testosterone, the primary gonadal hormone in males, is associatedwith some cognitive functions, particularly spatialskills and spatial memory. This hormone may also have neuroprotectiveproperties. We studied the effects of exogenoustestosterone on cognitive functioning in middle-aged hypogonadalmen with dysthymia .Methods: Fifteen hypogonadal men , suffering from dysthymia were enrolledin a randomized, double-blind clinical trial in which they receivedtestosterone 200 mg or matched placebo IM biweeklyfor seven weeks. Subjects completed a neuropsychologicaltest battery at the time of enrollment and at the end of thedouble-blind phase. The battery included the Rey auditoryverballearning test (Rey-AVLT), Rey Osterreich complex figuretest , anddigit-symbol coding test .N = 8) compared with the placebogroup (N = 7) in the immediate-recall trial (T2) anddelayed-recall trial (T3) of the Rey-CFT. This was exemplifiedby a significant time by treatment interaction in performanceon the T2 and T3 of Rey-CFT  = 5.127,P < .05, and F = 4.7, P < .05, resp.). No such interactionwas found in performance on either the auditory-verbalmemory test or the digit-symbol coding test. Conclusion:Normal testosterone levels may be important in the maintenanceof specific cognitive abilities, contributing to betterperformance of visual-spatial tasks but not auditory-verbalor attention tasks. These finding have implications for theassessment and treatment of age-related hypogonadism andpossibly also Alzheimer's disease, and should be replicated ina larger sample, and in nondepressed men.Repeated Measures ANOVA showed a significant improvementin the visual-spatial memory abilities of the testosteronetreated group  has been the focus ofseveral recent studies. In our present studies we investigatethe ability of the octopuses motor output programs to adaptto new tasks. To do so we forced our animals to performtasks challenging their standard repertoire of arm movements.We conducted a set of experiments that effected either,bend propagation and fetching movements, or requiredon-line central control of searching movements and an establishmentof learning processes. In our first experiment weintroduced a physical constrain to the base of the octopusarm. Animals were placed inside a transparent Perspex box(40 × 40 × 40 cm) with a hole at the center of every surfacethat allowed the insertion of a single arm only (1.5 cm×).During the experiment the subjects had to reach out througha hole to retrieve a food reward offered outside the box. Theaccuracy of the reaching towards a target movement did notimprove in consecutive experimental sessions. However, theaccuracy and speed of fetching movements improved bothwithin and across sessions. A second set of experiments investigatedthe ability of octopuses to learn to turn their armin a specific direction in an opaque Y shaped maze. The animalsreceived neither chemical nor tactile information onthe direction of the turn. Therefore the correct decision toturn left or right inside the maze could only be made basedon proprioceptive information on the position of the arm. 4out of 6 subjects were able to successfully complete this taskin less then 90 trials. Further experiments investigated if theoctopus can turn its arm inside a maze according to visualfeedback. 6 out of 9 animals learned to direct the movementof their arms inside a three ways choice maze based on visualinformation. These experiments show that octopuses are ableto modify the execution of motor primitives as well as moresearching and crawling related movements.Supported by Israel Science Foundation. M. Kuba was supportedby a Golda Meir fellowship. The 18 kDa Translocator protein (TSPO), formerly calledperipheral-type benzodiazepine receptor (PBR), exerts variouscell functions and is involved in a functional structuredesignated as the mitochondrial permeability transition pore(MPTP). Our previous studies indicated that TSPO may bean important component in the MPTP related pro-apoptoticmechanisms activated by the novel membrane-seeking antineoplasticagent erucylphosphohomocholine (ErPC3). Thus,we decided to use two well-known TSPO ligands, PK 11195and Ro5 4864, to study their interference with ErPC3's proapoptoticactivity. Surprisingly, PK 11195 and Ro5 4864 inhibitedapoptosis induction by ErPC3 in a concentrationdependentmanner. In addition, they appeared to blockcytochrome c release, and caspase-9 and -3 activationtypically induced by ErPC3. This indicates that the MPTPand TSPO take part in the activation of the mitochondrialapoptosis pathway by ErPC3. TSPO molecules are oftenfound in conjunction with VDAC and ANT, which aresuggested core components of theMPTP. ANT appears as abi-functional protein: an ADP/ATP translocator and a lethalpore regulated by multiple apoptosis regulators. To study inmore detail the mechanisms whereby ErPC3 may affectmitochondrialfunctions, for example, membrane potential, ATPproduction, we analysed in a first attempt a possible correlationbetween ErPC3, TSPO, and ANT by investigating cellularATP levels using human glioblastoma cell lines U87MGand U118MG. Treatment of these cells with TSPO ligandsand ErPC3 affected ATP levels. Depending on the cell type,PK 11195 and Ro5 4864 enhanced or reduced ATP levels,whereas ErPC3 reduced cellular ATP levels in all cell linestested. Interestingly, co-administration of these TSPO ligandswith ErPC3 restored cellular ATP levels. Together, theseresults suggest that not only TSPO but also ANT is involvedin ErPC3's action.Supported by the Volkswagen-Stiftung . Many studies have examined the relation between variousmovement parameters and the neural responses in the motorcortex of behaving primates. Encoding for many movementparameters have been shown, such as speed and direction,muscle activations, joint angles, and the sensory cues formovement. In such studies the primates are “overtrained”—trained for many months or years until they reach expert andconstant performance. In the current study we recorded fromthe primary motor cortex of a monkey for several monthsas she learned a three-dimensional point-to-point reachingtask. During this period her behavioral performance improvedfrom a novice level to highly proficient. We recordedthe full arm kinematics (using optic sensors), and 96 neuralsignals from a chronically implanted electrode array. Ourtask involved a wide variety of movements in order to spana large portion of the movement space and thus allow us tosample the tuning properties in a broad manner. We examinedthe changes in the encoding of these motor parametersin relation to the parameters of the enhanced movements. Insome cases we could track the encoding of a single neuronfor several days, as they remained convincingly well isolatedand identifiable. The study of the neural correlates of consciousness (NCC)has typically focused on a subjective definition of awareness.Using a backwardmasking paradigm, we dissociated betweenobjective awareness and subjective awareness by having participantsfirst produce a forced-choice response to the locationof a liminal target, and then report on their subjectiveawareness of the target presence. We recorded event-relatedbrain potentials (ERPs) and compared neural activity whenobservers reported being aware versus unaware of the targetbut localized it correctly, thereby isolating the neural correlatesof subjective awareness while controlling for differencesin objective performance. In addition, we compared neuralactivity when participants were subjectively unaware of thetarget presence and localized it correctly versus incorrectly,thereby isolating the neural correlates of objective awareness.Importantly, all conditions involved stimuli that were physicallyidentical and were presented for the same duration. Theresults show that the amplitude of the P3 component correlateswith the degree to which the target is consciously perceived Recent studies in animals and humans have shown that EEGactivity in the gamma range can be modulated by attention.In the present study we compared this activity for voluntaryand involuntary allocation of spatial attention in a spatialcuingparadigm with faces as targets. The visual stimuli andtrial timing were kept constant across attention conditionswith only the predictive value of the cue changing. Gammabandresponse was linked to voluntary shifts of attention butnot to the involuntary capture of attention. The presence ofincreased gamma responses for the voluntary allocation ofattention, and its absence in cases of involuntary capture,suggests that the neural mechanisms governing these twotypes of attention are different. Moreover, these data allowa description of the temporal dynamics contributing to thedissociation between voluntary and involuntary attention.The scalp distribution of this correlate of voluntary attentionis consistent with a top-down process involving primarilycontralateral anterior and posterior regions. Although the rules underlying the perceived intensity of binarymixtures has been investigated, only minimal effortshave been directed at elucidating the rules underlying theperceived pleasantness of such mixtures. To address this,84 subjects ranked the relative and absolute pleasantness of4 distinct binary mixtures  made of different mixing ratios and of the separated constituentsof the mixtures diluted with clean air to the overallair flow of the mixture. 3 mixtures consisted a relativelypleasant odorant mixed with an unpleasant one  and one mixture consisted of two unpleasantodorants . Each trial wasrepeated twice with odorant order counter-balanced andtrial order randomized. The mixture's separated constituentswere in turn ranked for their intensity on a VAS scale. Basedon these results, we propose here a novel prediction modelfor the pleasantness of binary mixtures from the pleasantnessof their separated components at different mixing concentrationsand their respective intensities. This model doesnot require presetting of an interaction constant between themixture components, nor does it require any factorization ofthe pleasantness weights. It does, nonetheless, require solidpsychophysical data of the separated components at their differentconcentrations, and currently it can only explain thebehavior of intermediate pleasantness of the mixture. μM-thick slices, in a plain that ought to preserve theinferior olive, the deep cerebellar nuclei and a parasagittalportion of the cerebellum. Slices were then placed onmembranes of 30-mm culture inserts with 0.4 μM pore size and cultured over culture medium containing50% basal medium, 25% Hanks'balanced salt solution,25% horse serum, L-glutamine, antibiotics and glucose.Slices were maintained in culture for 1–6 weeks at 37°Cwith 5% CO2 enriched atmosphere. Whole cell patch-clamprecordings from Purkinje cells (PCs) were made after removingthe inserts'wall and placing it in a recording chamberperfuse with 5% CO2 and 95% O2 enriched Ringer's solution.Our results show that these cultures form an activenetwork of cerebellar neurons. PCs preserved their characteristictwo-dimensional dendritic tree, and displayed subandsupra-threshold spontaneous activity. The subthresholdactivity consisted of depolarizing and hyperpolarizingpotentials that respectively decreased and increased in amplitudeupon depolarization, which suggests that they representschemical synaptic inputs. Supra-threshold activity,which was often observed, was manifested as overshootingaction potentials that were carried by Na+ and Ca++ currents.Since PCs retain their physiological and morphological characteristics,it is reasonable to assume that this organotypicculture will pave the way for reconstruction of the olivocerebellarloop in a dish, which will allow for simultaneousrecording from all the major components of the system.In order to unravel the functional organization of the olivocerebellarloop, one needs a simultaneous access to all itscomponents. Since it is rather impossible to achieve this inin-vivo conditions, we are developing a culture system thatcaptures the entire circuit, which is based on brain slicesof 7 to 18-day-old rats. Once isolating the brain, the cerebellumand the attached brain stem were sliced into 250–500  Collinear facilitation is a common phenomenon, but it hasbeen challenged recently at the human periphery. We probedthe facilitation using a Yes/No detection task by measuringthe false-positive reports  and hit rate (Phit)for a low-contrast Gabor target (between two flankers) thatappeared randomly at the fovea or at the periphery (2.4 deg)to the right or left side. We compared three target-flankerconfigurations: orthogonal at a distance of 15-lambada , and collinear or orthogonal at 5-lambada. Thereport for the target present was high  for thecollinear but not for the other configurations. The overall increasein the target-present responses only for the collinearconfiguration is consistent with the excitatory range of interactions.However, the sensitivity of the collinear configurationat 5-lambada is higher than the target but onlyslightly higher than the orthogonal configuration. Therefore,the usual expression of a facilitation effect as a sensitivitymeasure is distorted by the strong excitation . The existence of a similar pattern ofhigher Phit and Pfa for the collinear configuration at thefovea and periphery suggests that collinear facilitation is acommon phenomenon that affects both the periphery andfovea.Supported by the Israel Science Foundation and the NationalInstitute for Psychobiology in Israel. P < .05). In adult female mice no significantalterations in mobility were observed. Anxiety was reducedin male GVG-wt and GVG-Mthfr−/+ mice, expressedby a higher duration ratio center/margin, compared to Ctwtmice . In femalemice, anxiety was reduced in GVG-wt and Ct-Mthfr−/+,compared to Ct-wt, and MTHFR deficiency combined withGVG treatment abolished the anxiety related effect. Recognitionmemory was impaired, regardless of gender, in bothGVG-wt and GVG-Mthfr−/+ mice, as well as in Ct-Mthfr−/+mice. These mice did not distinguish between novel and familiarobjects. In a sociability task, a genotype effect was observedin male and female. This genotype effect was not observedin a social preference test, while in female GVG treatmentin wt and Mthfr−/+ mice reduced preference to an unfamiliarmouse (P < .05) Overall, MTHFR deficiency andGABA potentiation differentially affects a spectrumof behaviorsin male and female mice.Fetal-Anticonvulsant Syndrome may cause developmentaldelay, cognitive dysfunction, and behavioral impairments:hyperactivity, attention deficit disorder and autistic-likebehavior. We examined the interactions between geneticsusceptibility and anticonvulsant drug treatment, by performingbehavioral phenotyping of MTHFR deficient offspringperinatally treated with a GABA potentiating substance.Four groups of offspring were compared: Balb/c wildtype(wt) and Mthfr−/+ mice injected daily subcutaneouslyon postnatal days 4–10 with saline (Ct) or vigabatrin . GVG treatment, but not MTHFR, delayed motorand sensory reflex development. In the open field task,adult male GVG treated mice demonstrated increased mobility,regardless of genetic background. Hyperactivity wasexpressed in a longer distance moved by GVG-wt and GVGMthfr−/+mice (1255.6 and 1363.2 cm) and a higher velocity(4.2 and 4.5 cm/s), compared with Ct-wt mice  demonstratingthe importance of IMPA1 in early embryonic development.The embryonic lethality could be reversed by myoinositolsupplementation via the pregnant mothers. In theadult's IMPA1−/− brain IMPase activity levels were found tobe strongly reduced (up to 65% in hippocampus). However,inositol levels were not found to be changed. Rescuedadult IMPA1−/− mice exhibit a strongly increased sensitivityto pilocarpine-induced seizures, supporting the ideathat IMPA1 represents a physiologically relevant target oflithium. The IMPA1−/− mouse represents a novel model tostudy inositol homeostasis, and indicates that genetic inactivationof IMPA1 can mimic some lithium behavioraleffects. F = 29.1, df = 1, 40, P < .0001) and a significant  group x test effect. Post-hoc ttestsindicated the existence of a greater deficit among patientson the nonaffective relative to affective visual processingtests used in this study. Significant positive correlationswere found among patients between impaired FACEDISand FACE-ID performance and the GVP measures. Positive,negative and total PANSS scores correlated significantlywith FACE-DIS  and FACE-ID  performance. These findings indicate that inschizophrenia, basic visual processing deficits may contributeto the impaired ability to decode emotions based on facialexpression.Deficits in face emotion identification and discriminationwere previously reported in schizophrenia. However, it is notclear whether the impairment in decoding emotion basedon facial expression represents a specific dysfunction domainor may reflect generalized visual processing deficits.In the present study, we evaluated both emotion recognitionand generalized, nonaffective visual processing parameters(GVP) and their relationship with clinical statein schizophrenia patients. Thirty stable schizophrenia inpatientsand 15 age- and sex-matched control subjects participatedin the study. Decoding emotion processing assessed by(1) the face emotion identification test (FACE-ID); (2) theface emotion discrimination test (FACE-DIS). GVP was assessedusing (1) the closure flexibility-concealed figure task(CFT); (2) the perceptual organization (PO). For all patients,the positive and negative syndrome scale (PANSS) was administered.Patients showed significantly impaired performanceon FACE-DIS, although between-group differencesin FACE-ID were not statistical significance. Large effectsizebetween-group differences were also observed on bothGVP tasks. A MANOVA analysis including all four test measuressimultaneously indicated both a main effect of group. The dynamic notionsthat we find as crucial for the functioning of the networkare balance and stability. Balance refers to the functioningof the network and its components within a range of parametersthat enable good functionality. Stability assures thatfluctuations in the input and output of the network are notprohibitively large. Severe instability may drive the developmentaway from its normal route (as in autism), and mayeven lead to network collapse (as in schizophrenia). Regainingstability and balance is therefore the goal of a successfulintervention. Thyroid hormones had been long used in the treatment ofdepression, mostly as supplements to antidepressants, to enhanceor accelerate clinical response. Little is known of themechanisms underlying these effects, which we attempted touncover by using different pharmacological, behavioral andmolecular paradigms. In vivo microdialysis was used to evaluatethe effects of fluoxetine 5 mg/kg, T3 20 mcg/kg and theircombination, administered to male Sabra rats for 7 day, onserotonin levels and the activity of presynaptic serotonergicreceptors in the cortex and hypothalamus. Reduction of hypothalamicserotonin levels was observed in rats treated withT3 alone or combined with fluoxetine. Reduction in the activityof 5HT1b autoreceptors was observed in the hypothalamusof rats receiving T3 plus fluoxetine, but not in thosereceiving either compound alone. The novelty suppressedfeeding test was used to explore the effects of fluoxetine10 mg/kg, T3 20 mcg/kg and the combination of fluoxetine5 mg/kg+ T3 20 mcg/kg, for 12days, on the time requiredfor a food deprived animal to commence eating in an unfamiliarenvironment (latency). Only the fluoxetine 5 mg/kg+T3 20 mcg/kg combination caused a significant shortening oflatency. Finally, we studied the effects of fluoxetine 5 mg/kg,T3 20 mcg/kg and their combination, administered for 7 days,on mRNA levels of 5HT1a and 5HT1b receptors in differentbrain areas. In the raphe nucleus the combination of T3+ fluoxetinecaused a decrease in mRNA for both receptors. Similarreductions were observed in rats treated with T3 alone orcombined with fluoxetine in the amygdala, CA1 and dentategyrus (5HT1a receptor mRNA) and the frontal and enthorinalcortices (5HT1b receptormRNA). Taken together, the resultsof these different experimental paradigms suggest thatthe mechanisms underlying the antidepressant activity of T3may be mediated by changes in the activity of presynapticserotonergic autoreceptors. P < .0001) in entorhinal cortex, followed by perirhinal, temporaland cingulate cortex (P < .05). The striatum had thesmallest increase . In vitro, we found a significantsurvival difference between cortical and striatal neurons exposedto glutamate (P = .01) and TNFalpha (P = .002).Exposure to glutamate and TNFalpha reduced the numberof cortical neurons to 5.68%+/−4.3 74.55%+/−18.6 of controlrespectively while the number of striatal neurons was reducedto 21.04%+/−14.09 and 115.69%+/−25.01 respectively.A better understanding of the regional determinants governingsensitivity to neuroinflammation may help in identifyingnew targets for treatment or prevention of neuroinflammatorydamage in human diseaseNeuroinflammation is believed to play a major role in severalacute human neuruopathologies and chronic conditionssuch as Alzheimer's and Parkinson's disease. Recent observationssuggest that the intensity of the neuroinflammatory responseto various challenges is region dependent. The goalof our study is to expand and substantiate our knowledgeof regional sensitivity to neuroinflammation and explore theunderlying mechanisms. Neuroinflammation was induced invivo by intracisternal (ic) injections of endotoxin (LPS) inmale Sabra mice. Animals were tested for neurological andcognitive deficits using a neurological severity score (NSS)and the novel object recognition test (ORT). Regional neuroinflammationwas measured by quantitative autoradiographywith [3H] PK11195 a peripheral benzodiazepine receptorligand that marks the activation of Microglia. Quantitativeanalysis of neuroinflammation was performed infive brain areas. In vitro, we employed mixed  neuronal cultures exposed to glutamate and/orTNFalpha, for 24 h, with neuronal survival as an endpoint.ic LPS Mice showed moderate neurological deficits and significantdeficits in the ORT. Increased [3H] PK11195 densitywas found in all regions, with the highest increase  we recorded simultaneously local field potentials(LFPs) from deep brain stimulation (DBS) electrodes andmagnetoencephalographic (MEG) signals from the cerebralcortex (CTF 274 channel system) in Parkinson's disease (PD)patients with bilateral DBS electrodes in the subthalamic nucleus(STN). We report the results from two patients. Informationtransfer between the STN and cortex was evaluatedusing a multivariate autoregressive (MAR) model in combinationwith whole-head topographical mapping and sourcelocalization. In case 1  the right STN LFP predicted the MEG signalover the right sensorimotor area and the MEG fromthe rightsensorimotor and mesial areas predicted the right STN LFP.Similar bidirectional interactions were observed for left STNwith the signals predicted by STN LFP more focal over theleft sensorimotor area and the signals predicting STN activityfound over bilateral sensorimotor cortex. In case 2  bidirectionalinteractions were observed between the right STN andmesial areas. The left electrode in case 2 passed about 2 mmpostero-medial to the sensorimotor area of the STN. No couplingwas detected between this left channel and MEG; confirmingthe regional specificity of the cortico-STN coupling.We conclude that simultaneous recording of the LFP fromDBS electrodes and MEG enables one to establish patternsof coupling between cortex and focal subcortical structures.In the case of the STN, this coupling is clearly bidirectional,in keeping with its cortical input via the corticostriatal andhyper-direct pathways, and output back to cortex via globuspallidus and thalamus.Supported by Marie Curie Intra European fellowship (contractMEIF-CT-2006-038858), British Technion Society. μm between puncta). Finally, in vivo two-photon timelapseimaging of newborn neurons over 36 hours revealedthat synaptic puncta display a rich repertoire of dynamics,continuously appearing and disappearing. For example, only∼60% of synaptic puncta remained stable through the imagingsession. Taken together, these experiments provide an experimental“snapshot” into the dynamic behavior of synapseformation in the intact mammalian brain.Throughout adulthood, the olfactory bulb (OB) continuouslyreceives newborn neurons that integrate into thenetwork as functional interneurons. This unique populationserves as a model system to study how synapses areformed during neuronal integration into a preexisting network.Here, we set out to directly image newborn neuronsand their underlying synapses by combining in vivo imagingand electronmicroscopic (EM) analysis. Adult-born neuronswere transduced at the subventricular zone with lentivirusesto express a postsynaptic density protein fused with greenfluorescent protein (PSD95-GFP) revealing both dendritesand synapses. We first carried out an EM analysis of thePSD95-GFP puncta. To this end, we analyzed young developingneurons 10-14 days post injection (DPI) where only63% of PSD95-GFP puncta had a clear pre-synaptic partner.This indicates that 37% of the synapses are still developing.Notably, newborn neurons made synapses almost exclusivelywith axons of olfactory receptor neurons. Second,we analyzed synaptic distributions and dynamics of wholeneurons. At 10–14 DPI, newborn puncta were sparsely distributedalong dendrites (up to 20 microns between synapticpuncta). In marked contrast, puncta of mature neurons(at 57DPI) were distributed more densely  neurons.We found that whisker movements across surfaces arecomposed of whisking and texture-related vibration signals,both carrying information about surface roughness. Duringcontact with textures, TG neurons presented a broad rangeof responses, which encoded the two signals. To determinewhether these signals can support texture discrimination weexamined their dependence on surface roughness. We foundthat despite a large variability in this translation process, differenttextures are translated into distinct vibrations profiles.These response profiles vary across whiskers, are dependenton the radial distance of the textures, on whisking frequency,and may be influenced by head movements. Using the characteristicsof these signals, we employed discriminant analysisto statistically evaluate the ability of whiskers to discriminatebetween textures. Texture identity was correctly classifiedin 87% of whisks. This classification did not depend onwhisker identity and whisking frequency, while deterioratingwith radial distance. Finally, increasing the number of whisksand integration of information from multiple whiskers improvedtexture discrimination. These results indicate thatsurface roughness is translated into distinct whisker vibrationsignals that result in neuronal discharge pattern. The present study tests the hypothesis that in Alzheimer'sdisease early reduction in cytochrome oxidase (COx) activitycould initiate a cascade of events which includes oxidativestress (OS) leading to cognitive impairment via involvementof cholinergic neurons. Reduction in COx and memory impairmentcan be mimicked in rats by chronic administrationof sodium azide (NaN3).NaN3 or saline was given s.c. for 4 weeks (1mg/kg/hr) byminipumps to male Sprague-Dawley rats. After 2 or 5 weeks,brains were fixed and sectioned for immunohistochemicalmapping of the marker of OS, manganese-dependent superoxidedismutase (Mn-SOD), and markers of cholinergicneurons, choline acetyltransferase (ChAT) and of vesicularacetylcholine transporter (VAChT).NaN3–treated rats showed a significant decrease in COx activityin the cingulate and parietal cortex and in the hippocampus.At 2 weeks, NaN3 induced a significant increaseinMn-SOD (indicating the presence of OS) in the basal forebrainincluding diagonal band, medial septum, (the majorsources of cholinergic input to the hippocampus and cingulatecortex) and in the hippocampus. At 5 weeks, there wasa reduction of 20% in mean size of cholinergic neurons inthe diagonal band, suggesting that these neurons were understress although cholinergic neuron loss was not observed.There was a compensatory increase of about 100% in immunoreactivevaricosities and GAP-43 (a presynaptic membranephosphoprotein marker of plasticity) in the subgranularlayer of the dentate gyrus.The present study demonstrates a unique sensitivity ofcertain neuronal populations, among them, the septohippocampalsystem, to reduction in cytochrome oxidase activity.The present study also suggests that oxidative stress isinvolved in this process. The ability to maintain information for short periods of timeplays an essential role in cognition. One of the most intriguingaspects of short-term memory is its limited capacity, typicallyaround 3 or 4 items. Functional magnetic resonanceimaging (fMRI) research revealed a large network of brainareas involved in the short-term retention of information.Recently it has been suggested that activity in a specific partof this network, the posterior parietal cortex (PPC), is correlatedwith the behavioral estimates of capacity limitationsand might serve as a capacity-limited store . We present the results of a set of experiments thatfailed to find this close correlation between fMRI activity andbehavioral capacity limitations. Instead, we show that whenvisual rehearsal is more prominent in the task, fMRI activityin PPC increase with memory load beyond the behaviorallydetermined limits of capacity. We suggest that activity in PPCreflects the attentional demands of the short-term memorytask rather than a capacity limited store. This interpretationis consistent with the role of PPC in attentional processes andwith the close correlation between brain areas that are involvedin attention and those that mediate short-term memory. Hepatic encephalopathy (HE) is a major neuropsychiatriccomplication of both acute and chronic liver failure. However,its pathogenesis is still unknown. It has been suggestedthat the cognitive deficits characterizing this state result,at least in part, from an inflammatory response in thebrain. Ca nnabidiol (CBD) is an active compound of the plantCannabis Sativa known for its antiinflammatory properties.We hypothesized that CBD may have therapeutic potentialin chronic liver disease through antiinflammatory actions.Methods: Female Sabra mice were subjected to ligation ofthe bile duct (BDL). Sham operated animals were used ascontrols. 2 weeks and 3 weeks post-surgery, animals receivingeither vehicle or 5mg/kg CBD were evaluated for cognitivefunction in the Eight Arm Maze and the T-maze tests.The animals were sacrificed and their hippocampi were analyzedfor mRNA levels of IL-1 beta by RT-PCR analysis,and their livers were analyzed for MDA levels, indicating oxidativestress by the TBARS method. Results: IL-1 beta expressionin the hippocampus increased significantly in BDLmice 3 weeks post-surgery, and was restored to normal valuesby CBD. Oxidative stress in the liver increased in BDLanimals and was decreased by CBD. Cognitive function wassignificantly impaired in BDL mice and these impairmentswere also ameliorated by CBD. Conclusion: These results indicatean involvement of inflammatory processes in the hippocampusin the pathogenesis of HE. This inflammatory responsemay be associated with the behavioral impairments,and both were ameliorated by CBD. CBD may act via theadenosine system, since an upregulation of this system wasobserved in hippocampal slices of human HE patients, postmortem. The interaction of membrane-embedded voltage-activatedpotassium channels (Kv) with intracellular scaffold proteins,such as the post-synaptic density 95 (PSD-95) protein, is mediatedby the channel C-terminal segment. This interactionunderlies Kv channel clustering at unique membrane sitesand is important for the proper assembly and functioning ofthe synapse. In the current study, we address the molecularmechanism underlying Kv/PSD-95 interaction. We provideexperimental evidence, based on hydrodynamic and spectroscopicanalyses, indicating that the isolated C-terminal segmentof the archetypical Shaker Kv channel (ShB-C) is arandom coil, suggesting that ShB-C belongs to the recentlydefinedclass of intrinsically disordered proteins. We showthat isolated ShB-C is still able to bind its scaffold proteinpartner and support protein clustering in vivo, indicatingthat unfoldedness is compatible with ShB-C activity. Pulldownexperiments involving C-terminal chains differing inflexibility or length further demonstrate that intrinsic disorderin the C-terminal segment of the Shaker channel modulatesits interaction with the PSD-95 protein. Our resultsthus suggest that the C-terminal domain of the Shaker Kvchannel behaves as an entropic chain and support a “fishingrod” molecular mechanism for Kv channel binding toscaffold proteins. The importance of intrinsically disorderedprotein segments to the complex processes of synapse assembly,maintenance, and function is discussed. We perceive in order to act on the environment. Affordancetheory states that objects are perceived not only in terms ofshapes and spatial relationships but also in terms of possibilitiesfor action (affordances). That is, perception drives actionin a direct and immediate way. According to this assertion,seen objects should automatically potentiate components ofthe actions they afford. Previous studies have demonstratedaffordance by showing nonspatial compatibility effects forcentral objects, based on the orientation of their handles.However, it is possible that the visual asymmetry created bythe handles directed the subjects' attention towards one side,thus creating spatial compatibility effects, irrespective of anyaffordances. In order to dissociate between affordance andspatial compatibility effects, we tested whether respondingto manipulable objects could result in speeded responses,as compared to nonmanipulable objects with similar visualasymmetries. To this end, we presented pictures of manipulableand nonmanipulable objects, half of which containedmetal, on the right or left side of the screen. On each trial,subjects were required to judge whether the depicted objectcontainedmetal or not, by pushing a button with their left orright hand. Our results showed significant effects of both spatialcompatibility and of manipulability: Subjects respondedquickest andmost accurately when manipulable objects werepresented compatibly with the responding hand, and slowestwhen nonmanipulable objects were presented incompatiblywith the responding hand. These results suggest that both effectsmayprime responses equally. However, subjects' performancein a separate spatial perception task (landmark) correlatedwith the effect of compatibility, but not of manipulability,suggesting that whereas the former relies on perceptionspace, the latter might rely more on action space. Perception and action are interdependent and inseparable–an animal's motor behavior should be reflected in its perception.Indeed, electrophysiological studies in premotor cortexhave revealed visual receptive fields, selective for moving3D objects, that shift with the position of a monkey'sarm, regardless of gaze direction. This suggests a representationof visual space in hand-centered coordinates. In thepresent study, we explored hand-centered modulation of visualspace in the human motor cortex. Subjects performeda simple “Go” response task to a central visual target, bypushing a button on the left or right side of fixation, whilesimultaneously a 3D ball approached the left or the rightside. Between 40–120 ms later, a single TMS pulse was appliedto the primary motor cortex contralateral to the respondingfinger in order to elicit motor evoked potentials(MEPs). We found that the mean peak- to-peak MEP amplitudewas smaller when the ball approached the position ofthe responding hand, as compared to far from the hand, regardlessof the hand position with respect to fixation. We hypothesizedthat this rapid modulation reflected the suppressionof an existing motor plan (the “Go” response), causedby the approaching object. We designed a battery of experimentsto test this hypothesis, manipulating the type of visualstimulus presented, the required motor task, and the directionof subject's overt (changing fixation position) and covertvisual attention . We found thatthe hand-centered modulation of MEP amplitudes was criticallydependent upon the timing of the TMS pulse (70–80 ms), the type of visual stimulus , and the presence of an ongoing motor plan. Manipulatingthe location of visual attention only partially modulatedthese hand-centered effects, suggesting contributions ofboth eye- and hand-centered spatial representations to activityin primary motor cortex. Synaptogenesis is a fundamental process during neuronaldevelopment, learning processes, and regeneration aftertrauma. We have recently argued that in cultured Aplysianeurons prefabricated varicosities (VRs) serve as ready-to-gopresynaptic compartments. Thus VRs exocytose their vesicularcontents in a spike activity-dependent manner. Themechanisms by which VRs are formed are not entirely understood.Real-time confocal imaging of growth cones (GCs)and VRs revealed that VR formation is preceded by accumulationof vesicles and cytoskeletal elements in the centraldomain of a pausing GC. During the phase of organelleaccumulation,(lasting 8–22 minutes), the actin-rich peripheraldomain continues to extend and retract. When a “large”mass of organelles accumulates in the central domain, the GCresumes its net growth by actin-rich lamellipodia and filopodia,invaded by MTs. It is important to note that while theadvancing GC does not contain large quantities of organelles,it leaves behind a VR loaded by a mass of organelles. Withtime (8–25minutes), the splayed MTs within the VR bundleto form the core of the VR. This core is very dynamic andcan splay or even bend when the VR moves along the neurite.Imaging of Golgi derived vesicles labeled by synaptopHluorinsrevealed that the growth process is associated with constitutivefusion of vesicles with the GC's plasma membrane.Evoked exocytosis coupled to membrane retrieval operatesin both GCs and VRs. Taken together our observations areconsistent with the hypothesis that VRs are formed whenthe supply of anterogradely transported vesicles exceed theamount needed to support the elongation process, which islimited by the assembly of the actin and MT skeleton. This isalso consistent with the finding that VRs are almost homogeneouslyspaced along individual neurites, which representsthe local balance between organelle supply and elongation. Complete deficiency in activity-dependent neuroprotectiveprotein (ADNP), a multifunctional, heterochromatin 1-binding protein, results in dramatic changes in gene expression,neural tube closure defects and death at gestation day9 in mice. To further understand the cellular roles playedby ADNP, the HEK293 human embryonic kidney cell linewas used as a model for the identification of ADNP interactingproteins. Recombinant green fluorescent protein(GFP)-ADNP was localized to cell nuclei. When nuclearextracts were subjected to immunoprecipitation with specificGFP antibodies followed by protein gel electrophoresis,several minor protein bands were observed in additionto GFP-ADNP. In-gel protein digests followed by mass spectrometryidentified BRG1, BAF250a and BAF170, all componentsof the SWI/SNF (mating type switching/sucrose nonfermenting)chromatin remodeling complex as proteins thatcoimmunoprecipitate with ADNP. These results were verifiedutilizing BRG1 antibodies. ADNP shRNA down-regulationresulted in microtubule reorganization and changes in cellmorphology including reduction in cell process formationand cell number. These morphological changes are closelyassociated with the SWI/SNF complex multifunctionality(JBC 2007). Furthermore, using P19 cells as a differentiationmodel, we showed that ADNP expression and cytoplasm/nuclar distribution is unique in neuronal differentiatedcells compared to cardiovascular and nondifferentiatedpluripotent cells. Small hairpin RNA down regulation wasused to further investigate ADNP involvement in p19 neurodifferentiation.A ∼80% reduction in ADNP led to a substantialreduction in embryoid body formation and to a significantreduction (∼50%) in neurite number. These resultsposition ADNP in direct association with neuronal cell differentiationand maturation.Supported by BSF, ISF, Lily, and Avraham Gildor Chair, AdamsSuper Center and Allon Therapeutics Inc. We present analyses designed to test the idea that variabilityof single cells' activity in motor cortical areas, reflects underlyingprocesses associated with nonadaptation , adaptation (visuomotorrotation) tasks, and switching from one to the other. Underthe assumption that increase in variability is a result of neuronalprocesses, we investigate the hypothesis that adaptationstarts at pre-motor areas, higher in the hierarchy of computation,gradually transfers to primary areas, until a stable representationis formed there. In contrast, a standard task, thatincorporates merely the retrieval of an internal model andnot its formation, is expressed mainly by changes in primaryareas. To this end, we measured the across-trial variabilityof single cells responses, and found it has a significant dynamicsfor movement preparation period. During standardtask, although it is assumed to be a stationary process, singlecells in M1 showed a tendency of a gradual decrease in variabilitybut neuronal activity in SMA did not show any significantdynamics. Switching to adaptation task, caused variabilityin M1 to increase, and later on, decreased back to initiallevel. Interestingly, similar dynamics was found in SMA,but earlier in the adaptation session, returning to initial levelapproximately when movement reached its asymptotic bestlevel according to the learning curve. Surprisingly, when returningto standard task the dynamics in M1 was similar tothat during adaptation task and no significant dynamics wasseen in SMA as in the first standard task. These results suggestthat any switching between internal models is reflectedin M1 by an increase followed by a decrease in neuronal variability.Furthermore, they strengthen the notion that adaptationprocess starts in SMA and M1 follows it.Supported by Mafat, Johnson and Johnson,BSF,  and by a contributionsof Abraham and Ida Baruch Foundation and theRosetrees trust. Secondary brain damage often occurs after traumatic braininjury traumatic brain injury (TBI). TBI can result from explosions,including terrorist attacks, traffic and householdaccidents, and other forms of violence. Neuronal death dueto secondary brain damage and neurodegeneration have incommon an excitotoxic process leading from overexcitationof glutamate receptors to mitochondrial damage. Themitochondrial damage can lead to neuronal death, includingapoptosis. Our studies suggest that the mitochondrialTranslocator Protein (TSPO) plays an important role in thisprocess. Recently, we have developed compounds that bindwith high affinity to the TSPO and apparently block its apoptoticfunction. These novel compounds reduced basal apoptoticlevels in neuronal cells. Some of them also reducedapoptosis induced by glutamate in the SH-SY5Y cell line bymore than 50%. In our in vivo experiments we found thatone of our ligands (9a) (15 mg/kg) reduces the adverse effectsof kainic acid (9-10mg/kg) in rats. For example, seizures inducedby kainic acid are indicative for neurodegeneration inthe hippocampus. Severe seizure activity was reduced by 9aby more than 67%. As some of our compounds show antiapoptoticeffects others show pro-apoptotic effects, whichmay have implications for the development of potential anticancerdrugs. We envision that secondary brain injury due toTBI may be prevented by soldiers and paramedics carryingwith them one of the antiapoptotic drugs we have developedand use it on site. This may reduce the incidence of disabilitiespresently occurring in the aftermath of TBI. In addition,such a drug might also find application in the treatment ofneurodegenerative diseases.Supported by Dan Horovitz fund  Center for Absorptionin Science, Israel (L.V). +), carbamazepine (CBZ) andvalproate, at therapeutic concentrations, exert an inhibitoryeffect on forskolinandGαs-coupled receptor activated cAMPaccumulation. The aim of this work was to study the effects oflithium and carbamazepine on each of the membrane-boundisoforms of aednylyl cyclase (1–9). COS7 cells were transfectedwith each of the AC isoforms cDNAs with or withoutD1-dopamine receptor cDNA. AC activity was measuredas [3H]cAMP accumulation in cells pre-incubated for twohours with 1mM Li or 0.1mM CBZ followed by incubationwith either the D1 agonist FKS-82958 or forskolin. Therole of Mg2+ in Li's inhibition of AC was studied in membranepreparations from cells expressing AC5. When stimulatedby forskolin, a direct activator of AC, both 1mM Li+and 0.1mM CBZ inhibited only AC5 activity. When stimulatedvia D1 receptors, Li+-inhibitable isoforms were AC5and AC7 (∼40–50% inhibition) while CBZ inhibited all isoformsstudied  by ∼50%. In isolated membranepreparations of AC5-transfected cells stimulated AC5 activitywas completely abolished by 1mM Li, and 10mM Mg2+significantly counteracted Li's inhibition. Since forskolin isa direct activator of AC, the specific inhibition of forskolinstimulatedAC5 by both Li and CBZ suggests a direct effectof these drugs on this specific isoform. Reversal of Li's inhibitionof AC5 activated via the D1-dopamine receptor byMg2+ suggests that competition with endogenous Mg2+ ionsis involved in the mechanism of the inhibition. Since CBZinhibited all studied isoforms including AC5 and AC7, it ispossible that AC5 and AC7 are involved in the mechanism ofmood stabilization.Bipolar disorder has been hypothesized to be associated withan enhanced signaling activity of the cAMP cascade. Themood stabilizers lithium ;40 seconds, 5 kHz) that coterminates with a mild footshock(unconditioned stimulus (US); 0.5 seconds, 1.5 mA). Ratswere trained with 5 consecutive CS-US pairings with averageITI of 180 seconds. We microinfused the actin polymerizationinhibitor cytochalasin D into the lateral amygdala (LA),a brain area mediating fear conditioning, and studied its effectsonmemory formation. Microinfusion of cytochalasinDimmediately before fear conditioning training impaired theformation of long-termfear conditioning memory. CytochalasinD had no effect on fear conditioning memory retrievalwhen microinfused immediately before the test 24 hours aftertraining, indicating also that cytochalasin D did not impairnormal synaptic transmission in LA. The present resultsshow that actin polymerization in LA is essential for fear conditioningmemory formation. μM), in the presenceof tau (1 μM), as evaluated by electron microscopy. Additionally,NAP-treated microtubules appear to be significantlylonger and more curved compared to the rigid, short microtubulesthat were observed in the absence of NAP. In conclusion,NAP treatedmicrotubules assume a different structure–namely longer and smoother microtubular structures areformed when NAP is present. Thus, perhaps the interactionbetween NAP and microtubules resulting in conformationalchanges (length and shape) leads to the assembly and microtubulesreorganization. These findings may be of great importancein elucidating the mechanism of NAP nueroprotectiveand neurotrophic roles.NAP (NAPVSIPQ), a short peptide, derived from activitydependentneuroprotective protein (ADNP), was revealedto be a novel neuroprotective drug candidate. Femtomolarconcentrations of NAP appear to provide neuroprotectionin vitro against tetrodotoxin, N-methyl-D-aspartate, naturallyoccurring cell death, dopamine toxicity, tumor necrosisfactor-α toxicity and oxidative stress. NAP was further shownto reduce mortality and morbidity, produce cerebroprotection,reduce apoptosis and accelerate learning and memoryabilities in a broad variety of in vivo models. A significantinteraction between NAP and tubulin unraveled a possiblemechanism of this novel peptide. Through this interactionNAP seems to promote tubulin assembly and microtubulesreorganization even in the presence of zinc intoxication. Thisstudy is aimed to assess the characteristics of NAP interactionwith microtubules. Pelleting assays were used to determinethe effect of NAP on tubulin and co-assembly into microtubules,in the presence of tau. The assembled microtubuleswere examined by electron microscopy. NAP (1 pM) treatmentincreased microtubule density  the monkeyshad to detect the head direction of another monkey (presentedon a screen) and to use this information to make asaccade to one of two dots (either left or right of the monkeyface). In the control condition (colormatching) the monkeyshad to use the color information provided by the fixation dot(presented in between the eyes of the monkey face) to makea saccade to the dot with the same color. Eye movements ofthe monkeys were recorded using a homemade iris-fit-eyetrackingsystem. During both conditions, i.e., independentof which cue was used, activation was found bilaterally in(or near) the frontal eye fields, probably reflecting the needto make saccades. For the contrast “color matching minusgaze following” specific activation was found bilaterally inthe inferior temporal gyrus, a region known to be involved incolor processing. The opposite contrast (gaze following minuscolor matching) revealed a bilateral activation in the superiortemporal sulcus (STS), most consistently in the middlepart of the sulcus: the mSTS. A region in the posterior STSis known to underlie eye gaze following in humans. Hence,although human and nonhuman primates seem to rely ondifferent directional cues, they may deploy similar and possiblyhomologous cortical areas to follow the gaze of a conspecific.Supported by the EU program “PERACT” and a grant from theBMBF (01GA0503). n = 12) while that of the NaCltreatedrats was 20.5 ± 4.6 . Conclusion:The preliminary results obtained support the concept thatdecreasing excess glutamate in blood/brain may serve as analternative therapeutic strategy in the management of malignantgliomas.Studies performed in the last few years have shown that malignantglioma cells secrete in the peritumoral space massiveamounts of the neurotransmitter glutamate, and by doingso, promote their own expansive growth at the expense ofthe neighboring neurons that undergo excitotoxic cell death.Since these studies suggest now that interfering with brainglutamatemay control glioma cell proliferation and invasion,and may limit brain neuronal injury caused by glutamate excess,we have evaluated in the present study the therapeuticefficacy against glioma of a novel neuroprotective strategyrecently developed in our laboratory that is based onthe ability to cause a decrease of excess brain glutamate levels.By accelerating a naturally occurring brain-to-blood glutamateefflux, we cause a decrease of deleterious glutamatelevels in brain. This is achieved by the administration of oxaloacetate(OxAc) which, by scavenging blood glutamate levels,increases the driving force for the efflux of glutamatefrom brain into blood. Methods: Cultured C6 glioma cellswere implanted in rat brain to induce tumor growth and itsaccompanying neovascularization. OxAc was daily preparedand added to the drinking water of the implanted rats whilethe rats in the control group drunk a NaCl solution at thesame osmolarity of the OxAc solution (0.4 M). Each groupconsisted of 12 rats housed in individual cages. The OxAc orNaCl treatment was started five days after glioma implantationand the tumor development was followed using MagneticResonance Imaging (MR)I up to three weeks. Results:MRI analysis shows that OxAc-treated rats displayed a foldtumor growth of 8.9 ± 1.9 ( Tourette syndrome (TS) is characterized by chronic motorand vocal tics and has a high comorbidity ratewith obsessive compulsive behavior (OCB) and attentiondeficit/hyperactivity disorder (ADHD). Despite the differentclinical manifestations of these disorders, they have all beenassociated with a common neuronal pathway: the corticobasalganglia loop. Most of the nuclei of the basal ganglia useGABA (gamma-aminobutyric acid) as their primary neurotransmitterfor both inter and intranucleus informationtransfer. Bicuculline (GABAA antagonist) injection to theprimate putamen evokes motor tics resembling the primaryTS symptoms while injections to different domains withinthe globus pallidus external segment (GPe) produce behavioralcorrelates of the comorbid disorders (stereotypy and hyperactivitywith attention deficits). In our study we use extracellularmultielectrode recording to characterize the changesin firing patterns of multiple single neurons and to uncoverthe neuronal interaction within small neuronal networksfollowing the injection. Our results demonstrate that localblockade of GABA leads to the formation of intermittenthigh-frequency activity within the GPe. Moreover, neuronswithin the injected domain transition from uncorrelated firingto a synchronized firing pattern. The observed changesin neuronal activity are highly correlated to the behavioralsymptoms as assessed by the limb kinematics and video analysisof expressed behaviors. Neurons within the GPi displayhighly locked activity prior to the tic performance. This investigationof GABAergic transmission within the corticobasalganglia loop provides unique insight into the informationencoding within these circuits and how the breakdownof normal activity leads to the severe clinical symptoms associatedwith TS. Our studies of HFS within the GP demonstratethat it leads to a locked response to stimulation whichchanges the firing rates and breaks down abnormal correlatedactivity. N = 30 eyes) and had corrected-to-normalvisual acuity. The mesopic CS was measured under conditionsof full darkness, using natural density filters to cover themonitor, allowing a background luminance of 0.03 cd/m2.The CS measured for Gabor targets was with spatial frequenciesof 3–9 cpd. In addition, we tested the influence of externalblur  on the toleranceof the visual functions at night. The results show thatCS was affected twofold more than the VA under night conditions, compared with the day conditions. The crowding effectdid not increase under night conditions. Under the blur condition,VA is only slightly affected, whereas CS is remarkablyreduced (66%). Thus, visual functions are affected differentlyunder different visual conditions; while tasks performed nearthreshold are affected remarkably, supra-threshold tasks areless affected. Therefore, visual perception cannot be predictedfrom standard visual acuity test.Visual perception changes dramatically under day and nightconditions. Visual performance under vision-limiting conditions,for example, night vision of all people with either impairedor outstanding night-vision, is affected. In this studywe explored how different light conditions change the visualabilities of humans. We measured basic functions of the visualsystem such as visual acuity (VA), day contrast sensitivity(CS), and foveal mesopic CS. The subjects were testedmonocularly  has become one of the leadingmethods in neuroscience. It was recently suggested thatresting state fMRI can be used to define the default stateof brain activity, functional connectivity and basal activity.The measurement of basal activity through resting-statefMRI opened new horizons of this methodology. Here weshow that cluster analysis of the repeated blood oxygenationlevel dependent (BOLD) measurements of the restingstatesignal resembles the anatomical and cyto-architectonicarrangement of the tissue in cortical and subcortical graymatter as well as in the white matter. Therefore, withoutimposing functional paradigms on the BOLD signal(as in rest fMRI), separating the functional contributionto the signal fluctuation from the anatomical contributionis challenging. Nevertheless we suggest that multidimensionalbrain MRI acquisition  can be used for parcellation of the braininto regions that could not be extracted with conventionalMRI. Drugs of abuse act through intervening in the normal activityof the reward system. The reward system is composed frominterconnected distinct brain regions, including the ventraltegmental area (VTA), the main source of dopamine in thebrain, which synapses onto the nucleus accumbens (NAc)neurons. The psychostimulant cocaine inhibits dopamine reuptaketo VTA neurons, as a consequence synaptic dopamineconcentration in the NAc elevates, and a typical psychostimulanteffect is achieved. NAc dopamine levels can also bemodulated by changes in the activity of VTA dopaminergicneurons. Over excitation of these neurons or its reduced inhibitioncan lead to enhanced dopamine release in the NAc.Therefore we aimed to determine whether cocaine increasesthe activity of VTA neurons through inhibition of GABAAreceptors-mediated currents. Rat brain slices containing theVTA were prepared, and VTA dopaminergic neurons wereidentifiedmorphologically and electrophysiologically. Wholecell GABAA inhibitory post synaptic currents (IPSCs) wererecorded using standard patch clamp technique, in responseto electrical stimulation of the pre frontal cortex (PFC) afferentsand bath application of dopamine. We found a significantreduction of GABAA-mediated IPSCs following applicationof 30 microM dopamine. This reduction was blockedeither by dopamine D1/D5 receptors antagonist SCH23390or by the dopamine D2 receptor antagonist eticlopride. Althoughthe molecular mechanism by which dopamine reducesIPSCs is not fully understood, these results reveal a newpossible aspect of cocaine action in the VTA. This findingsuggests that in addition to cocaine inhibition of dopaminereuptake, a reduction of IPSCs occurs, and together theseevents mediate the development of cocaine addictive properties.Supported partially by grant from the National Institute forPsychobiology in Israel. The human activity-dependent neuroprotective protein(ADNP) gene was mapped to chromosome 20q12-13.2, aregion associated with aggressive tumor growth, frequentlyamplified in many neoplasias. Human ADNP mRNA expressionwas shown to be significantly increased in colonand breast cancer tissues in comparison to normal adjacenttissues, while inhibition of ADNP expression by antisenseoligodeoxynucleotides results in HT-29 (colon cancer) celldeath associated with increases in P53 expression. The currentresearch aims at improving ADNP knockdown in orderto potently inhibit cell proliferation in cancer therapy.Assays were preformed using 3 cell lines: HT29 (colon cancer),A375 (melanoma) and PC3 (prostate cancer). Cell viabilitywas measured by the MTS colorimetric assay. Inhibitionof growth was performed by antisense oligodeoxynucleotides.ADNP knockdown was examined at the mRNAlevel, using quantitative real time PCR, and at the proteinlevel, using western blot analysis. Dramatic enhancementsin ADNP knockdown were obtained as follows: (1)The use of a transfection reagent that increases the uptakeof the ADNP antisense into cells. (2) The use of the aureolicacid antibiotic, Mithramycin, which binds selectivelyto GC-rich DNA sequences and blocks preferential bindingof proteins to GC-rich elements in gene promoters (suchas the ADNP promoter). Both inhibition of ADNP mRNAby antisense oligonucleotides, and inhibition through theblockade of ADNP transcription factor from binding to itspromoter caused a significant decline in ADNP expression.Down regulation of ADNP inhibited cell proliferation, suggestingADNP inhibition as a novel approach for cancer therapy.Previous studies have shown that ADNP is essentialfor brain function (, a cholinesterase (ChE) andmonoamine oxidase inhibitor with neuroprotective activity,given orally for 2 weeks at a dose of 2.9 mumoles/kg,prevented microglial activation and the appearance ofoxidative-nitrative stress in discrete brain areas induced byicv injection of streptozotocin. This dose was too small toinhibit either enzyme.The aim is to determine whether ladostigil produced theseeffects by acting directly on microglia, and/or indirectly,by preventing neuronal damage. Methods: The effect of ladostigiland its active metabolites was measured on the releaseof NO induced by LPS (10 mug/ml) from mouse microglia,and on cytotoxicity induced by the tert-butyl hydroperoxide(TBHP) in SNKMC cells. The nitrite levels weredetermined spectrophotometrically with Griess reagent. Theantiapoptotic effect of the compounds was measured by decreasein caspases 3/7 or prevention of the fall in the mitochondrialpotential by JC1, and cell death, by trypan bluestaining. Results: Ladostigil, its metabolites which lacked eitherthe propargyl or the carbamate moieties or aminoindanitself at concentrations of 1 nM-1 muM reduced by almost50% the release of NO from microglia. Higher concentrationswere less effective. On the other hand, only ladostigiland metabolites containing a propargylamine group(100 nM-10 muM) significantly reduced apoptosis, the fall inmitochondrial potential and cell death induced by TBHP inSKNMC cells indicating that two different mechanisms wereinvolved in these actions of ladostigil. Conclusion: The reductionof microglial activation and nitrative stress inducedby a low dose of ladostigil in the rat brain can result from adirect action on microglia. Recent data suggest an active participation of astrocytes inneurotransmission by dynamic interactions with neurons.However the contribution of astrocytes may not only resultfrom individual cells, but also from cellular networks, as theyexpress numerous gap junctions. The aim of this work wasto determine whether the connectivity of astrocytic networksparticipate in hippocampal neurotransmission and plasticity.Synaptic transmission was studied in Cx30 (one of the twogap junction proteins in astrocytes) knockout mice, whoseastrocytic network connectivity is reduced by ∼50%. Fieldexcitatory postsynaptic potentials in Cx30−/− mice are reducedby ∼35% compared to wild-typemice. This decrease isnot due to changes in intrinsic properties and excitability ofCA1 pyramidal neurons or postsynaptic receptor density. It israther due to a decrease in glutamate synaptic concentration,as the frequency but not amplitude, of mEPSCs is decreasedin Cx30−/− mice and the ratio of AMPA to NMDA synapticcurrents is unchanged. The altered synaptic transmissionis due to Cx30 deletion, as it is not observed in young mice(?P10), where Cx30 is not yet expressed. In addition, this effectis specific to glutamatergic transmission of CA1 pyramidalcells, as miniature IPSCs from pyramidal cells, as wellas mEPSCs from interneurons, are not changed in Cx30−/−mice. The contribution of astrocytic networks to short andlong-term synaptic plasticity was also studied. Paired-pulsefacilitation was increased, whereas post-tetanic potentiationwas reduced in Cx30−/− mice. Prolonged repetitive stimulation led to an increased initial facilitation,followed by a slower synaptic depression. Furthermore longtermplasticity is also altered in Cx30−/− mice, as they showa 70% decrease in the amplitude of LTP. Altogether these resultsindicate for the first time that astrocytic gap junctionsregulate neuronal excitatory transmission and plasticity.Supported by Human Frontier Science Program, Agence Nationalede la Recherche, French Ministry of Research. Removal of divalent open channel block by depolarizationplays a critical role in learning and memory, which is mediatedby the N-methyl-D-aspartate (NMDA) channel. Otherchannels also exhibit open channel block, but the physiologicalmechanism of its removal is still unknown. We show herethat lipids produced by phospholipase C (PLC) and hypoosmoticsolutions remove divalent open channel block fromthe Drosophila Transient Receptor Potential-Like (TRPL)channels by bending the plasma membrane. Membranebending increased single channel current and caused impermeablecation influx. The GsMTx-4 toxin, which specificallyinhibits mechanosensitive channels, blocked the lipids effect.We found remarkable commonality between the effects oflipids on the Drosophila TRPL and the mammalian NMDAand TRPV3 channels. We suggest a new lipid-dependentmechanism to alleviate open channel block, which operatesunder physiological conditions, in synergism withdepolarization. The profound effect of lipids modulation allowscross talk between channel activity and lipid-producingpathways. We offer a novel mathematical analysis for diffusion imagingdata, which is able to separate between free water andthe remaining brain tissue. In diffusion imaging we are ableto magnetically trace the motion of water molecules. Propertiesof the motion depend on the surrounding tissue, and theamount of hindrance the molecules face. By analyzing thoseproperties we are able to differentiate between tissue types. We can also analyze thedirectionality of the tissue (for whitematter), which allows usto infer connectivity measures between different parts of thebrain. The conventional way to analyze the diffusion propertiesof water molecules is named Diffusion Tensor Imaging(DTI), but this analysis fails to describe a tissue, which is inclose proximity to free water. For healthy patients free waterin the brain is found in the ventricles, and CSF filled cavities.Clinically, there are diseases and conditions that can berelated with free water in the brain, especially in the form ofedema. Edema is common, for instance, for patients sufferingfrom brain tumors, stroke or other brain trauma. By applyingour framework on such datasets we were able to mapthe relative volume of the free water compartment across thebrain. Once the free water is mapped we can eliminate it inorder tomeasure the properties of the remaining brain tissue.Using this method we have correctly identified white mattertracts that pass next to the ventricles, and more importantlywere able to delineate the tract of white matter bundles thatpass through edematous areas. This analysis allows better inferenceas to the condition of the tissue due to the edema. by the Edersheim-Levi-Gitter Institute. When one side of the brain learns to perform a perceptualtask, does the other side remember what has been learned?The expectation from receptive field size is that low levels inthe visual hierarchy will be small, leading to specific local improvement,while higher levels will reflect generalized training,learned and remembered by all . These tasks were always performed with testarrays in the center of the test screen. More recently, we introducedeccentric search arrays , which were exploited later to test transfer oflearning effects between hemispheres. We found transfer foreasy tasks and not for hard tasks when subjects performedcolor and orientation feature search, each within one hemifield.However, the method used left an ambiguity that thetransfer we found could be interpreted as transfer acrosstasks, and not between hemispheres. We now test the possibilityof cross-hemisphere transfer by designing a paradigmwhereby two independent tasks with very similar average degreesof difficulty are performed in the two hemifields. Wetrained subjects on a local detection (orientation pop-outtask) in one hemifield and on global identification  in the other hemifield.Following training, we switched the sides of the tasks. Wefound transfer for the trained dimension for easy cases, suggestingthat the transfer was due to a hemifield transfer. Weconfirmthe Reverse Hierarchy Theory that as long as the perceptualtask is easy enough to be performed at high corticallevels, transfer will occur to new conditions that depend onthe same, broad-spectrum, receptive fields. Results supportcross-hemispere transfer for easy task conditions.Supported by National Institute for Psychobiology in Israel, USIsraelBinational Science Foundation. Parameters distributions and interrelations in compartmentalmodels of neurons Noam Peled and Alon Korngreen TheMina and Everard Goodman Faculty of Life Sciences andThe Leslie and Susan Gonda (Goldschmied)MultidisiplinaryBrain Research Center, Bar-Ilan Univ., Ramat-Gan, Israel.Our understanding of the input-output function of singleneurons has been advanced by biophysically accurate multicompartmentalmodels.The large number of free parametersin these models requires the use of automated approachesfor finding their optimal values in a very multidimensionalparameter-plane. Here we use genetic algorithm as a stochasticoptimization algorithm. Due to inherent noise in measuringequipment and the stochastic nature of the neuron, thedetermination of the accuracy of the obtained parameters isnear impossible. Here we show that finding the parametersdistribution viaMonte Carlo simulations reveals the sensitivityof each parameter to noise. Furthermore, we calculate theaverageHessian matrix over all the global minima to discoverthe interrelations between the parameters. To use a stochasticoptimization algorithm a distance function must be declared,which calculates the distance between a given modeloutput and the desire one. In this work we used several distancefunctions which are in used in this field. We comparebetween them, and discuss which can be suitable for suchkind of a problem and which one not. It is well established that various brain regions, such as thefrontal eye fields (FEF), supplementary eye fields (SEF), andthe intraparietal sulcus (IPS), are involved in various aspectsof eye movement planning and execution in both humansand primates. However, the reference frames in which informationis represented in each of these areas is hotly debated.Specifically, it is unclear whether the direction of asaccade, its exact origin, final destination point  or combinations of these representationsare multiplexed in these regions. Recently, new multivariateclassification methods have been used to assess thereliability of distinctive spatial patterns of the fMRI responses(SPfR) in the visual cortex. We applied similarmethods in orderto examine the spatial nature of representation of memorybased saccades in cortical regions. Human subjects performedamemory saccade task in which equal amplitude saccadescould be executed from several starting points and ina number of directions. We find that the SPfR in the FEF,SEF and IPS are positively correlated when the same saccadesare repeatedly executed. The patterns become uncorrelatedwhen saccades of the same magnitude and direction are executedfrom different starting points. These findings suggestthat these regions all contain a neural representation which issensitive to both the direction and starting point of the saccadeand thus, the representation is not entirely oculucentricbased, but rather, it is also coded in head, body or world coordinateframes. Introduction Previous studies suggested an impairment ofexecutive functions in patients after cerebellar stroke. Otherstudies showed contradictory results. The specific role ofthe cerebellum in cognition is still unknown. The presentstudy investigated cognitive deficits in the acute phase aftercerebellar stroke, the recovery of possible symptoms andthe effect of a cognitive training. Moreover, differences betweenthe vascular territories, the lesion side and the involvementof cerebellar nuclei were examined. Methods Twelvepatients with acute cerebellar stroke of the superior or ofthe posterior inferior cerebellar artery were matched withhealthy controls and were examined by an extensive neuropsychologicaltest battery in the acute phase, after twoweeks and three months. Lesions were localised by magneticresonance imaging in the acute phase and after threemonths. One half of the patients received a cognitive training,which was developed for patients with an impairmentof executive functions after damage to the prefrontal cortex.Results A significant impairment in theWisconsin Card SortingTest as a measure of action planning could be shown. Patientswere also impaired in changing categories of a verbalfluency test (Regensburger Wortfluessigkeitstest) as a measureof cognitive flexibility. After three months differenceswere no longer significant. There was no difference betweentreated and untreated patients and no effect of the locationof the stroke. Conclusions The present study suggests an impairmentof executive functions in the acute phase after cerebellarstroke. These deficits could not be explained by disturbancesof attention or visuospatial abilities or by depression.No effect of the neuropsychological training could beshown, possibly because of the small number of patients anda spontaneous recovery of symptoms. The effect of the cognitivetraining should be investigated in a larger group ofpatients.Supported by BMBF, German-Israeli Cooperation in Neuroscience(01GA0508) and IFORES . Depression is a highly prevalent, severe and often lifethreateningdisorder. Despite the advances that have beenmade in the development of antidepressants, there are clearlystill unmet clinical needs that should be addressed. To answerthese needs, neuropeptide systems have started receivingincreasing attention for the development of novel antidepressants.Pituitary Adenylate Cyclase Activating Polypeptide(PACAP) is a neuropeptide that exhibit central andperipheral effect via selective G-protein coupled receptorsnamely PAC1, VPAC1 and VPAC2. We are investigating involvementof PACAP and its receptors in the etiology ofpsychiatric disorders. Using primary rat enriched neuronalcell cultures we have demonstrated that acute (6 hours) andprolonged (48–72 hours) treatment with PACAP38 significantlyup-regulates mRNA levels of Brain Derived NeurotrophicFactor (BDNF), the neurotrophin that is thoughtto be involved in the etiology of affective disorders and inthe mechanism of action of antidepressants.. Our resultshave also revealed that expression of PACAP and its receptorsare affected in primary cortical and hippocampalcell cultures treated for 72 hours with antidepressants representingdistinct classes. Interestingly, changes in PACAPreceptors expression resulting from antidepressant treatmentwere highly and negatively correlated with BDNF expression.To examine these findings in vivo, we administeredimipramine (3 mg/kg) for 21 days to C57Bl6 mice.This chronic treatment resulted in a significant increasein PAC1 mRNA expression in hippocampus and a decreasein BDNF expression both in hippocampus and prefrontalcortex. Our findings suggest that antidepressantsmay influence synaptic plasticity via modulation of PACAPBDNFsignaling and further understanding of these phenomenamight contribute to the understanding of etiologyof affective disorders and development of novel antidepressants. Association between maternal exposure to infection duringpregnancy with increased liability to schizophrenia in theoffspring has inspired the development of the prenatal immunechallenge model of schizophrenia in which the syntheticcytokine releaser polyinosinic-polycytidilic acid (PolyI:C) is used to activate the maternal immune system. Adultoffspring of poly I:C treated dams exhibit a wide spectrumof cognitive deficits reflective of schizophrenia, including selectiveattention abnormalities as measured in latent inhibition(LI) and discrimination reversal (DR). Importantly, thenature of deficits exhibited in the two tasks were reportedto differ depending on the time of poly I:C challenge, withchallenge early in gestation leading to attentional overswitching(disrupted LI and rapid DR) and late in gestation to attentionalperseveration (intact LI and slow DR). We heretested the effects of neonatal poly I:C administration on thesetwo tasks. Male rats were injected on postnatal day 4 withpoly I:C (2mg/kg or 4mg/kg) and tested at adulthood in LIand DR. Neonatally treated rats had disrupted LI and slowDR superimposed on learning and/or performance deficitin both tasks. This deficit pattern may have relevance tochronic schizophrenia or autism. While present results supportthe notion that the long-term deleterious effects of polyI:C challenge depend on the timing of the challenge, comparisonto another neonatal manipulation shows that the natureof the insult and not only its timing, determines theoutcome. The aim of the study is to investigate memory and learningin aged rats in tests based on differential task demands and toassess the potential of ladostigil (TV-3326) (a novel drug withantiinflammatory activity)1 to prevent aged-related cognitivedecline.n = 10) and 15–16 months  in the courseof habituation during 4 consecutive days followed by suddenchange in this environment. Ten rats from AC were thenrandomly assigned for chronic oral treatment with ladostigil(1 mg/kg/day) till the end of testing (A-TV). To assess referencememory (RM) YC at the age of 3.5 months and aged ratsat 19–20 months were trained in the holebox (HB) to searchfor food in 4 fixed positioned holes, marked by light. Spatialmemory was also assessed one month later in the MorrisWater Maze (MWM) test.Place memory and detection of novelty in open field test(OF) were evaluated in male Wistar rats, aged 2.5months,the GABA receptor antagonist, penicillin (100 U/uL) or byelectrical stimulation of the SPG. Laser Doppler flowmetryand EEG are simultaneously recorded over the surfaceof the treated region to monitor brain perfusion and neuronalactivity, respectively. Vessels diameters and BBB permeationare measured offline using homemade MATLABscripts. The analysis entails vessels identification followingdye injection under control conditions, followed bymeasurementsof changes in extravascular fluorescent intensity. Histologicalanalysis was assessed following the in-vivo experimentto confirm BBB opening.The presented method offersa new tool to study mechanisms underlying alterationsto brain vascular characteristics including vessels diameterand permeability under normal and pathological conditions.The blood–brain barrier (BBB) is designed to separate thebrain's interstitial space from the blood. In both humanand animal models there is still lack of reliable quantitativemethods for studying the mechanisms underlying vesselpermeability under healthy and disease conditions. Wereport here a new method for estimating BBB permeabilitybased on analysis of fluorescent images of surfacevessels in the rat cerebral cortex. Rats are anaesthetizedand fixed under a fluorescent stereo-microscope. A cranialwindow is opened over the cerebral cortex and the durais removed. During the experiment the brain is continuouslysuperfused with artificial cerebrospinal fluid (ACSF).The animals are then injected intravenously (IV) with thealbumin-binding, BBB nonpermeable dye Evans Blue  or with Lucifer Yellow . Fluorescent imagesof the cortical surface are collected at fixed intervalsbefore, during and following dye injection to identifyblood vessels and to follow changes in fluorescent intensitywithin the brain parenchyma. To disrupt the BBBbrain was perfused with the bile-salt sodium deoxycholate, NaThis work was supported partly by “BrainsGate.” A fundamental issue in the study of the human visual systemconcerns the neuronal dynamics that may underlie theemergence of a visual percept. In local field measurementsa number of putative signals have been described as relatedto visual processing including transient potentials (ERP),delta waves, alpha-beta power disynchronizaiton (ERD) andgamma power modulations. A striking characteristic of humanperception is the ability to maintain a conscious visualpercept for an extended period of time. Here we employedthis phenomenon to identify putative candidates for objectperception. Recording was done using sub-dural electrodesthat were implanted in patients with epilepsy strictly for clinicalpurposes. During recordings subjects were exposed toimages of objects lasting 2 seconds. The task of the subjectswas to report contrast changes in the images. Our resultspoint to gamma power as the most consistent electrophysiologicalmarker whose activity was maintained in close correlationwith the perceptual state of the subjects. Another clearcut electrophysiological signal whose activity wasmaintainedthroughout the percept was ERD. In contrast to the gammaenhancement, this signal showed a much broader tuning tovarious image properties.Supported by ISF grant to R. Malach and US Israel BSF grantto Malach and Fried. Optic neuritis (ON) is a common condition that causes reversibleloss of vision in young patients. It derives from idiopathicinflammatory demyalination. There is an ongoingdebate about whether ON derives from parvocelluar or magnocelluardeficit. Visual function improvement is commonin this disease, and is usually attributed to peripheral nerverecovery. Our previous study has suggested that central reorganizationprocesses, that is, the lateral occipital complex(LOC), may also be involved in recovery. The aim of thepresent work is to study the behavioral and cortical changestaking place following an ON episode, in a longitudinalstudy. We have found that, after the acute phase, ON eyeshad normal or near normal visual acuity, contrast sensitivityand color perception; however, they still had difficultiesin recognizing objects defined by motion. This may supporta specific magnocelluar deficit in ON. In order to study apossible cortical origin for the behavioral results, we havestudied fMRI activation pattern in the ventral and dorsalpathways. While the former may be more concerned withvisual acuity and is mainly considered to be stimulated bythe parvocelluar system, the latter may contribute to motionperception and is mainly stimulated by the magnocelluarsystem. We have compared the patterns of fMRI activationelicited by stimulation of the affected and the healthy eyes,along the visual cortical hierarchy. As previously, we foundreduced fMRI activation in V1 during stimulation of the affectedeye compared with the healthy eye. However, the magnitudeof difference in fMRI signal decreased with progressionalong the visual hierarchy, both in objects and motionrelated areas, suggesting cortical adjustment to abnormal input.Those preliminary fMRI results, however, did not supporta different role for the affected eye in ventral and dorsalpathways.Supported by The Caesarea Edmond de Rothschild foundation. The entopallium (E) in birds is the major thalamorecipientforebrain structure of the tectofugal pathway The E receivesmost of its input from the nucleus rotundus, the avian homologof the mammalian thalamic pulvinar complex . Previousresearch has characterized the tectofugal pathway inmammals and pigeons as an extra geniculate pathway leadingvisual information to the cortex. This pathway has beensuggested to be involved in bottom-up attentional control.We show that, in the barn owl, entopallial cells respond toauditory as well as visual stimuli, suggesting that the tectofugalpathway is not strictly visual but carries multisensory information.We characterized single unit responses in the Eto binaural localization cues including interaural time difference(ITD) and interaural level difference (ILD), as wellas average binaural sound intensity (ABSI). Similar to visualreceptive fields, auditory receptive fields were typically largeand covered most of the contralateral space. In addition, amajority of the cells presented nonmonotonic rate level functionswith a preference towards weak intensity sounds. Interestingly,most multisensory neurons in the E respondedstronger to spatially aligned visual and auditory stimuli thanto the sum of the responses to the unimodal components (superadditiveenhancement). Finally, we show that the bimodalenhancement is context dependent appearing more robustlyin responses to rare stimuli, a result that is in-line with thenotion that the E is involved in multisensory control of spatialattention.This work was supported by a grant from the National Institutefor Psychobiology in Israel and a BIK. μM) hadno effect on metabolic activity and cell viability. Incubationfor 72 hours increased cell metabolic activity with the exceptionof Paroxetine and Imipramine at 10 μM that proved tobe cytotoxic. Cotreatment with antidepressants (3– 10 μM)and PACAP or it's antagonist PACAP(6– 38) was ineffective incells exposed to Paroxetine 10 μM. Moreover, co-treatmentwith PACAP and Imipramine 3– 10 μM had an adverse effecton cell viability. In summary, our results point towardPACAP signaling involvement in synaptic plasticity processesmediated by antidepressants.According to the monoaminergic hypothesis of depression,most of the antidepressants are aimed to stimulatemonoamine systems. In spite of their predominant effecton monoamine neurotransmitter levels, these drugs mayalso mediate changes in synaptic plasticity by modulatingneuropeptide action in brain areas, such as hippocampusand prefrontal cortex. Pituitary Adenylate Cyclase ActivatingPolypeptide (PACAP) is a neuropeptide exertingpleiotropic effects via three types of receptors, PAC1, VPAC1and VPAC2. We have investigated the effects of various antidepressantson the expression of PACAP, its receptors andbrain derived neurotrophic ffactor (BDNF), a neurotrophinimplicated in the mechanism of action of antidepressants.Using a real-time PCR analysis, we found that selective serotoninreuptake inhibitors, Paroxetine and Citalopram, significantlyand dose-dependently decreased PAC1 and VPAC2mRNA levels following 72-hour treatment, whereas tricyclicantidepressant Imipramine exhibited an opposite effect. Noeffect on VPAC1 expression was observed. Furthermore,we found an intriguing correlation between the changes inPAC1/VPAC2 and BDNF expression after treatment with antidepressants.In addition, we examined the effect of these antidepressantson neuronal cell survival, using a cell proliferationassay based on metabolic activity. Incubation of corticalneurons for 24 hours with antidepressants  or valproic acid (AN-216)did not elicit a significant effect. The GABA amides of theantidepressant nortriptyline, BL1021, or fluoxetine, BL1024,significantly increased the latency of nociceptive reaction ofBalb/c mice to heat and displayed significantly higher analgesiceffects than the parent antidepressants. Intraplantar injectionof formalin to Balb/cmice resulted in a typical biphasicflinching behavior of the injected paw. In this modelBL1021 and BL1024 significantly reduced the early nociceptiveand the late inflammatory peripheral responses comparedto equimolar po doses of nortriptyline, fluoxetine,or equimolar mixtures of the antidepressants and GABA orgabapentin. Skin samples from the injected paws, exhibitedsignificantly lower levels of interferon- gamma and TNF-alfain mice treated with BL1021 compared to those treated withnortriptyline, and to the mixture of nortriptyline and GABAor gabapentin. InWistar rats injected intraplantarly with carrageenan,BL1021 showed significantly better efficacy in inhibitingedema, than those treated with nortriptyline. In addition,a significantly increased latency of nociceptive reactionby these rats was demonstrated using the hot-plate-test.The notably better efficacy of the amides compared to theirparent drugs towards both the central perception and the peripheralphase of pain, make them promising candidates forthe treatment of acute and neuropathic pain conditions.This research was partially supported by BioLineRx. n = 19) was55% larger (P < .002) than the averaged sEPSCs in neuronsfrom pseudo-trained  and naïve rats , which had similar values. Principal componentanalysis (PCA) of the amplitude distributions was appliedto further characterize the nature of the change. PCAshowed that the variability between cells resulted from twodifferent components: (1)Homogenous change of all sEPSCsin a given cell. (2) The proportion of large versus small spontaneousevents. Such analysis showed homogenous increaseof around 1.5 pA in all synapses in pseudo-trained comparedto naïve (P < .02). Such increase was not paralleled with increasein the averaged amplitude of spontaneous events dueto an statistically insignificant change in the proportion betweenlarge  and small  events. In contrast, in neurons from trained rats,when compared with pseudo-trained, only a fraction of thesmall sEPSCs (3.75–7.25) in each cell was substituted by verylarge sEPSCs (10–25pA). The size of this fraction varied betweencells and ranged between 0–100% of the small sEPSCsin the averaged pseudo-trained cell. Our data show that whilethe change between the pseudo-trained and the naïve groupscould be described as a uniform change over the whole populationof cells and synapses, the change between the trainedand the pseudo-trained group is apparent in only fractionof synapses and to a different extent in each cell, imposing afundamental change in the information processing and codingwithin the piriform cortex network.We have previously shown that rule learning of an olfactorydiscrimination task is accompanied by increased synaptic efficacyin the piriform cortex. In the current study we investigatedthe quality of this change by recording spontaneousexcitatory post synaptic currents (sEPSC) in piriform cortexpyramidal neurons. The averaged amplitude of the sEPSCsin neurons from trained rats -epigallocatechin-3-gallate (EGCG)prevented neuronal cell death, both in vivo and in vitro, aswell as revealed a neurorescue effect against several toxinsinducedcell death. It has been clearly demonstrated that a“domino” cascade of neurotoxic complex events can initiateneurodegeneration in Parkinson's (PD) and Alzheimer's diseases(AD). Thus, it is assumed that a combination of wellestablished neuroprotective drugs, such as antioxidants andiron chelators , and neurotrophic drugs , will be amore effective therapy for these diseases.In the present work, EGCG alone  andin combination with rasagiline  hasbeen studied in vivo, using neurorescue paradigm of MPTPmodel of PD. The drugs were administered orally to miceC57/Bl, 4 days after MPTP (4 × 20 mg/kg/day). The MPTPtreatedmice demonstrated a progressive demise of dopaminergicneurons in substantia nigra (SN) (assessed by immunohistochemistry),followed by significant decrease in the striataldopamine (DA) content (assessed by HPLC), as previouslyreported by us. However, EGCG alone, and more importantly,the cocktail of EGCG plus rasagiline, significantlyrescued cell function of SN dopaminergic neurons, indicatedby elevation of the DA content in the striata. Additionally,the administration of these drugs significantly attenuated celldeath of SN DA-containing neurons, as demonstrated by tyrosinehydroxylase-cell labeling. The present findings indicatethat EGCG alone and in combination with rasagilinemay have a positive impact on aging and neurodegenerativediseases to retard or perhaps even reverse the accelerated rateof neuronal degeneration. N-arachidonoyl dopamine (NADA) is an endogenous lipididentified in our lab, which modulates signal transduction innociceptive pathways . NADA is foundin the mammalian nervous system and activates the nonselectivecation channel, transient receptor potential vanilloidtype 1 (TRPV1). NADA also activates cannabinoid receptor1 and inhibits the NF-kappa B, NFAT and Activator Protein1 signaling pathways. To investigate the metabolism ofNADA through the cytochrome P450 (CYP450) metabolicpathway, we studied the in vitro production of hydroxylatedmetabolites and their activity at recombinant humanTRPV1 receptors. Method: Rat liver and brain microsomalfractions were isolated using differential centrifugation. Themicrosomal metabolites of NADA were partially purifiedfrom methanolic extracts on solid phase cartridges. Metaboliteswere were identified by HPLC/quadrupole time-of-flightmass spectrometry and quantified tandem mass spectrometry.Major hydroxylated metabolites were tested for calciuminflux on human recombinant TRPV1 receptors overexpressedin human embryonic kidney cells (HEK293). Keyresults: Following microsomal activation in the presence ofNADA, omega and (omega-1) hydroxylated metabolites wereformed. These hydroxylated NADA metabolites were activeat recombinant human TRPV1 receptors, inducing a dosedependentcalcium influx .Both metabolites exhibited lower potency and efficacycompared to NADA. Conclusions and implications:CYP450 enzymes are capable of metabolizing several fattyacids  and fatty acid-containing lipids forming a larger familyof neuromodulators with potential activity at various lipidreceptors. The current study shows that NADA metabolismoccurs through microsomal enzymes. Future studies will examinethe antiinflammatory activity of these metabolites.Supported by NIDA . Oscillatory bursting activity is commonly found in the BG ofthe Parkinsonian brain. The frequency of these oscillations isoften similar to Parkinson's disease (PD) tremor, but their relationshipto the tremor and other Parkinsonian symptoms isstill under debate. We studied the frequency-dependency ofinformation transmission in the BG networks by recordingsimultaneously from multiple electrodes located in the primarymotor cortex (MI) and in the globus pallidus (GP) oftwo vervet monkeys before and after MPTP treatment andinduction of PD symptoms. We mimicked the PD burstingoscillations by stimulating at different frequencies (1–15 Hz)through micro-electrodes located in MI or GP. Since thebursts used in this study contained 8 pulses given at 200 Hz,the high  frequency, 20 seconds long, tests can bedepicted as fragmented-DBS pattern, enabling us to examinethe effects of high frequency DBS without the distortionof stimulation artifact. Our findings show that in the normalstate, micro-stimulation of one structure does not modulatethe discharge rate in the other structure. The functionalconnectivity between MI and GP is greatly enhanced followingMPTP treatment. In the frequency domain, GP neuronsusually responded equally to 1–15Hz stimulation burstsin both states. By contrast, MI neurons expressed low-passfilter properties, with a cut-off frequency around 5 Hz. Finally,muscle activation evoked by MI micro-stimulation wasmarkedly attenuated at frequencies higher than 5 Hz. Thelow-pass properties of the BG networks suggest that despitetheir similar frequencies-PD tremor is not directly driven(beat to beat) by the BG 5–10 Hz burst oscillations. BG highfrequency stimulation would similarly be filtered in the cortexor in previous level. We therefore suggest that DBS alleviatesthe PD symptoms by blocking the abnormal oscillationsof the BG networks and re-establishment of downstream tothe BG compensatory processes. μM), (2) MF stimulation was precededby activation of the MLIs by surface stimulation, (3) MFstimulation was preceded by anotherMF stimulation (repetitivestimulation). However, no further prolongation of theresponses in conditions 2 and 3 occurred in the presence ofGABAzine. This indicated that prolongation of the responsesin these conditions was due to a lack of the inhibitory component,and not a change in the excitatory component. WhenMLIs receive input from MFs they inhibit other MLIs thuspreventing them from contributing to following MF inputs.Therefore, the possibility that the MLIs act to limit the timewindow of PC integration is of limited significance.Cerebellar Purkinje cell (PC) responses to mossy fiber (MF)stimulation, are composed of a fast excitatory componentfollowed by prolonged inhibition. It was suggested that theinhibitory component, generated by the molecular layer interneurons(MLIs), limits the time window for synaptic integration,and ensures a precisely timed output . However, it was previously shown that a singlestimulus to the parallel fibers (PFs) inactivates the inhibitorycomponent for tens of milliseconds . Thus, inputs that are composedof high frequency spike trains , arelikely to inactivate the inhibitory component. To asses therole of the MLIs in shaping the time course and spatial organizationof MF responses, we used the voltage sensitivedye RH-414, and imaged responses to stimulation of MFsin the isolated cerebellum of a Guinea pig. We confirmedthat the responses to MF stimulation are spatially organizedin a radial patch occasionally bounded by measurable inhibitoryresponses. We found that this inhibition which existsthroughout the responding patch, shapes the time coursebut not the spatial organization of MF responses. Responseswere prolonged when either (1) GABAergic transmition wasblocked (GABAzine 5  Neurogenesis—the formation of new neurons in the adultbrain—is considered to be one of the mechanisms by whichthe brain maintains its lifelong plasticity in response to extrinsicand intrinsic changes. The mechanisms underlyingthe regulation of neurogenesis are largely unknown. We discoveredthat Toll-like receptors (TLRs), a family of highlyconserved pattern-recognizing receptors involved in neuralsystem development in Drosophila and innate immune activityin mammals, regulate adult hippocampal neurogenesis.We show that TLR2 and TLR4 are found on adult neuralstem/progenitor cells (NPCs) and have distinct and opposingfunctions in NPC proliferation and differentiation bothin vitro and in vivo. TLR2 deficiency in mice impaired hippocampalneurogenesis, whereas the absence of TLR4 resultedin enhanced proliferation and neuronal differentiation.In vitro studies further indicated that TLR2 and TLR4directly modulated self-renewal and the cell-fate decision ofNPCs. The activation of TLRs on the NPCs was mediatedvia MyD88 and induced PKCalpha/beta-dependent activationof the NF-kappaB signalling pathway. Thus, our studyidentified TLRs as players in adult neurogenesis and emphasizestheir specified and diverse role in cell renewal. Theseresults were recently published in Nature Cell Biology in thecover and were accompanied by News and views by Marinoand Pluchino. It was also chosen as editor's choice in ScienceSTKE.This study was supported, in part, by an NRSAD award and bya research grant from Mr and Mrs Richard D. Siegal. A close relation between structural and functional featuresin the brain is a long-standing axiom, albeit its mechanism ispoorly understood. The Supplementary Motor Area (SMA),a brain area in the medial wall of Brodmann's area 6, has beensubdivided based on cytoarchitectonic features into posteriorand anterior parts: SMA proper and pre-SMA, respectively.However, the functional relevance of these subdivisionshas not yet been fully revealed. The location of theSMA between areas involved in executive and cognitive aspectsof action in the prefrontal cortex points to a possiblein-between representation of functional hierarchy within it.On the whole, animal and human studies suggested the involvementof the SMA in processing voluntary aspects of actionthat underlie self-generated processes such as volitionand planning. The goal of our study is to uncover principlesof functional organization in the human SMA. For that purposewe will use fMRI on healthy subjects with paradigmsthat differ in their mode of action (language versus motor),planning load (simple versus complex) and the source of actinitiation . Based on these tasks, wewill establish an SMA-selective functional localizer. Thirteenhealthy subjects participated in the study. The “complex” versus“simple” condition activated the SMA proper, while the“internally guided” versus “complex” condition activated thePre-SMA. The results demonstrated functional organizationwithin the SMA area with the pre-SMA more related to thecomplex and internally guided acts then the SMA proper.This research was supported by the Adams Super Center forBrain Studies. Low-frequency tremor is one of the pivotal symptoms ofParkinson's disease (PD). In parallel, the firing pattern ofthe basal ganglia (BG) and cortical neurons becomes burstyand, in part, oscillatory and synchronized. Albeit the coappearanceof the tremor and the changes in discharge patternsuggests a connection between them, their interrelationremains illusive. Either one of the phenomena could causethe other, both could be caused by some unknown confoundingfactor and, finally, they could be completely unrelatedand caused by different aspects of the disease. In this study weexamined the contribution of sensory feedback paths to thedischarge patterns of GP and M1. We have recorded from thearm related area of M1 and the GP of a healthy African greenmonkey (Cercopithecus aethiops), while applying forced oscillations to the left arm at several discretefrequencies for a duration of 90 seconds per frequency. Wereport the following results: 60/152 (39%) of the M1 neuronsdisplayed a discharge pattern that was phase locked andcoherent to the movement induced by the experimental procedure.The coherence showed a tendency to increase withthe increase in movement frequency and amplitude, perhapssuggesting reaction to acceleration rather than to movementfrequency. 12/62 (19%) of neurons in the GPe showed a dischargepattern that was phase locked and coherent with themovement. Interestingly, the maximal coherence in the majorityof neurons was achieved at 5 Hz, which is coincidentlythe frequency of the PD tremor. The phase locking did notseem to be affected by amplitude changes, suggesting that thereaction was indeed to movement frequency rather than toacceleration. Our results imply that PD tremor is probablynot the cause of the change of discharge patterns of M1 andGP neurons in MPTP-treated primates. Future recordings inthe GPi and in the MPTP-treated primate model of PD willbe performed to validate this conclusion. Magnetic stimulation of nerves is attracting increased attentionrecently, as it has been found to be useful in therapyof neural disorders in humans. In an effort to uncoverthe mechanisms of magnetic stimulation we apply magneticstimulation on ex-vivo neuronal preparations and demonstratethe first magnetically evoked activity in cultures. Magneticpulses initiate neuronal activity only in 1D patternedcultures of hippocampal and cortical neurons. The sensitivityof neurons to the magnetic pulses is affected by coil orientation,geometry, morphology, pharmacology, neural activityand neuronal density. Reciprocally, magnetic stimulation,with either single or repetitive pulses, has an obvious effecton immediate and progressive neuronal activity. In a relatedexperiment the interaction between myelination and TMS isexplored by applying TMS on Wistar and Myelin Deficient(MD) rats and by magnetically stimulating myelinated cultures.Intriguing findings regarding TMS on rats in generaland differences between myelinated and non myelinated systemswill be described. These findings may have an impacton the way TMS research is conducted on humans. Learning to predict the sensory component resulting fromthe organism's own activity enables it to respond appropriatelyto unexpected stimuli. In sharks, predictable electricfields of the electrosensory sense are filtered in the principalneuron of the Dorsal Octavolateral Nucleus (DON). Postsynapticinteractions between the electro-sensory primary afferents(aff) and parallel fibers (pf) are the proposed underlyingmechanism. We used the isolated brain stem of theshark to characterize these two inputs. Intracellular recordingand labeling ensure that our study in confined to theprincipal neuron and application of extracellular field ensurevoltage modulation at remote areas. We found that: (a) theaff postsynaptic potential (EPSP) has a faster rise time (3.9± 1.8 ms), low amplitude (2.9 ± 1.74 mV) and short duration(17.4 ± 7.8 ms); (b) facilitation was never encountered;(c) threshold for action potentials was 3.5 mV when evokedby aff stimulation. (d) The EPSP was insensitive to change inpostsynaptic potential, induce by intracellular current injectionor by applied extracellular fields. Hence, the aff input islocated close to the spike initiation site and the EPSP has thecharacteristics of electric transmission. The pf input is characterizedby (a) EPSP had a slow rise time (8.8 ± 3.5 ms),a high maximal amplitude (12 ± 5.58 mV) and long duration(36 ± 15.1ms); (b) prominent facilitation was elicitedby short train of stimuli; (c) threshold for action potentialwas 20 mV when evoked by pf stimulation. The highly efficientconnection between the afferent input and the principalneuron leaves little room for summation with parallelfibers response. Hence the filtering is most likely mediatedvia secondary neurons that adjust the sensitivity to afferentinput. The removal of degenerated myelin is essential for repair byregeneration after injury to axons and for minimizing damageto intact axons and myelin in multiple sclerosis. Microgliaremove degenerated myelin by phagocytosis. We focuspresently on complement receptor-3 (CR3) and scavengerreceptor-AI/II (SRA) mediated myelin phagocytosis inmicroglia. Paradoxically, these receptors are expressed in microgliaafter injury to CNS axons but myelin is not phagocytosed,suggesting that phagocytosis can be modulated betweenefficient and deficient states. We sought after mechanismsthat modulate myelin phagocytosis and shall presentlydiscuss three that involve Galectin-3 , cAMP andRho/Rock. First, Gal-3 is expressed in microglia that phagocytosebut not in microglia that do not phagocytose myelin.Additionally, Gal-3 stabiles K-Ras-GTP that activates PI3Kwhich, in turn, activates phagocytosis. An explanation is offered,thereby, for efficient and deficient phagocytosis by microgliathat, respectively, express or do not express Gal-3.Second, cAMP plays a dual role in phagocytosis in a concentrationdependent manner: it activates phagocytosis at normallevels through PKA and inhibits phagocytosis at highlevels through PKA and Epac. Thus, phagocytosis is inhibitedby increasing cAMP levels pharmacologically. Third,Rho/ROCK signaling activates the production of stress fibersand downregulates filopodia formation. Conversely, the inhibitionof Rho/ROCK signaling disrupts stress fibers and upregulatesfilopodia formation along with augmenting phagocytosis,thus suggesting that the three are causally linked. Notably,the latter two mechanisms are of special interest withrespect to regeneration in view of the observations that elevatedcAMP levels and Rho/ROCK inhibition promote regenerationby overriding growth-cone collapse induced bydegenerated myelin.Supported by Israel Science Foundation and the Ministry ofHealth. The population size of distinct nerve cell types is determinedby intracellular programming that is later modified by extracellularsignals. Uncovering developmental cues that regulatethe nearly fixed number of dopaminergic (DA) neuronsis important for understanding the contribution of aberrantDA development to neurological disorders. Althoughthe physiological and clinical aspects of the DA system havebeen intensively studied, relatively little is known about thelineage of DA cell clusters and the mechanisms controllingtheir progenitors number. We demonstrate in zebrafish embryosthat the number of diencephalic DA cells increases followingattenuation of canonical Wnt pathway without affectingthe fates and number of neighboring neurons. Wefound that Wnt8b is a modulator of DA cell number thatrequires the activity of the Fezf2/Fezl transcription factor inthis process. Birthdating analysis indicates that Wnt inhibitiondoes not delay proper exit of DA progenitors from thecell cycle. Fate mapping identified the DA progenitor zonein the diencephalic anlage of the neural plate and show thatthis neurogenin- positive DA progenitor domain is affectedby Wnt attenuation. Conditional inhibition of Wnt and ofcell proliferation demonstrates thatWnt restricts the amountof DA progenitors during a window of plasticity, which occursat primary neurogenesis. Our findings show that diencephalicDA population size is modulated inside the neuralplate, much earlier than expected, and illustrate how robustpatterning signals precisely regulate cell number.Supported by National Institute for Psychobiology, BenozyioCenter, National Parkinson Foundation, Israel Science Foundation. r = 0.93and r = 0.75, right and left hemisphere respectively), forthe N170 latency , as well as high validity measures for theN170 laterality (r = 0.71) and its face selectivity (r = 0.76).Our results suggest that the face-selective N170 can be reliablymeasured in a simultaneous ERP-fMRI setup after theapplication of proper artifact removal tools.The ERP component N170 is a well-established ERP markerof face-selective neural response. Although numerous studieshave investigated face-selective neural responses with ERPand functional MRI, the current study is the first to measureface-selective ERP response simultaneously withMR acquisition.Given the massive distortion MR acquisition generatesin the EEG signal, our goal here was to assess the reliabilityand validity of the N170 during functional MRI data collection.To that end, 10 individuals participated in an ERP experimentin the scanner. Half of the scans were collected duringand half without MR acquisition. Reliability and validityof the N170 were measured by correlating, across subjects,several measures that were recorded during MR acquisitionfollowing artifact removal, with the same measures that werecollected without MR acquisition. These measures were amplitude,latency, face-selectivity (the difference between theamplitude to faces and nonface objects) and laterality (thedifference between the amplitude to faces over the right andthe left hemispheres). We found very high test-retest reliabilitycoefficients for the N170 peak amplitude ( P < .01) in MAO-B activity in the combined lesionmodel, with no significant change in MAO-A activity.The increase in MAO-B activity following the combined lesionwas associated with a significant increase in GFAP expression.Using microdialysis technique, the effect of chronicMAO-A and MAO-B inhibition in rats bearing either singleor combined lesion was investigated. Rats were treateddaily with either saline, clorgyline (1 mg/kg) or rasagiline(0.05 mg/kg) and on the 14th day striatal microdialysateswere collected following a single systemic injection of LDOPA/Carbidopa (25 and 6 mg/kg respectively). DA levelswere 10 fold higher in the clorgyline groups in both types oflesions compared to controls. Rasagiline, on the other hand,increased DA levels moderately with more pronounced effectin the combined lesion than in the single lesion group. These results indicatethat most of the MAO-A activity in striatum is not located ineither DA or 5-HT axonal varicosities. In addition, MAO-Binhibition becomes important in the maintenance of higherL-DOPA-derivedDA levels in the striatum in advanced stagesof PD.The MAO-B inhibitor drug, rasagiline is an effective adjuncttreatment to L-DOPA in Parkinson's disease (PD), howeverIsrael Society for Neuroscience 95its precise action on dopamine (DA) metabolism still needsto be clarified. Since in advanced PD there is pronounced degenerationof serotonergic and noradrenergic, as well as DAneurons, we have used amodel of serotonergic (5-HT) as wellas DA depletion in the rat striatum as a closer model of PD,and have investigated the striatal metabolism of L-DOPAderivedDA by MAO subtypes in this model system. StriatalMAO activity and GFAP expression were investigated followingDA lesion with 6-hydroxydopamine alone (single) orwith additional 5-HT lesion with 5,7-dihydroxytryptamine(combined). There was a significant increase  by another .This field has practical implications as a mean to alleviatesensory deficits for populations, such as the blind andthe deaf, who may be able to rely on an alternative sensorymodality to gain missing information about the outsideworld. How does the brain learn to adopt and optimizea new sensory modality? Several fundamental questions involvemapping of one sensory modality onto another: Is activesensing crucial for a significant learning progress? Whatare the dynamics involved? Which motor strategies are optimaland how they can be achieved? Addressing these questionsis valuable for understanding how the human brainrepresents the outside world through the senses. In the currentresearch, an adaptation of a novel sensory modality wasinvestigated in normal human subjects. Adult human participantswere dressed with long elastic rods on their fingers,mimicking rat's whiskers. The participants were given 4 perceptualtasks: roughness estimation, poles localization in thehorizontal and radial dimensions, and 3D shape recognition.Interestingly, with little or no practice humans were able tolocalize objects and estimate roughness as accurate as, andeven better than, rats in equal tasks. The number of availablewhiskers did not affect horizontal or radial localization accuracy,while significantly affecting shape recognition. For ahorizontal localization task, active sensing was significantlysuperior to passive sensing. Contact time analysis revealedthat subjects rely primarily on temporal cues in horizontallocalization, and ignore proprioceptive information. Furtheranalysis in humans and rats is required in order to testwhether these two species use similar sensory-motor mechanismswhen faced with similar tasks, and, more globally, tounderstand how brains learn to adopt new sensory modalitiesand how to optimize such learning.This work was supported by the German BMBF–Israeli MOSFoundation. In previous studies we found that prenatal stress during thelast week of gestation in rats impairs spatial learning only inthe male offspring but induces anxiety in both genders.The aim is to determine whether excess maternal corticosterone(COR) alters programming of the fetal brain therebyinducing learning deficits and anxiety.n = 6) were adrenalectomized (ADX)on day 9 of pregnancy via the dorsal approach, 3 were shamoperated(SO) and the remaining 3 rats were left undisturbedand served as controls (C). Maternal resting levels of CORwere maintained by addition to the drinking fluid  of 25 μ/ml. On days 13–21 of gestation, 3 ADX andthe 3 SO rats were stressed once daily by varied stressors. Inorder to replicate the elevation of plasma COR induced bystress, 3 ADX rats were injected s.c, once daily with COR(3 mg/kg). All the offspring were tested at the age of 60 daysfor spatial memory deficits in the Morris water maze and foranxiogenic behavior in the plus maze (PM).Pregnant Wistar rats is a Polypeptide (PACAP) is a multifunctional neuropeptidethat binds to two classes of GPCR receptors. Type I is knownas the PAC receptor and type II (VPAC1 and VPAC2) receptorsare known as VIP receptors. In this study, we have investigatedgene expression profiles of PAC1 isoforms  and type II receptors inthe developing and aging rat brain. Gene expression studieswere performed using Stratagene MxPro Real Time PCR apparatus.Our data show that type I splice variants were highlyexpressed in the rat brain of newborns with marked decreasein expression during later stages of development. The mRNAlevels of VPAC2 receptor were significantly lower than that oftype I receptors in newborns. Yet, during maturation therewas significant upregulation of VPAC2 mRNA expression.VPAC1mRNA was hardly expressed in newborns, but its levelsincreased with age in a pattern similar to that observedfor VPAC2. During early stages of postnatal development theexpression of type I receptor in the hippocampus was significantlyhigher in females than in males, whereas no significantdifference was observed in the sexually mature animals.No sex dependent differences in expression were observed forthe type II receptors. When we examined the expression patternsof type I and type II in the cortex, hippocampus, cerebellumand striatum, we found that type I receptor predominatesin the hippocampus, while expression of VPAC1 wasmore prominent in the cortex and VPAC2 in the striatum.In summary, our experiments confirm that type I and typeII receptors are differentially expressed during postnatal developmentin various parts of the brain. High expression oftype I binding sites and its gender differences in the developinghippocampus will contribute to our understanding ofthe role of PAC1 receptor in normal brain development andfunction. Dopamine serves a crucial role in classical and instrumentalconditioning. Animal studies have shown that activityof midbrain dopamine neurons can be described accuratelyby computational models of reinforcement learning, andspecifically by the temporal difference model. Projections ofdopamine neurons have been suggested to provide the striatuminformation on the temporal difference error during reinforcementlearning. Recent fMRI studies have used reinforcementlearning models to analyze neuroimaging data obtainedin healthy subjects during learning, and have shownthat this approach allows tracking putative activity of midbraindopamine neurons in the striatum. Parkinson Disease(PD) is known to involve depletion of midbrain dopamineneurons. As expected, this depletion has been shown to resultin deficiency to acquire tasks which depend upon intactfunctioning of the dopamine system and the striatumin particular. No imaging study so far, however, tested thefunctionality of dopamine activity in the striatum of PD patientsusing computational reinforcement learning models.The aim of this project was therefore to study dopamine activityin the striatum of PD patients compared to healthycontrols using computational reinforcement learning modelsand fMRI.Nine PD patients and 16 age matched healthy controlswere scanned while performing a reinforcement learningtask. Subjects' choice behavior and actual rewards obtainedduring the task were analyzed using a temporal differencelearning model. The output of the model includesa prediction error (PE) term which is the delta between expectedand actual outcome of a certain stimuli chosen bythe subjects. This PE regressor is then correlated with fMRIbrain activity. If dopamine activity is providing predictionerror to the striatum, and is the source of the correlation observedin healthy subjects between the striatal fMRI signaland the PE regressor, such a correlation should not be observedin PD patients. Spontaneous neuronal network activity is an essential attributeof the nervous system. Such activity is also found inprimary neuronal cultures, which we used to investigate thepossible contribution of network activity to neuronal survival.We have previously demonstrated that when chronicallysilenced by tetrodotoxin (TTX), cultured cortical neuronsundergo a process of progressive cell death over a periodof up to two weeks. In addition we found that the remainingminiature excitatory synaptic currents (mEPSCs) have a crucialrole in the induction of this neuronal death, pointing toa cellular inability to cope with otherwise nontoxic calciuminward currents. In the current study we set to investigatethe molecular mechanisms responsible for this TTX inducedneuronal degeneration. The relatively slow rate of neuronaldegeneration and the absence of necrotic features such ascell swelling andmembrane rupture, made apoptosis amajorcandidate for the observed neurodegeneration. We thereforetested TTX treated neurons for the expression of differentapoptotic markers. While some classical apoptotic featuressuch as positive TUNEL staining, mitochondria fission andthe enhanced transcription of proapoptotic genes were indeedpresent, neither caspase 3 activation nor DNA ladderingwere evident. As to the upstream death signal, we foundthe calcium sensitive enzyme calpain to be involved, since itsblockade by its endogenous blocker calpastatin significantlyreduced neuronal death triggered by TTX. This result concurredwith our original hypothesis regarding the involvementof calcium in the apoptotic process. In summary, TTXinduced neuronal death appears to be a caspase-independentformof programmed cell death that shares at least part of theapoptotic pathway. OLETF rats are a model of hyperphagia-induced obesity.OLETF pups are heavier than their LETO controls at the timeof birth and present hyperphagic characteristics early in life.In the present study, we used cross-fostering to assess the influenceof the postnatal environment on short and long termobesity and examined differences between the sexes. Bodyweight was examined frombirth every fifth day and intake afterweaning was assessed daily. In the second lactating week,an independent ingestion test was performed. The pups weresacrificed and blood plasma was collected for Leptin analysisat weaning or at postnatal day (PND) 90. Three differentfat pads were collected and weighed. The estrous cycleof the females was monitored from PND 40 until PND75.The postnatal environment appeared to have a strong influenceon short term obesity. OLETF males and females raisedby LETO dams were leaner than controls, with normalized(to LETO controls) fat levels. LETO pups raised by OLETFdams were only slightly heavier than LETO controls, but withsignificantly higher fat percentages. Interestingly, in the independentingestion test, the genotype of the pups insteadof their phenotype determined intake: OLETF pups overateeven when their body weight was normal. On the other hand,LETO pups ate as controls regardless of their body weightor fat percentages. After weaning, even though they becameoverweight, OLET Fmales remained leaner than controls untilthe end of the experiment. OLETF females managed torecover all the fat and weight. LETO rats returned to theirlean genotypical profile. Furthermore, the structure of theestrous cycle was affected by the postnatal environment. Insum, there is a gender effect: Males can be successfully biasedto a more “lean” adulthood, while females, though affected,manage to show an almost complete recovery.Supported by NIH/NIDDK R01DK057609-06A1. Cocaine-induced modifications of glutamatergic synaptictransmission in the brain reward system play a key rolein adaptations that promote addictive behaviors. In particular,the activation of ionotrophic glutamate N-Methyl-D-Aspartate receptor (NMDAR) in the VTA is critical forthe initiation of cocaine sensitization. However, the role ofNMDARs in the NAc, the brain region that mediates theexpression of sensitization, remains to be explored. Usinglocomotor-sensitization as a behavioral paradigm, we foundthat repeated cocaine injections resulted in an increase inNR1, NR2A and NR2B subunits of the NMDAR in the NAc,21 days after the last cocaine injection. However, no changein these subunits was found one day following the last cocaineinjection. These changes were associated with an increasein the GluR1 subunit of the AMPA receptor. Interestingly,we found an increase in ERK activity which correlatedwith the increase inNMDAR subunits 21 days followingcessation of cocaine injections. Taken together these resultssuggest that the NMDAR system, through activation of ERKsignaling, is part of the long term neuroadaptations that resultsin the expression of cocaine sensitization. Understandingthe mechanisms that underlie the alterations of NMDARactivity following repeated cocaine exposure, will enable usto identify targets for the design of therapeutic agents inbrain areas thatmediate not only the development of cocaineaddiction, but also addiction to other drugs of abuse.Supported by grant from the Israel Science Foundation (ISF). Archer fishes (Toxotes jaculatrix) are famed for their abilityto shoot down insects resting on foliage above water usinga jet of water from their mouth. To get a good jet of water,the snout sticks out of the water while the rest of the fishremains underwater. They direct the jet of water by pressingtheir tongue against a groove in their mouth while forcing thegills' covers inwards. After the prey is dislodged from its position,several archerfish compete for the falling prey by rapidlypredicting the point where the insect will later land at thewater surface. Each fish can initiate a single turn to point itsbody towards the position where the prey will later land. Thisturn occurs within 120–150 ms after the prey is dislodged. Anopen question is how the retina encodes visual informationin order for the fish to achieve rapid reaction to prey landing.This extreme behavior of the archer fish is interesting tostudy and may serve as an important test case for our understandingof population neural codes of the retina. In orderto predict the target landing position, the archer fish retinaneeds to transmit information to the brain about target position,speed and direction of flight. One possibility for suchinformation transmission from the retina is by specialized directionand speed selective ganglion cell. Another possibilityis integration of information from several ganglion cells bythe fish brain to estimate the target's initial trajectory. Usinga 256 multielectrode array to record from the archerfishretina we study how visual information critical for detectionof target trajectory is encoded in the ganglion cell spikes.This work was supported by The Center for Complexity Science,Rich Foundation and Zlotowski Center. The International Headache Society defined trigeminal neuralgiaas unilateral disorder characterized by paroxysmal sudden,intense attacks of facial or frontal pain that last for a fewseconds and is limited to the distribution along one or moredivisions of the trigeminal nerve. Important in the historyof medical treatment and today still, gold standard' was thesuccessful treatment with carbamazepine in 1962. Pregabalinhas shown good results in the treatment of neuropathic painassociated with postherpetic neuralgia and diabetic peripheralneuropathy. The aim of this observational study was consideringthe possible benefits of pregabalin in the treatmentof trigeminal neuralgia. Methods: We investigated 53 patientssuffering from classical, chronic and symptomatic trigeminalneuralgia. They have been treated with pregabalin tittradedfrom 75 mg to 600 mg daily. Over a period of one year theywere prospectively followed and every patient was asked tofill out a standardized individual pain diary.After a period of 8 weeks 24.5 percent of patients experiencedcomplete pain relief remaining over the whole year ofobservation. The majority of patients  showeda remarkable pain reduction and reduction of attack frequency.Under 50 percent pain reduction under treatmentonly with pregabalin was observed by 26.4 percent. 4.8 percentterminated the treatment. Conclusion: In this prospectiveclinical trial pregabalin has proven to be effective concerningthe relief and reduction of pain as well as the reductionof attack frequency. The positive effect of pregabalin onpatients suffering from trigeminal neuralgia is comparable toother anticonvulsant drugs reported for carbamazepine andgabapentin. Of importance are pharmacological characteristicsof pregabalin. Pregabalin has shown less side effects, hasthe advantage of a rapid titration potential, fast pain reductionand it is easy to use by its administrations twice a day. P < .001). However, offspring of femalesthat underwent weanling stress or acute shocks beforemating were 6% heavier at weaning (P < .001). Performancein shuttle avoidance, and activity in the open field,were not altered by either preconception stress model. Childhoodstress to the mother marginally decreased anxiety in elevatedmaze, but acute preconception shocks had little effect.In contrast, acoustic startle response was doubled in malesof both experimental groups. These initial findings suggestthat adversity to a female, even before sexual maturity, as inchildhood abuse, may affect her fertility, and in her futureprogeny, birth-weight and aspects of their behavior, dependingupon their gender. Our findings also suggest that trauma,proximate to conception as in rape, may alter offspringbehavior.Pregestational adversity impacts offspring affective behavior. Here, as amodel of the possibleeffect of childhood abuse to a mother, we examined whether3 days of varied, unpredictable, stress to a weanling femalerat would impact its future progeny. Stress protocol was PN27:10 minutes swim, room temperature. PN 28:3×0.5 hoursraised platform, 1-hour intervals. PN 29: shock 6×0.8 mA/1s,0.5min intervals. In another group, we modeled the possibleeffects of rape on the offspring by shocking female ratsimmediately before mating .Conception rates of weanling stressed females werevery low (3/9), but shock before mating did not affect conceptionrates. One-hundred-and-seventy-one offspring wereevaluated. Birth-weight of offspring of childhood stresseddams was 10% lower . The val allele was significantlyovertransmitted from a heterozygote parent to femaleex-smokers and not to male ex-smokers. There wasno association between BDNF and current smoking status.Changes in salivary cortisol in the TSST were modulated byval66met and sex. Tests of within-subjects effects showed asignificant three way interaction . In male subjects val/val homozygotes showeda greater rise in salivary cortisol than val/met heterozygoteswhereas in female subjects the opposite was observed. Testsof between subjects affects showed a significant BDNF x sexinteraction (P = .040). This is the first report showing associationbetween the BDNF val66met polymorphism andquitting smoking. The val allele is preferentially transmittedto female ex-smokers. Moreover, val/val female ex- andnever smokers show blunted salivary cortisol responses tothe TSST suggesting that the effect of BDNF on smokingcessation is partially mediated by modulation of HPA-axisresponsivity.Attempts to prevent young people from initiating smokinghave been notably unsuccessful suggesting that focusing onthe underlying genetic and psychosocial factors in encouragingsmoking cessation is an important public health strategy.Towards this end, we investigated the role of the val66metBDNF polymorphism in contributing to “kicking the habit”in a group of young smokers. Since psychological stress is hypothesizedto be a principal component in initiating, maintainingand cessation of smoking the effect of val66met onsalivary cortisol responses in a laboratory stress test was explored.Three young groups (<35 years) were genotyped forthe val66met polymorphism: 275 ex-smokers (1 year abstinent),233 current smokers and 1017 never smokers. 57 subjects(never and ex-smokers) were also examined in the TrierSocial Stress Test (TSST). Significant association was observedbetween BDNF and the ex-smoking phenotype , participants were asked to respond asquickly and as accurately as possible to each Go stimulus,and in the other condition (delayed) they were asked to timetheir responses to the offset of the stimulus, thereby decreasingtask difficulty and imposing a more automated responseset. As expected, speeding increased the error rate.However, contrary to the expectation (and to participants'subjective reports), that speeding would impair awarenessof performance, we found the opposite to be true–errorswere more likely to be unnoticed when the task was easier.We suggest that this tradeoff reflects two qualitatively differenttypes of errors arising from the different cognitive demandsof the Immediate and Delayed conditions. We proposethat unaware errors reflect pure lapses of sustained attentionand are therefore more susceptible to changes in taskdemands, while aware errors mostly reflect failures to inhibitresponses, and are therefore most susceptible to increasedresponse speed. This finding is important becauseit identifies the conditions under which error awareness canbe maximally challenged, which is especially useful for ERPand fMRI experiments which require a significant numberof aware and unaware errors for comparison betweenthem. Malignant gliomas are the most common brain tumors,which in most instances are resistant to radiation andchemotherapy and therefore remain largely incurable. Thenovel chemotherapeutic drug, Erucylphosphohomocholine(ErPC3) has shown potent antineoplastic activity on variousmalignant tumor cell lines. ErPC3 activates the mitochondrialapoptosis pathway. The mitochondrial apoptosispathway is triggered by opening of the mitochondrial permeabilitytransition pore (MPTP). By genetic manipulation,we found previously that the MPTP associated TranslocatorProtein (TSPO) is needed for apoptosis induction by ErPC3.Presently, we study ErPC3 induced apoptosis levels in theglioma cell lines, U118MG, A172 and U87MG: (1) by usingthe cell death detection ELISAplus kit of Roche, and (2)by Fluorescence Assisted Cell Sorting (FACS) determiningthe percentage of cells in the pre-G1 phase of the cell cycle.We found, for example, that the classical TSPO ligand, PK11195 (25 uM), reduces the levels of apoptosis triggered byErPC3 in the U118MG glioma cells by 80%. We also showby viability experiments using Propidium Iodide that PK11195 reduces the percentage of dead cells after ErPC3 treatment,e.g., PK 11195 (25 uM) reduces the proportion of deadU118MG cells by 75%. Using the dye JC-1, we found that PK11195 attenuates ErPC3 induced opening of the MPTP in theU118MG, A172 and U87MG glioma cell lines. For example,PK 11195 (25 uM) causes a 57% reduction in the number ofU118MG cells displaying opening of the MPTP. Thus, it appearsthat ErPC3 reduces viability of cancer cells via openingof the MPTP leading to cell death, including apoptosis. Furthermore,it appears that the TSPO ligand PK 11195 can preventantineoplastic effects of ErPC3 by preventing the openingof the MPTP and cell death, including apoptosis. Thesedata provide further evidence that the TSPO can be targetedfor novel approaches to treat cancer.Research support: WK, LV, ML, and MG . The notion that context influences perception and behavioris not new. Yet, there is little knowledge about the principlesand the actual details of this process. In this study wehave run a series of experiments on human participants investigatingto what extent it affects our behavior and whetherongoing activity expresses the brain's internal context: whatinformation it contains and what cortical regions representit. For assessing the effect of prior information on performancewe have developed a behavioral paradigm in whichan orientation cue informs participants about subsequenttarget shape. We used a spatial 2-alternative-forced-choicecontrast discrimination task, while pre-cueing target orientation(cued condition) or not (un-cued condition) for manipulatingexpectation on the orientation domain. Duringthe performance of the psychophysical task, EEG activity wasrecorded from the entire skull (64 electrodes) simultaneouslywith high resolution recording of eye movements. We founda significant effect of pre-cueing target orientation on detectingtarget location, providing positive evidence for the debatableeffects of attention to stimulus features on task performance.Preliminary analysis shows that this behavioral effectwas accompanied by reduced ocular activity before and duringtarget onset. On the brain activity level (EEG), we arecurrently examining the manifestation of these interactionson the correlations between the single-trial pre-stimulus (ongoing)activity and the participant's prediction of target orientation(cue versus un-cued conditions), as well as on taskrelatedcortical dynamics in related areas.This work was supported by the German Federal Ministry ofEducation and Research, Israeli Ministry of Science and TechnologyFoundation. Both the primary auditory cortex (A1) and Anterior EctosylvianSulcal Auditory Field (FAES) are believed to be involvedin localization of sound. In both fields, neurons have beenfound to be sensitive to the direction of sound sources. Furthermore,FAES is known to project heavily to the deep layersof the superior colliculus. We have recently shown that theposterior part of AES has special response properties, withan over-representation of frontal space relative to A1 and theanterior part of AES. We examined the selectivity of a singleunit to azimuth and elevation in the FAES (aAES andpAES) and compared it to neural responses in A1. We usedvirtual space stimuli consisting of short noise bursts (100 ms)filtered through head-related transfer functions covering thefrontal region . In order to find the physical cues towhich the neurons were sensitive, we tested the same neuronswith modified stimuli in which some of the physical cueswere changed . Spatial sensitivity was quantifiedby the mutual information (MI) between stimuli andresponses. The overall selectivity to spatial location was similarin A1, posterior AES and anterior AES. Single neuronsshowed sensitivity to all three physical cues. However, at thepopulation level, modifying any of the physical parametersresulted in significant reduction in the sensitivity to azimuthof neurons in pAES, but not in aAES nor in A1, and a significantreduction in the sensitivity to elevation in both pAESand aAES but not in A1. We conclude that integration mechanismsunderlying spatial sensitivity in pAES are differentfrom aAES and A1: azimuth sensitivity in pAES is not dueto interaural level differences only, but is shaped in additionby the direction-dependent spectral cues. It is often assumed that the auditory system is adapted,through both evolutionary and developmental processes, tothe statistics of the sounds to which it is exposed. However,actual examples of auditory adaptation to the structure ofnatural sounds are rare. In a groundbreaking study, Aertsenand collaborators (1979) coined the term “acoustic biotope”and studied neural responses to a small set of representativenatural sounds. Yet, while natural sounds are obviously onlya small subset of all possible sounds, there is no statisticalcharacterization of this set among all sounds. A parametricrepresentation of natural sounds could be used to guide experimentsthat appropriately sample the space of all sounds,thus exploring the nature of the neural responses to relevantsounds. Furthermore, better understanding of the structureof natural sounds could reveal the underlying evolutionaryreasons for perceptual phenomena such as auditory masking,temporal integration, and auditory pattern recognition.For example, Nelken et al. (1999) analyzed a large set of naturalsounds and suggested that comodulation masking releaseis an adaptation of the auditory system to natural statistics.We explored the structure of natural sounds using dimensionalityreduction methods. By resynthesizing sounds fromreduced representations, we evaluated the importance of theignored dimensions. Principal component analysis of spectrogramsshowed that spectro-temporal structure could besubstantially reduced (to about 6 components) without affectingthe naturalness of the sounds. On the other hand, thephases had to be represented relatively faithfully in order toavoid serious distortions. We explored parametric representationsof phases using linear regression and reduced encodingof the regression errors. The OLETF rat has been extensively studied as a model ofhyperphagia-induced obesity. OLETF pups are heavier thantheir LETO controls at the time of birth and they present hyperphagiccharacteristics in independent ingestion and nursingtests throughout lactation. In the present study, we usedthe cross-fostering strategy to assess the influence of thepups' genotype on the dams' obesity levels at the time ofweaning. The aim was to attain a better understanding of theinteraction between the dams and the pups and how this influencestheir tendency towards obesity. Body weight of thedam was examined every fifth day and her intake was assesseddaily. At the end of the third postnatal week, a nursing testwas performed. At the time of weaning the dams were sacrificedand blood plasma and three different fat pads werecollected and weighed. LETO dams appeared not to be influencedby the strain of the pups, and presented similar physiologicalparameters at the time of weaning, when raising pupsof both strains. In contrast, OLETF females were strongly influencedby the strain of the pups: raising genetically “lean”offspring induced them to accumulate even greater amountsof fat, and to present increased body weight and Leptin levelsat the time of weaning, even though their intake wasthe same as controls. In the nursing test, both OLETF andLETO dams nursed for similar durations when raising pupsfrom the opposite strain. This nursing length was significantlylonger than that observed in the LETO control strain,but significantly lower than the time usually observed in theOLETF strain. Taken together, the results suggest a stronginfluence of the offspring's characteristics on maternal behaviorand the dam's physiological adaptation to lactation.Obese OLETF dams appear more susceptible than controlsto this influence.Supported by NIH/NIDDK R01DK057609-06A1. The development of therapeutic strategies in traumatic braininjury (TBI) is hampered by insufficient understanding ofpathological and protective roles played by discrete molecularprocesses. Experimental induction of protective pathwaysis therefore a powerful research model, possibly contributingto future drug design and testing. In our ongoingwork, endogenous protective pathways were inducedin a mouse model of closed head injury (CHI) by usinglong-term heat-acclimation ,a physiological model which is capable of facilitating protectionagainst various stressors including TBI. The benefits ofHA on motor and cognitive functions, neurodegenerationand brain edema were initially established. Subsequently,multiple pathways suggested as being pivotal in either HAor neuroprotection (NP) were studied in an effort to investigatetheir involvement in endogenous NP following CHI.HA-induced NP was associated with a network of concertedchanges consisting of absolute and dynamic alterations offactors and processes. These included augmented pre-injurylevels of hypoxia-inducible factor-1, erythropoietin receptor,brain-derived neuroptrophic factor (BDNF) and antiinflammatorycytokines, all of which are well-establishedas being neuroprotective. Pre-injury changes were complementedby modified post-injury dynamic responses harboringsustained post-injury hypothermia, reduced expressionof pro-inflammatory cytokines and selective enhancement ofBDNF-positive microglia after injury. When combined withselective pharmacological manipulation, the use of the HACHImodel enabled us to determine the necessity of Aktphosphorylation for NP, bringing to light the potential therapeuticvalue of this pathway. Taken together, the findings substantiatethe use of this paradigmfor the study of endogenousprotection, providing valuable insight which can conceivablybe utilized for development of treatment interventions in aphysiological-mimetic manner. Endocannabinoids released from the postsynaptic neuronalmembrane can activate the presynaptic CB1 receptorsand inhibit neurotransmitter release. In hippocampalslices, depolarization of the CA1 pyramidal neurons elicitsan endocannabinoid-mediated inhibition of GABA releaseknown as depolarization-induced suppression of inhibition(DSI). Utilizing the highly reduced postsynaptic neuron/synaptic bouton preparation from CA1 region of hippocampus,we have begun to examine endocannabinoiddependentshort-termdepression (STD) of inhibitory synaptictransmission under well-controlled physiological andpharmacological conditions in an environment free of othercells. Application of the CB1 synthetic agonist WIN55212-2 and endogenous cannabinoid 2-AG produced a decreasein sIPSC frequency and amplitude, indicating the presenceof CB1 receptors at synapses in this preparation.Endocannabinoid-dependent STD is different from DSIfound in hippocampal slices and the neuron/bouton preparationfrom basolateral amygdala (BLA) since depolarizationalone was not sufficient to induce suppression of spontaneousinhibitory postsynaptic currents (sIPSCs). However,concurrent application of the mGluR agonist DHPGand postsynaptic depolarization resulted in a transient (30– 50 seconds) decrease in sIPSC frequency and amplitude. Applicationof DHPG alone had no effect on sIPSCs. Thedepolarization/DHPG-induced STD was blocked by the CB1antagonist SR141716A and the mGluR5 antagonist MPEP,and was sensitive to intracellular calcium concentration. Theobserved STD was not related to depletion of the readilyreleasablepool of neurotransmitter, probed with high sucrosechallenges. Comparing the present findings with earlierworks in hippocampal slices and BLA, it appears that endocannabinoidrelease is less robust in isolated hippocampalneurons. MRI is the most important imaging method in studying microstructuresand functions of normal and diseased CNS.Huntington's disease (HD) is a hereditary neurodegenerativedisease, manifested mainly by a cognitive decline and hyperkineticmovement disorder. The hallmarks of the conditioninclude striatal neurodegeneration. Quinolinic acid (QA) injectionto the mid-striatum unilaterally causes a slowly progressingexcitotoxic lesion which resembles the neurodegenerationin HD 1). Stem cells have been proposed as a possibletreatment to neurodegenerative disorders. However, amajor setback post-implantation is proving the viability ofthe implanted cells. It is difficult to delineate these cells fromnormal brain tissue noninvasively. In this study, we labeledmesenchymal stem cells (MSC) post differentiation to neurotrophicfactors producing cells with superparamagneticiron oxide (SPIO) particles, and transplanted them posteriorto the QA lesion. We were able to detect the migration of theSPIO labeled cells towards the lesion over a period of severalweeks. The MRI images clearly show the accumulationof SPIO in the lesion and mainly on its borders. Moreover,one animal that had a cortical damage showed accumulationof the SPIO in the cortex, implying that the cells canreact to chemotactic signals derived from the lesion site, andfind the paths to migrate towards it. Control animals wereinjected with SPIO particles alone, and exhibited no accumulationand no path of migration. Post-mortem histologicevaluation demonstrated that the distribution of the cells wascomparable to the MRI images. These findings prove that inthis experimental model of HD, the cells are viable, and thatMRI can be used as a platform to detect the paths of migration.This gives hope to future research on these cells, chieflyon their pharmaceutical capacity . It isgenerally accepted that the cascade generated by tau overexpressionculminates in impaired organelle transport leadingto neurodegeneration. Several mechanisms have been proposedto link tau overexpression and impaired axoplasmictransport. Nevertheless, the underlying mechanisms are notclear. Here we developed a novel cellular platform and usedconfocal microscope imaging to address the above questions.For the study, we overexpressed human wild-type tau ordouble mutant tau (containing both mutations K257T andP301S) fused with cerulean. In order to label polymerizingmicrotubules we expressed the plus end microtubule trackingprotein EB3-GFP. For imaging of anterograde and retrogradetransport we imaged cherry-SNAP-25 and the fluidphase endocytotic marker–sulphorhodamin 101 respectively,and for imaging of mitochondria we used the mitotracker–RPAC. Overexpression of cerulean-tau generates three abnormalphenotypes characterized by (1) transient appearanceof MicroTubules-Array (MTA) in the axon. The MTAlocally disrupted the axonal transport and spontaneously disappearedwithin 48–72 hours; (2) reversal of the polar orientationof a significant fraction of the MTs. This led tomassivemitochondria and vesicular “traffic jam;” (3) the accumulationof tau and MTs at the submembranal domain, concomitantwith condensation of organelles within the axon corefollowed by neurodegeneration. As in other model systems,the pathological effects of the mutant form of human tauwere more prominent than its wild type form, indicating ourmodel systemmay be suitable for the study of tauopathies.Toconclude, we unraveled a new mechanism that underlies theaberrant transport characteristic of tau overexpressing neurons,namely, the reorientation of MTs polarity and their displacement. The construction of grammatical sentences relies on syntacticrules, as well as on lexical information associated with theverb in the sentence. This fMRI study explored the retrievalof verb-dependant lexical information and the processingof syntactic structures during sentence comprehension, byidentifying their cortical locations and patterns of activation.Stimuli were either verbs that select prepositional-phrases(PP) or noun phrases (NP), but not sentential complement, or verbs that select PP orCP, but not NP . For syntacticdifferences, we compared sentences containing syntacticallycomplex complements (CP) with sentences containingsyntactically simpler complements (NP). For lexical differences,PP-complements were used, allowing comparison ofsyntactically identical structures, but differential lexical information.Nineteen Hebrew speakers performed a semanticdecision task on auditorily presented sentences. ComparingCP-complements with NP-complements resulted inclear activations in several areas, including left-IFG (Broca'sarea), bilateral STG (Wernicke's area), MTG and SMG, aswell as medial precuneus. Comparing sentences includingCP-verbs with PP-complements and sentences including NPverbswith PP-complements (CP-verbs > NP-verbs) revealedactivations only in bilateral MTG and medial precuneus.The reverse comparisons yielded no activations. The resultsregarding the lexical activations can be attributed to eitherlexical-syntactic differences between the sentences, or tolexical-semantic differences between the verbs. However, theextensive network of areas identified in the syntactic comparisoncan clearly be attributed to the syntactic processing ofembedding, in this case CP-complements of verbs. This indicatesthat complex syntactic structure load on many corticalresources.This study was supported by The Levie-Edersheim-Gitter InstituteFor Functional Brain Imaging. The anterior intraparietal cortex (aIPS) is known to be involvedin visually guided grasping. Recently, we have shownthat this area is also active when we observe grasping movements.Here we investigate to what extent the performance inan imitation task and the aIPS activation is dependent on theviewpoint of the observer. Ten subjects observed video clipsof right or left hands making grasping movements. Importantly,in one set of clips the hands were shown from an egocentricpoint of view (as if the observer is the actor), whilein the other set the clips were shown from an allocentricpoint of view (as if the actions are made by an actor facingthe subject). The results confirm our previous findings thatin the egocentric point of view, the fMRI activation in theaIPS is contralateral to the observed hand . Interestingly, for an allocentric point of view,the representation is ipsilateral. Subsequently, we looked fora behavioral correlates for this phenomenon: Subjects observedsequences of finger tapping movements made by theright or left hand from an egocentric or allocentric point ofview and had to imitate them with their right hand. Imitationof the right egocentric and left allocentric clips was significantlyfaster than imitation of the left egocentric and right allocentriclyaligned clips, respectively. To summarize: actionsseen from an egocentric point of view elicit greater activationin the contralateral aIPS, and consistently, faster imitationswith the observed hand. Actions seen from an allocentricview point (as performed by someone else) elicit greateripsilateral aIPS activation and faster imitation of the oppositehand. The results suggest that simulation of observed actionsis affected by the field of interaction between the action ofthe actor and the viewer's mental simulation. μM in Aplysia). In contrast toAplysia sensory-motor synapses, repetitive exposures to 5HTdo not lead to long-term facilitation. This suggests that inthe octopus 5HT is not directly involved in mediation oflong-term synaptic modifications. However, we describe astrong 5HT reinforcing effect on LTP induction whereby inthe presence of 5HT high-frequency stimulation trains of ashorter duration than in control, are required for inductionof a saturated level of LTP. Our study therefore supports thenotion raised by recent experimental and theoretical studiessuggesting that heterosynaptic modulation of homosynapticactivity-dependent long-termsynaptic plasticity is an importantand universal principle in complex learning systems.Comparative analysis of brain function in invertebrates withsophisticated behaviors, such as the octopus, may advanceour understanding of the evolution of the neural processesthat mediate complex behaviors. In a previous study we discovered a hippocampal-like LTPin the octopus vertical lobe (VL), an area of the octopus braininvolved in learning and memory. Here we studied whetherthe well known mechanisms of molluscan 5HT-dependentsynaptic plasticity are conserved in the octopus VL system.We found that as in other mollusks, and in contrast to vertebrates,5HT has a facilitatory effect on synaptic transmission,albeit at about one order of magnitude higher concentrations, medium or long  duration increases theneural response to, and behavioural accuracy with, a tactiletarget. At the same time, simply closing the eyes canaffect the cortical representation of a tactile stimulus. Usinga novel active tactile search task, we explored the effectof closing the eyes in a completely dark room. Matching ofmechanical nuts and bolts was both faster and more efficientwhen the eyes were closed compared to when they wereopen, despite equal amounts of visual information. Thus,the simple act of closing the eyes can modulate behaviouralperformance, and presumably the underlying neural processing.These transient changes in connectivity may representthe starting point for the more substantial changesinvolved in the visuotactile plasticity seen with longerdeprivation.Supported by the Natural Science and Engineering Council ofCanada. Neurologists have long noted the asymmetry of hemispatialneglect, which is much more frequent and disablingfollowing lesions of the right hemisphere (RH). RH dominancefor spatial attention has been proposed, but its neuralbases have not been elucidated. The present fMRI study revealsbi-hemispheric left-hemifield superiority in activationof the intact visuospatial attention network, thus proposinga hemispace- rather than hemisphere-superiority as the basisfor attention asymmetry. Using mixed block-event relateddesign paradigm we presented pictures of either facial expressionsor houses for 150 ms to the left and the right hemifieldsseparately. Nineteen right-handed healthy adult femalesparticipated in the studies. Multistudy statistical brainmaps of the left versus right visual field contrast revealed thatLVF epochs differentially activated a cortico-subcortical network,which has previously been associated with covert visuospatialattention. This LVF enhanced activation was evidentbilaterally .The magnitude of the LVF superiority effect wasestimated by a ROI analysis on the right and left IPS. ThreewayANOVA disclosed an overall LVF superiority, which wasmore prominent in the RH. Our study disclosed bilateralLVF superiority in a network that has been associated withcovert visuospatial attention, thus suggesting a hemispaceratherthan hemisphere-based model for attention asymmetry.This model first offers a unified framework for understandingmanifestations of visuospatial attention asymmetryin both the lesioned and the intact brain. In view of recentintra-operative and electrophysiological findings we proposethat superior neural connectivity within the RH and/or fromthe RH to the LH might underlie the bi-hemispheric leftwardbias. This new insight may shed light on the mechanismsof functional hemispheric lateralization in the intactbrain and may help elucidating the neural bases of attentiondisorders. The vibrissa sensory-motor system is organized as nestedloops. In the lowest order loop in the brainstem, sensoryneurons in the trigeminal nucleus project to the motoneuronsin the facial nucleus. What is the role of this excitatoryfeedback in controlling the firing patterns of motoneurons?We explore this issue using a simplified model of thesystem, which includes a neuron coupled to itself with adelay. This conceptual single-neuron model stands for anyloop where all the neurons in each nucleus fire in full synchrony.Preliminary results reveal that feedback effects dependon the factors that cause motoneurons to fire. One possibilityis that the facial motoneurons are stimulated periodicallyby a central pattern generator (CPG). Assuming a sinusoidalstimulation, we find that the average firing rate dependson the stimulus frequency via an inverted U-shapedfunction. At low frequencies, the neuron fires one spike percycle, whereas at high frequency the neuron fires once everyfew cycles or not at all. The sensory feedback can increasethe number of spikes per cycle, and hence the firing rate, butnot the underlying frequency, which is governed by the CPG.Another possibility is that motoneurons are pacemakers. Inthis case, weak or moderate feedback has almost no effectif the delay duration is on the order of 10ms, which is theexperimentally-measured value of the first peak feedback response.With weak to moderate feedback, and our simplifiedmodel of the loop, only sensory neurons that fire at thesecond half of the whisking cycle, such as specific Whiskingcells, Detach cells, or Touch cells that encounter objectsduring retraction, can affect the timing of the next motoneuronsspike. Analysis of a network model, in which divergingfeedback events induce a positive (delayed) couplingbetween different pacemaking motoneurons, is currently inprogress.Supported by ISF Grant 311/04, ISF Grant 959/06, and BSFGrant 2003222. The NMDA receptor (NMDAR) is critically involved in theinduction of long-term potentiation (LTP)–a type of experiencedependent change in synaptic strength considered beingthe cellular basis of learning and memory. Under physiologicalconditions, NMDAR activity is tightly regulatedby glycine–the endogenous obligatory co-agonist of NMDARs.In turn, the synaptic availability of glycine is controlledby glycine transporter 1 (GlyT1). Elevation in extracellularglycine levels can be achieved by knockout of theGlyt1 gene in forebrain neurons, which augments NMDARmediatedcurrents, and is sufficient to influence and bias associativelearning as shown here using the Pavlovian conditionedfear procedures. First, forebrain neuronal GlyT1 deletionenhanced both the magnitude and persistence of theconditioned freezing response to a tone conditioned stimulus(CS) previously having been paired with a foot shockunconditioned stimulus (US). This effect remained apparenteven in aged 24-month old mice. Second, enhanced contextualfear was observed in these mutant mice when the animalswere explicitly conditioned to a novel context in the absenceof any discrete CS. Third, such excessive conditionedresponding was not at a cost to the selectivity of associativelearning. Indeed, sensitivity to the CS pre-exposure effect and protracted CS-US intervals  was more pronounced in these animals.The responsiveness to CS preexposure or CS-US traceinterval was enhanced in the mutant mice. Hence, ratherthan simply strengthening any potential associative links betweenstimuli, increased ambient glycine concentration insynapses can facilitate selective learning and enhance cognitiveflexibility. We propose that factors such as CS-US contiguity/contingency and CS/US associative history ought tobe taken into consideration when evaluating potential cognitiveimproving interventions using Pavlovian conditioningprocedures Genome scan and fine mapping of an inbred Arab-Israelifamily sample mapped a schizophrenia susceptibility locusto human chromosome 6q23 . Genotyping of single nucleotide polymorphisms(SNPs) was performed . Themost significant genetic association with schizophrenia forsingle SNPs and haplotypes was within a 500 kb genomicregion, which harbors the Abelson Helper Integration Site1 (AHI1) gene and an adjacent putative gene, C6orf217.AHI1 is a well-established neurodevelopmentally implicatedgene, involved in Joubert Syndrome with brain malformationand mental retardation . In contrast,C6orf217 is a putative gene of unknown function. Insilico analysis in our laboratory predicted the gene codingsequence of C6orf217 on the basis of ESTs cluster (Uni-Gene Hs.510098). The longest open reading frame of existingshows no structural similarity to any known protein. The putativecoding sequence and protein show similarity to chimpanzeeand rhesus monkey genomes, but is not conservedin other organisms. Relatively highly conserved regions werefound inside intronic sequences of the gene. Possible responsibilityof the sequence for regulatory or other functions onan RNA level was explored. The putative gene was found tobe a primate specific unique RNA or protein-coding gene.Rapid amplification of cDNA ends PCR of the transcriptfrom whole brain cDNA library confirmed the expression ofmRNA sequence in brain, defined the transcript boundariesand identified the unique splice variant that is expressed inthe human brain (Accession number EU130902).DNA andcDNA samples from 35 schizophrenic, 35 bipolar and 35healthy control brains were obtained from the Stanley Arraycollection (www.stanley.org). Taqman gene expression analysisfor both C6orf217 and AHI1 transcripts is in progress.Further analysis will explore the possible role of C6orf217 inschizophrenia pathogenesis. Alzheimer's Disease (AD) is the most common late-life dementia.Diverse lines of evidence suggest that amyloid-betapolypeptide (A-beta) plays a central role in pathogenesis ofAD. Current AD hypothesis states that soluble A-beta assembliesform in a concentration-dependent manner and triggerdown-regulation in the number, strength and plasticityof synaptic connection, resulting eventually in cognitivedecline. Although A-beta hypothesis gains strong support,the endogenous processes triggering synaptic dysfunction inAD remain obscure. Recent findings suggest that A-beta releaseand, therefore, its concentration in extracellular spaceare regulated by synaptic activity through vesicle exocytosis.Therefore, decreased synaptic activity reduces A-beta level,a process that should improve memory function. However,on other hand, memory-related forms of synaptic plasticityare manifested as increase in synaptic activity. We use optical,electrophysiological, and molecular techniques in hippocampalcultures to explore the casual relationship betweensynaptic activity, A-beta release and plasticity of synaptic networksat physiological and pathological conditions. We addressfollowing questions. First, whether amount and patternof neuronal activity differentially affect A-beta release?Second, what are the immediate effects of endogenously releasedA-beta on transmitter release associated with differentpatterns of neuronal activity? And third, what are the mechanismstransforming accumulation of A-beta to synapse loss,the primary factor contributing to memory decline in ADpatients. Understanding the initiation phase of synaptic dysfunctionby A-beta is essential for the development of newstrategies to prevent memory decline in AD. m0 = 10 we find that hippocampalneurons have on average 40–80 inputs while cortical neuronshave 50–100, depending on neuronal density. The ratioof excitatory to inhibitory neurons is determined usingthe GABAA antagonist bicuculine. This ratio changes duringdevelopment and reaches the final value at day 7-8, coincidingwith the expected time of the GABA switch. Forhippocampal cultures the inhibitory cells comprise about30% of the neurons in the culture while for cortical culturesthey are about 20%. Such detailed global informationon the connectivity of networks in neuronal cultures isat present inaccessible by any electrophysiological or othertechnique.We introduce a novel approach for the quantitative assessmentof the connectivity in neuronal cultures, based on thestatistical mechanics of percolation on a graph. This allows usto follow the development of the culture and see the emergenceof connectivity in the network. The culture becomesfully connected at a time equivalent to full term. The spontaneousbursting activity that characterizes cultures developsin parallel with the connectivity. The average numberof inputs per neuron can be quantitatively determined inunits of m0, the number of activated inputs needed to excitethe neuron. For  P < .0004), in the thalamic and hypothalamicareas (P < .001), in field CA3 of the hippocampus (P < .001),and in left entorhinal and perirhinal cortex (P < .002). In6-OHDA rats, signal enhancement was found in the lateralhabenula (P < .003), in the thalamic and hypothalamic areas(P < .001) and in field CA3 of the hippocampus (P <.003). No significant signal enhancements in left entorhinalor perirhinal cortex were found. Comparison of signal enhancementvolume between sham and 6-OHAD rats revilesa reduction of 64% (P < 6 ∗ 10-7) and 69% (P < 5 ∗ 10-8)in the left and right lateral habenula respectively and of 82%(7 ∗ 10-9) and 64% (P < 5 ∗ 10-6) in left and right field CA3of the hippocampus respectively in 6-OHDA rats. These resultssupport our previous hypothesis of reduced raphe activityin 6-OHDA rats suggesting alternations in the couplingbetween the dopaminergic and serotonergic systemsin PD.Parkinson's disease (PD) is a neurodegenerative diseasewhich is primarily considered to affect movement due to lossof dopaminergic cells. However, a large percentage of PD patientssuffer, in addition, from mental disorders. This suggeststhe involvement of the serotonergic system in the disease.Our previous studies demonstrated reduced connectivitybetween the basal ganglia and the raphe nuclei (themain serotonin generator) through the habenula complexin unilateral 6-OHDA injected rats. Our aim in this studywas to evaluate these findings by comparing the anterogradeconnectivity of the raphe nuclei between sham and6-OHDA rats. Direct intracranial injection to the raphe nuclei of paramagnetic manganeseions which are known to enter neurons, transfer anterogradelyand cross synapses, was monitored for 96 hoursby T1-weighted MRI. A unique model-free principal componentanalysis was used and comparison between groups performed. Significant signalenhancement (compared to baseline) was observed in the lateralhabenula , which isknown to precipitate a wide variety of post-pubertal behavioral,cognitive and pharmacological abnormalities implicatedin schizophrenia. The prenatal PolyI:C model also capturesa “prodromal phase” in the form of enhanced sensitivityto acute dopaminergic stimulation by amphetamine,which is apparent already before the onset of the fullblownschizophrenia-related phenotype in adulthood. Usingthis model, we revealed that chronic haloperidol exposure during periadolescence(day 35 to 70) did not confer any protective effectsagainst prenatal infection-induced sensorimotor gatingdeficiency emerging in adulthood (PND 90). In fact, periadolescencehaloperidol treatment in control animals led toadult sensorimotor gating deficits . On the other hand, theprenatal infection-induced potentiation of psychostimulantsensitivity in adulthood was blocked by preventive haloperidoltreatment.Our experimental findings thus highlight bothbeneficial as well as detrimental long-term effects of chronicexposure to the typical antipsychotic drug haloperidol duringperi-adolescence. Grouping of small stimuli, presented in the visual field, intoglobal objects is an important question in contemporaryneuroscience. Studies have found that principles of perceptualorganization exist, suggesting that the spatial relationshipsbetween the local retinal inputs are the parametersthat may determine the observer's performance in groupingglobal images. An alternative view for grouping is to considerthe temporal activity of the neural representations, suggestingthat binding induces a stimulus-dependent synchronybetween the grouped elements. It was previously shown thatdetection of low-contrast Gabor patches (GPs) is improvedwhen flanked by collinear GPs, whereas suppression is observedfor high-contrast GPs. The facilitation resembles theprinciples of Gestalt theory of perceptual organization. Wepropose a model for contour integration in the context ofnoise that incorporates a temporal element into this spatialarchitecture. It is based on the following principles: (1) theresponse increases with increasing contrast, whereas the latencydecreases; (2) activity-dependent interactions: facilitationfor low and suppression for high activity (3) the varianceincreases with contrast for both responses, rates, and latency;(4) inhibition has a shorter time-constant than excitation.When a texture of randomly oriented GPs is presented, theresponse to every element is decreased due to fast inhibitionbetween the neighboring elements, thus shifting the activityto the facilitatory regime of the collinear interactions. Duringthe next stage, the slower excitation induces selective facilitationonly along the contour elements. Consequently, theresponse to the contour is increased, resulting in decreasedvariance of the response rate and latency, an effect that providesbetter correlation between the contour elements. Thus,collinear facilitation increases the saliency of contours by decreasingthe response variance of both the rate and temporalcodes.Supported by the Israel Science Foundation and the NationalInstitute of psychobiology in Israel. We have carried out a 3-dimensional (3D) morphometricstudy at electron microscope (EM) level to investigate the effectof a Neural Cell Adhesion Molecule (NCAM) mimeticon synaptic and dendritic spine plasticity in the hippocampusof aged rats. NCAMs are members of the Ig superfamilyexpressed on the surface of neural cells involved in cellcellinteractions and synaptic plasticity. NCAM signals via adirect interaction with the fibroblast growth factor receptor(FGFR). FGL  isan NCAM mimetic consisting of a 15 amino acid peptide derivedfrom the FGF binding site of NCAM. FGL (icv) facilitateslearning and spatial memory consolidation, and canreduce the B-amyloid load in rats. Aged rats   were injected subcutaneouslywith FGL (8 mg/kg) at 2-day intervals until19 days after the experiment start; control rats were injectedwith sterile water. Animals were perfused with fixative, andcoronal brain sections containing the hippocampus cut at100 um, and hippocampal volume was measured. Tissue wasembedded and ultrathin sections viewed in a new JEOL 1400EM (120 kv) with a high resolution AMT digital camera usedfor image capture. Analyses were made of synaptic and dendriticparameters following stereological analyses and 3D reconstructionvia images from up to 150 serial sections (seehttp://synapses.bu.edu). FGL altered neither hippocampalvolume, nor spine or synaptic density in the medial molecularlayer. However, it increased the ratio of mushroom tothin spines, the number of endosomes, and the abundance ofspine apparatus, whilst it decreased synaptic and spine curvature.This indicates that FGL induces large scale changesin synapses and dendritic spines in the hippocampus of agedrats complimenting data showing its marked effect on cognitiveprocesses.Supported by EU FPVI Promemoria Contract no. 51201. Stimulus-specific adaptation (SSA) in auditory cortex wasinvestigated in the halothane-anesthetized rat. We used oddballsequences, in which a rare (deviant) tone appeared overa background of common (standard) tones. We recorded localfield potentials and multiunit activity. The response to atone, when deviant, was substantially stronger than the responsesto the same tone when used as standard. The frequencydifference between deviants and standards could beas small as 20%, substantially smaller than the typical widthof cortical tuning curves. At a frequency difference of 10%,the responses to standard and deviants weremostly the same.The stronger response to the deviant may be due to a reductionin the responses to the standard, but may also be dueto change potentials evoked by the violation of the expectationscreated by the presentations of the standard tone. Totest for change potentials, we embedded the deviant tones ina sequence in which many different tones were played randomly,so that each tone was as frequent as the deviant inthe oddball sequence. In such a sequence, the appearance ofthe deviant tone is not associated with violation of expectationsand change potentials are not expected. We show thatthe response to a deviant over a background of many standardsis similar to the response to the deviant over a backgroundof a single standard. Nevertheless, a simple modelbased on fatigue cannot account for the qualitative patternthe results, and it seems that the fact that a stimulus is novelin the sensory scene plays a significant role in cortical SSA. Inan attempt to generate change potentials, we assigned a behavioralimportance to a specific frequency by using it as aconditioned stimulus (CS) in a fear conditioning procedure.Preliminary results suggest an enhancement in the responsesto CS and the presence of change potentials when the CS isused as a deviant, but not when other tones are used as deviant,in oddball sequences. The masking (suppression) effect can be achieved eitherwhen noise is used, or when the target and mask sharethe same physical properties. Thus, the properties of efficientmasking are not well defined. We probed the efficacyof the suppression effect on target threshold by manipulatingthe ISI (0–120 milliseconds), contrast (0–80%), spatialfrequency , and orientation (0–90 degrees).The relationships between facilitation using collinearflankers and suppression were also tested under these conditions.We found that suppression increased with increasingIsrael Society for Neuroscience 109contrast (being effective above 4.25 times the target threshold);it was maximal for simultaneous presentation  and equal target-mask SF but decreasedwith increasing ISI. Suppression is maximal for neariso-orientations and decreased for increasing orientation differences.Collinear flankers did not produce facilitation forISI = 0 but it produced more suppression for ISI = 30. Thus,efficient masking is not noise per se, rather, it is determinedby combining parameters such as the similarity between thetarget and mask in their temporal presentation as well astheir physical properties (similar SF and orientations) andthe balance between excitation and inhibition. The resultssuggest that iso-orientation inhibition is stronger than crossorientationinhibition.Supported by a grant from the Israel Science Foundation. Climbing fiber activation evokes a large all-or-none responsein Purkinje cells (PCs), known as the complex spike (CS).The CS, triggered by massive EPSPs to the dendritic arbor,consists of dendritic calcium currents and somatic sodiumspikes. It is thus expected that the properties of these eventswill depend on the PCs membrane potential. Furthermore,we have recently showed that the membrane potential of PCattains two stable state values: a hyperpolarized quiescentstate (down state) and a depolarized active state (up state).Therefore, we examined the CS waveform that was elicitedduring the up state and compared it to the waveform obtainedduring the down state. To this end, we performed invitrowhole cell and loose-patch recordings fromPCs. We useconcentric metal electrode to stimulate the climbing fibersand to evoke CSs. Intracellular current injection was used toshift the cells between the two stable states. We found thatduring the down state the CSs, which waveform tends to bemore stable, were characterized by 4–6 fast fluctuations thatfollowed the initial spike. In the upstate the CSs, which waveformtends to have a longer duration, were characterized bysignificantly higher variability of fewer and slower fluctuations.These differences may account for a lower thresholdfor calcium activation during up state. Since calcium concentrationhas been shown to play a pivotal role in synapticplasticity, it is tempting to speculate that plastic processes inthe cerebellar cortex, which are triggered by climbing fibers,are more effective during the up state. A large body of evidence from behavioral, neuropsychological,and neuroimaging studies, supports the idea that visionfor-action and vision-for-perception aremediated by distinctneuroanatomical and functional systems. Yet, an ongoing debateexists as to whether visual illusions, that by definitionaffect the way people perceive objects, have similar effectson visuomotor control. In this study we have attempted todifferentiate–within the same experimental design–the effectsof the real size and the apparent size of objects on actionand perception. To this end, two real rectangular objectsof different sizes were presented within a variant of the Ponzosize-contrast illusion. Most experimental trials were designedsuch that the object that was perceived as the larger one wasactually physically smaller than the other object. This designallowed us to focus on trials in which subjects have overtlydecided that one of the objects is the smaller (or larger) ofthe pair, and to test whether or not the opening between thefingers of the grasping hand goes in the direction of this erroneousdecision. The results showed that although subjectswere affected by the illusion when making size decisions, theopening of their fingers in flight reflected the real size differencesbetween the two objects. This pattern of results was reversedin a second experiment, in which subjects were askedto make perceptual estimations of size. In this case, the estimatesreflected the illusory size of the objects. Thus, the realand apparent differences in the size of the objects had oppositeeffects on action and perception. These findings provideevidence for a double dissociation between visuomotor controland visual perception in the context of visual illusionsand support the idea that visuomotor control and visual perceptionare mediated by distinct functional systems. Activation of endogenous stem cells has been proposed as anovel form of therapy in a variety of neurological disorders,including traumatic brain injury (TBI). Vascular endothelialgrowth factor (VEGF) is expressed in the brain following TBIand serves as a potent activator of angiogenesis and neurogenesis.Methods: TBI was induced with closed head injury insabra mice. Mice were injected with BrdU to label newborncells. We administered exogenous VEGF into the lateral ventriclesusing miniosmotic pumps to evaluate the effects onrecovery and functional outcome as assessed with the neurologicalseverity scale score. Immunohistochemistry was usedto study the fate of newborn cells at 90 days post TBI.Our results show that VEGF significantly increases the numberof proliferating cells in the subventricular zone and in theperi-lesion cortex. This increase is associated with a significantlybetter functional outcome following TBI as measuredwith the neurological severity scale. Fate analysis showed thatmost newborn cells differentiated into astrocytes and oligodendrogliaand not into neurons.VEGF significantly augments angiogenesis and neurogenesisafter TBI butmost newborn cells adopt a glial fate. Nevertheless,there is a significant improvement in recovery rates andfunctional outcome as a result of these changes.This work was supported in part by a grant form the IsraeliDefense Forces. The arms of an octopus, the therewith-conducted movementsand the coordination of these movements play an essentialrole in the natural behaviour of this animal. Locomotion,foraging, probing and mating are dependent on proficientarm use. In particular searching and probing movementsare hypothesized to be largely autonomous . For the octopus survival,nonvisual arm coordination and also the ability to remembera beneficial food patch are essential for its daily survival.These two issues became the basis for our experimentaldesign. Our present study seeks to investigate if an octopuscan learn to navigate a two ways choice maze based only onproprioceptive information. We used a plexiglass plate witha Y shaped maze glued to it. The octopus had to insert onlyone of its arms into the maze and reach a goal box locatedon both ends of the Y maze. Six adult Octopus vulgaris wereintroduced to the maze baited on both sides to determinethe individual side preferences of the animals. Once this wastested the goal side was either ascribed at random, or contraryto the animals side preference. To control that chemicalcues did not influence the animals' decision an equalamount of food was put into both goal boxes, but only availablein the correct goal box. A criterion for successful learningwas the completion of 8 out of 10 trials. Four out of sixanimals complete this task in less than 90 trials. Using a simpletwo ways choice discrimination-learning paradigm, ourstudy shed new light on the ability of the octopus to controlits motor output based on proprioceptive information only.Supported by Israel Science Foundation. M. Kuba was supported by a Golda Meir fellowship. Studies performed in zebrafish and chicken indicate thatBone Morphogenetic Proteins (BMPs) play an importantrole in the development of catecholaminergic (dopaminergicand noradrenergic) neurons in the CNS. However, theBmp or combination of Bmps controlling the developmentof these cell populations in mammals is still elusive. In additionBmp2 and Bmp4 have been implicated in pituitary development.However, the role of other Bmps in this processis still elusive. Using in situ hybridization, we compared thespatio-temporal expression pattern of different BMPs to developingcatecholaminergic neurons in mice. We found thatmembers of the 60A subgroup, Bmp-5, -6 and -7, are expressedin close vicinity to the neuronal population of ourinterest. Next, we could show that dopaminergic, and noradrenergicmarkers are normally expressed at postnatal day0, in Bmp-5, -6, and -7 knockout mice. This indicates thatBMP5, BMP6, and BMP7 as individual genes are not essentialfor the presence of dopaminergic and noradrenergic neuronsin vivo. These results are very surprising, since previousin vitro data and results obtained in chicken and zebrafish,suggested the dependency of noradrenergic neurons on thoseBMPs. Based on our results we hypothesize that BMPs arefunctionally compensating for each other. In order to testour hypothesis, we will characterize monoaminergic populationsin BMP compound mutants. In addition, Current experimentsaim to characterize the role of BMPs in pituitarydevelopment. For this purpose we are analyzing the mRNAexpression of different hormones produced by the anteriorpituitary by in situ hybridization and RT-PCR.The work was supported by the ISF, The National Institute of Psychobiology, and the Ministry of Health. The embryonic mid-hindbrain organizer (MHO) is composedof a transient cell population located at the developingmidbrain-hindbrain junction, that controls the formationof the brain stem. Mouse mutants with a caudallyIsrael Society for Neuroscience 111shifted MHO show an increase in number of dopaminergicneurons and a decrease in number of serotonergic neurons.Interestingly, cranial nerves, originating close to theMHO are not affected in these mutants, indicating that theMHO has a specific effect on cell populations forming adjacentto it. Behavioral studies revealed that these mutantsshow increased activity and altered locomotor response topsychostimulants. The major noradrenergic nucleus in thebrain, the locus coeruleus originates at the intersection ofFgf8 that mediates MHO activity and dorsalizing Bmp signals.Deleting Fgf8, leads to a loss of the whole mid- andhindbrain region including the locus coeruleus. However, thespecific role ofMHO position and activity for the generationof the locus coeruleus has so far been unknown. Inactivatingbmp7 in zebrafish or blocking Bmp-5 and -7 signalingin chicken have indicated that these morphogens are necessaryfor the formation of the LC. However, if Bmp function isconserved in mammals and if Bmp-5 and -7 have redundantfunctions is elusive. Here we provide evidence that mousemutants with a caudally enlarged Otx2 expression domainand concomitantly caudally shifted MHO (En1+/Otx2) haveless noradrenergic neurons. Unexpectedly En1+/Otx2 mutantsshowed an enlarged Fgf8 expression domain and nochanges in Bmp-5, -6, or -7 expression. A further analysisof Bmp-5, -6 or -7 knockout mice indicate that the LC developsnormally in these mutants. Taken together, our dataindicates that the MHO controls the development of the LCthrough an Otx2/Gbx2 interaction and that Bmp-5, -6 or -7are not required, as individual genes, for the formation of themammalian LC in vivo.This work was supported by ISF, National Institute of Psychobiologyin Israel, and Ministry of Health. In the last decade a large amount of electrophysiological researchhas focused on high frequency brain activity in humans,and specifically on the “induced gamma response”(iGBR). The scalp recorded iGBRs is manifested typically asan increase in the gamma band (>30 Hz) peaking around250 milliseconds post stimulus, following the presentationof a visual stimulus. The iGBR was hypothesized to representthe neural synchronization involved in various cognitivefunctions such as binding and consciousness. Our findingsshow a strong correlation between the induced gamma activityand eye movements (recorded by an eye tracker). However,the direction of causality is still unclear. In the currentstudy we present a possible model explaining the appearanceof iGBR in the EEG data and its relation to eye movements.In filtered (30–100 Hz) single trials the iGBR is seen as asharp peak which appears strongly (but in opposite polarities)in central channels and in the electroocular channels(EOG). In all four EOG channels  the peak appearsat the same polarity. The pattern in the EOG channels describedabove cannot represent a simple saccade. Since a vertical saccade will typically be demonstratedby opposite polarization of the vertical superior and inferiorchannels .We discuss the possible involvement of a convergenceor divergence movement in the manifestation of the iGBR. Traumatic brain injury (TBI) is an important cause of focalepilepsy. Animal experiments indicate that disruption of theblood-brain barrier (BBB) plays a critical role in the pathogenesisof post-traumatic epilepsy (PTE). Objective: To investigatethe frequency, extent and functional correlates ofincreased BBB permeability in PTE patients.Thirty two patients were included in the study, with 17suffering from PTE. All underwent brain magnetic resonanceimaging (bMRI) and were evaluated for BBB disruption,using novel quantitative techniques. Cortical dysfunctionwas measured using quantitative electroencephalography(qEEG), and localized using standardized low resolutionbrain electromagnetic tomography (sLORETA).P = .02), no relation to the sizeof the cortical lesion (P = .19) was found. Increased BBBpermeability was found in 76.9% of PTE patients comparedto 33.3% of nonepileptic patients (P = .047), and could beobserved several years following the trauma. Cerebral cortexvolume with BBB disruption was larger in PTE patients(P = .001). In 70% of patients, slow (delta band) activitywas co-localized, by sLORETA, with regions showing BBBdisruption.TBI patients displayed significant pathological qEEG slowing.No significant differences were found between spectralqEEG analyses from PTE and nonepileptic patients. WhilebMRI revealed that PTE patients were more likely to presentwith intracortical lesions  disruption occurs under many diversepathological conditions, and recent studies suggest itmay be involved in the pathogenesis of neurological disorders.Visually based evaluation of contrast-enhanced brainimaging is often used to detect BBB disruption. However, noestablished method exists for the quantitative evaluation ofBBB permeability in human patients. We have recently establishedtwo methods for evaluating BBB permeability in humans,utilizing brain MRI scans. The first method comparesT1- weighted magnetic resonance brain scans before and followingthe administration of Gadolinum-DTPA. Examininggroups of 16 voxels at a time and searching for statisticallysignificant changes in signal enhancement results in a semiquantitativeestimation of the spatial location and extentof BBB disruption. In the second, dynamic method, repetitiveT1 scans are performed during contrast agent administration.Following blood vessels elimination the dynamicsof contrast agent concentration in each pixel are calculated.A quantitative map of BBB function is created accordingto the activity of the BBB throughout the parenchyma.Using both methods we receive a highly sensitive estimateof BBB patency throughout the brain parenchyma. Ourstudy shows that BBB disruption is common in diverseneurological and systemic conditions and possibly lasts forlong periods. Furthermore, the extent of disruption, itsprogression with time, and functional correlations can beidentified. R = 0.8,P < .001). We suggest that NSS is a reliable tool for invivocontinuous evaluation of neurological damage in headinjuredmice, and its value at 1 h predicts the extent of motordysfunction, cognitive damage and brain water characteristicsas depicted by T2-weighted MRI. Combined assessmentof neurobehavioral and cognitive functions along withMRI is most useful in evaluating recovery from injury, andwas successfully applied in testing of novel pharmacologicaltreatments.Memory and neurobehavioral dysfunctions typically occurafter human and experimental traumatic brain injury. ANeurological Severity Score  was developedfor evaluation of trauma severity in mice. The objectrecognition task (ORT) measures specific episodic memoryin rodents, and is expressed by the percent time spent at anovel object . The present studydescribes the effect of injury severity on the spontaneous recoveryof neurobehavioral and cognitive outcome after severeand mild focal trauma in mice. Mice were subjected toclosed head injury  andNSS was further evaluated during 25d.NSS decreased by 3.86 ± 0.26 and 2.54 ± 0.35 units in the severeandmild injured mice, respectively. ORT was performedbetween days 3 and 28 after trauma. Whereas DI in noninjuredmice is ∼75%, se51.7 ± 6.15% on 3rd day and 66.2 ±6.81% verely injured animals show DI of 51.7 ± 6.15 % and66.2 ± 6.81% at days 3 and 21 after trauma, indicating inabilityto distinguish between familiar and novel objects. Incontrast, mildly injured mice do not show cognitive impairmentthroughout the same period.NSS1h strongly correlatedwith the damage seen on MRI 24 h post injury  and photoactivation experimentsrevealed that presynaptic molecules are continuously incorporatedinto and lost from individual synaptic structuresover various times scales, from minutes to many hours.Moreover, these dynamics can be accelerated is some cases bysynaptic activity. Finally, we find that synaptic molecules canbe continuously exchanged between nearby synaptic structuresat significant rates that greatly exceed the rates at whichsynapses are replenished with molecules arriving from somaticsources. Our findings thus support the possibility thatkey presynaptic molecules are continuously lost from, incorporatedinto and exchanged among nearby presynaptic sitesat significant rates and thus further highlight questions asto how presynaptic sites manage to maintain their structuraland functional characteristics over long durations.Supported by US-Israel Binational Science Foundation (BSF),German Israel Foundation for scientific R and D (GIF). The hippocampus is crucial for episodic and spatial memory.In freely-moving rodents, hippocampal pyramidal neuronsexhibit spatially-selective firing when the animal passesthrough a neuron's “place field,” and theta-band oscillationis continuously present during locomotion. Here we reporton the first hippocampal recordings from echolocating bats,mammals phylogenetically distant from rodents. Big brownbats (Eptesicus fuscus) were trained to crawl and forage formealworms in an open-field arena, while we recorded localfield potentials and single unit activity from hippocampalarea CA1 using a tetrode microdrive, and tracked the positionof light-emitting diodes on the animal's head. Theserecordings revealed place-cells very similar to rodents, as wellas rodent-like high frequency ‘ripple’ oscillations. Theta oscillation,however, differed from rodents in two importantways: (i) theta occurred when bats explored the environmentwithout locomoting, using distal sensing via echolocation;(ii) theta was not continuous but occurred in short intermittentbouts. The intermittence of theta suggests that modelsof hippocampal function relying explicitly on continuoustheta may not apply to bats. These data support the hypothesisthat theta in mammals is involved in sequence-learning,and hence theta power increases with sensory-input rates–explaining why theta-power correlates with running-speed inrodents and with echolocation-call-rate in bats. Finally, wedemonstrate rapid modulation of hippocampal spatial representationin the bat, with a ∼1-second timescale, which is1-2 orders of magnitude faster than previously reported. Futureplans include recording of neural activity from the hippocampusof freely-flying bats, using a telemetry system–aswell as the analysis of the relation between the animal's behaviorand the network activity of dozens of simultaneouslyrecordedsingle units from bat hippocampus. μM) and aresuitable and convenient for studying calcium dependent exocytosis.Previous work has shown that sea urchin vesiclescontain a high calcium concentration. Fluorescent confocalmicroscopy demonstrated well defined calcium dynamics.Here we analyzed the calcium fluctuations. The presence ofbleaching required the use of nonstationary stochastic analysis.This analysis showed that the variance of the calciumsignal is larger than the mean; the calcium signal can not bedescribed as a Poisson process. We speculate that this extravarianceanalysis can contribute to the understanding of theprocesses that control intracellular calcium. We found that,as expected, the highest levels of calcium induced fluorescencewere in the center of the secretory vesicle. The Fanofactor (variance\mean fluorescence) is the lowest in the centerand increased monotonically towards the edge of the vesicle.The highest extravariance is at the edges of the secretoryvesicle. Due do this extra variance, we speculate that thereis an interaction between the calcium in the vesicle and thecalcium in the cytosol. Moreover, we speculate that the secretoryvesicle takes part in the regulation of cytosolic calciumconcentration and may dramatically alter the local calciumconcentration near the surface of the vesicle.Calcium ions have several important functions in synaptic insynaptic communication. They are directly involved in thetriggering of secretory vesicle content release by exocytosis.Synaptic vesicles however, are too small for confocal opticalanalysis. Sea urchin eggs have larger vesicles , we showed influent readers that the response to speech sounds in the auditoryassociation cortex is enhanced by congruent letters  and suppressed by incongruentletters . Interestingly, temporal proximitybetween auditory and visual input was critical for thiscongruency effect to occur. We interpreted these results asa neural correlate of letter-sound integration, driven by thecongruency of letter-sound pairs learned during reading acquisition.Furthermore, we suggested that the modulation ofauditory cortex was the result of feedback from the superiortemporal sulcus (STS). In a subsequent study, we usedevent-related fMRI to investigate the effect of task instructionson neural letter-sound integration, and investigatedthe interactions between STS and auditory cortex directlythrough the analysis of effective connectivity using GrangerCausality Mapping. Our findings indicated that top-downtask demands can overrule the stimulus-driven (bottom-up)integration mechanism. Furthermore, effective connectivityanalysis provided support for the feedback modulation of auditorycortex by STS based on the letter-sound congruency.These findings provide a working model for letter-sound integrationin the “literate brain,” which serves as a basis forinvestigating deviant literacy development. Recent findingsfrom our lab indicate anomalous processing of letter-soundpairs in auditory cortex and STS in dyslexic readers. Presynaptic GABA(B1a)-Rs play an important role inhippocampus-dependent synaptic plasticity, learning andmemory. However, the mechanisms transforming activationof GABA(B1a)-Rs to plasticity and memory function remainelusive. To address this question, we use functionalFM-based imaging to quantify probability of transmitter releaseand distribution of functional presynaptic terminals atthe level of single synapses in hippocampal cultures. Our resultsshow that mice lacking presynaptic GABA(B1a)-Rs exhibitreduced short-term and long-term presynaptic plasticity.Given that presynaptic GABA(B)Rs act as a high-passfilter, preferentially inhibiting transmission of single spikes,we propose that these receptors might regulate synaptic plasticitythrough fine-tuning the level of ongoing backgroundsynaptic activity. To test this hypothesis, we first quantifiedthe effect of baclofen, an agonist of GABA(B)Rs, on transmitterrelease for single spikes (mimicking background activity)versus burst inputs in WT cultures. Our results showthe degree of presynaptic facilitation for bursts is maximizedat the optimal level of GABA(B)-Rs activation. At low baclofenconcentrations (∼0.1 uM) hippocampal synapses actas band-pass filters with low degree of short-termfacilitation;moderate concentrations of baclofen (∼1 uM) significantlyincrease facilitation index, whereas higher baclofen concentrations(>20 uM) induce pattern-independent inhibition,and consequently reduces presynaptic facilitation. Interestingly,chronic treatment of hippocampal neurons with 1uMbaclofen resulted in enhanced long-term presynaptic plasticity.However, 50uM does not affect the capacity of synapticnetwork for modifications. These findings indicate that thecapacity of neuronal network to undergo persistent modificationsis regulated by the level of ongoing background activitythrough presynaptic GABA(B)-Rs. “Reverspectives” (by artist Patrick Hughes) consist of truncatedpyramids with their smaller faces closer to the viewersuch as to allow a realistic scene to be painted on them. Withtheir pictorial perspectives that reverse the physical deptharrangement, reverspectives provide a bistable paradigmof competing depth percepts, with illusory depth beingstrongest monocularly and beyond critical viewing distances .“Properspectives” are the same solid pyramids, painted onthe inside, thus possessing a pictorial perspective that conformswith (and thus augments) real depth. Vergence eyemovements were recorded (EyeLink II system) comparativelyfor monocular and binocular reverspective and binocularproperspective conditions . Gazelocations were signaled by LEDs, inserted in 8 positions onthe model. While fixating identical LED-positions, the eyesconverged with veridical depth percepts and diverged withillusory depth percepts. These results indicate that pictorialcues are as effective as physical cues for vergence control. Myasthenia gravis (MG) is an autoimmune disease characterizedby muscle weakness caused by antibodies to the nicotinicacetylcholine receptor (nAChR) at the post-synapticsite of the neuromuscular junction (NMJ). Experimental autoimmuneMG (EAMG), the animal model of MG, whosechronic phase closely resembles human MG, is widely usedto study numerous aspects of MG. The plasminogen activator(PA) system and matrix metalloproteinases (MMP) areextracellular proteolytic enzymes which modulate cell migration,cell-matrix interactions and signaling pathways. Itis also known that inflammatory cells express the uPA receptor(UPAR) and that tissue PA (tPA) and urokinase PA (UPA)activities are elevated in inflammatory areas. A part from exploringthe inflammatory aspect of the myasthenic NMJ andbased on our previous findings on the involvement of the PAsystem in CNS autoimmune conditions, in the present studywe tested the association of the PA system with EAMG pathogenesis.EAMG was induced in female C57bl mice by immunizationwith purified Torpedo AChR. Four groups wereused: mice genetically deficient in UPA, UPAR, and tPA andwild type (wt). In comparison to the wt all the knock out (ko)mice developed a more severe disease: disease incidence was30% in the control wt group, versus 60%, 100% and 80% inthe UPA−/−, UPAR−/− and tPA−/− groups respectively. However,lymphocyte reactivity towards mitogens was reducedin cells derived from all the ko mice. The addition of peptidesderived from PAI-1 increased T-cell reactivity in vitroby 20–70%, whereas, tPA caused inhibition. Our results implythat a network of functionally redundant proteases is involvedin EAMG pathogenesis. Modulation of the PA systemcould serve as a potential target for treatment of EAMG andMG. P .05). ARTS maybe involved in neuronal apoptosis, but its precise role is stillunclear.The pro-apoptotic protein ARTS is a member of theseptin family, but is derived by alternate splicing from theH5/PNUTL2/hcdcrel2a/2b gene and differs in its C-terminalfrom other products of this gene. ARTS promotes apoptosisinduced by a variety of apoptotic stimulators. In cells ofhuman peripheral tissue origin, ARTS is located in the mitochondriaand translocates to the nucleus at the start of apoptosis,but in rat cortical neurons ARTS is localized in bothcytoplasm and nucleus. ARTS induces apoptosis by bindingto and antagonizing IAPs (inhibitors of apoptosis proteins),thus removing caspase inhibition and activating theapoptotic cascade. ARTS is strongly expressed in the brainand may play an important role in the nervous system. TheARTS protein in peripheral cells has a molecular size on gelelectrophoresis of 32 kDa in human and 28 kDa in rat. HoweverARTS in human brain tissue has a molecular weight of28 kDa and 22 kDa in rat brain tissue. We have sequencedthe ARTS cDNA from rat brain. Alignment between the putativeamino acid sequences of human and rat ARTS shows83% identity. Rat brain ARTS lacks 5 amino acids in the Nterminalregion, a 14 amino acid sequence between aminoacids 76 and 89 and 3 amino acids between 123–125. Theeffect of a few apoptotic stimuli were tested on rat E18 corticalprimary neuronal cells for their effect on the expressionof ARTS and active caspase-3 (apoptosis indicator).Neurons were grown in Neurobasal medium containing B-27 additives. Removal of B-27 at DIV 7 induced apoptosis.Western blot showed an increase in ARTS protein expressionin cells which were incubated 24 h in medium withoutB27. High concentrations of glutamate (1–75 mM) alsoinduced apoptosis. At 50 mM, glutamate increased expressionof ARTS and active caspase-3 (P < .05). ARTS maybe involved in neuronal apoptosis, but its precise role is stillunclear.The pro-apoptotic protein ARTS is a member of theseptin family, but is derived by alternate splicing from theH5/PNUTL2/hcdcrel2a/2b gene and differs in its C-terminalfrom other products of this gene. ARTS promotes apoptosisinduced by a variety of apoptotic stimulators. In cells ofhuman peripheral tissue origin, ARTS is located in the mitochondriaand translocates to the nucleus at the start of apoptosis,but in rat cortical neurons ARTS is localized in bothcytoplasm and nucleus. ARTS induces apoptosis by bindingto and antagonizing IAPs (inhibitors of apoptosis proteins),thus removing caspase inhibition and activating theapoptotic cascade. ARTS is strongly expressed in the brainand may play an important role in the nervous system. TheARTS protein in peripheral cells has a molecular size on gelelectrophoresis of 32 kDa in human and 28 kDa in rat. HoweverARTS in human brain tissue has a molecular weight of28 kDa and 22 kDa in rat brain tissue. We have sequencedthe ARTS cDNA from rat brain. Alignment between the putativeamino acid sequences of human and rat ARTS shows83% identity. Rat brain ARTS lacks 5 amino acids in the Nterminalregion, a 14 amino acid sequence between aminoacids 76 and 89 and 3 amino acids between 123–125. Theeffect of a few apoptotic stimuli were tested on rat E18 corticalprimary neuronal cells for their effect on the expressionof ARTS and active caspase-3 (apoptosis indicator).Neurons were grown in Neurobasal medium containing B-27 additives. Removal of B-27 at DIV 7 induced apoptosis.Western blot showed an increase in ARTS protein expressionin cells which were incubated 24 h in medium withoutB27. High concentrations of glutamate (1–75 mM) alsoinduced apoptosis. At 50 mM, glutamate increased expressionof ARTS and active caspase-3  and either no change or decrease inevoked (agonist-induced) activity in whole cell two-electrodevoltage clamp experiments. The same phenomenon is observedwhen the channels are activated in a receptorindependentmanner, by co-expression of G[betagamma]subunits or by application of G[betagamma] to bath solutionin excised patches. These changes are completely reversedby co-expression of G[alpha]i subunits. Paradoxically,the total activity  remainsunchanged. In contrast, coexpression of phosducin(common G[betagamma] scavenger molecule) reduced thetotal activity. Biochemical data suggested that the rise inGIRK1/2 density is accompanied by increase in the concentrationof G protein subunits (mostly G[betagamma]) inplasma membrane (co-trafficking). We developed a kineticmodel of GIRK1/2 activation by G[betagamma] which accountsfor the activation of the channel via G protein cycle.This model is based on the idea of graded contributionof each G[betagamma] liganded GIRK monomer to channelopening. The model renders sufficiently fast activationrate by agonist application (tau of 1-2 s). We assumed cotraffickingof GIRK1/2 with different amounts of G proteinsubunits to the membrane and simulated the channel activitywith different channel concentrations inmembrane (densityeffect). The model reasonably reproduced the observeddata . However, the model failed to account for thedifference observed between the co-expression of G[alpha]iand phosducin. This fact points towards additional, possiblyallosteric, function of G[alpha]i subunit in modulationof GIRK channel activity. The plasticity hypothesis of major depression states that glucocorticoids(GCs)may be detrimental to neuronal plasticitywhile monoamines, as well as antidepressants, may reconstitutecellular plasticity. Given the key role norepinephrine(NE) and GC play in stress and depression, our aim is tosearch for a shared NE and GC intracellular pathway affectingplasticity with relevance to depression and its treatment.In SH-SY5Y human neuroblastoma cells, DEX, a syntheticGC receptor agonist, altered cellular morphology oppositeto the differentiative effects of NE. This was accompaniedby a reduction in mRNA and protein expression of the differentiationmarkers Gap-43 and L1 as well as protein levelsof an additional marker laminin. Down-regulation was alsoobserved in the transcription factor CREB and in phosphorylatedCREB (pCREB). NE treatment increased Gap-43, L1and laminin protein and mRNA levels as well as pCREB proteinlevels. The opposite effects of NE and DEX on identicalgenes suggest a common signaling pathway. The MAPK inducedtranscription factor AP-1 (c-Jun/c-Fos) can modulatethe aforementioned genes. Both ERK and c-Jun were activatedfollowing NE treatment, while DEX did not affect theseproteins yet reduced c-Fos expression. Co-administration ofDEX and NE resulted in over-activation of the ERK pathway,associated with an increase p-c-Jun and c-Fos, and wasaccompanied by differentiative morphology. In addition, coadministration,as well as NE, increased AP-1 activity. Furthermore,in these cells expressing solely the Gi coupled alpha2adrenergic receptor, pCREB was hyper-activated in anERK independent manner. These results suggest AP-1 as aconvergent point for NE and DEX induced signaling pathways.Elucidating a pathway affected by stress and antidepressants,represented by DEX and NE, respectively, involvedin neuronal plasticity may contribute to understanding thebiological basis of depression, its etiology and treatment.Supported by Israel Ministry of Health. Recently, with the advance of intracellular recording, it wasfound that neurons in the mammalian cortex exhibit spontaneoustransition in membrane potential from UP to DOWNstates. It has been suggested that these oscillatory fluctuationsin membrane potential, which are the cellular manifestationof the brain’s rhythmic activity, reflect network- ratherthan cellular-properties. However, the biophysical mechanismsunderlying these network oscillations are still debated.Using an in-vivo whole cell technique, we recorded from 56pyramidal neurons in the prefrontal and somatosensory corticesof adult rats under Ketamine-Xylazine anesthesia. Themembrane potential of the cells displayed rhythmic alternations(average frequency of 3 Hz), between high and low levelsof membrane potentials and were manifested as a prominentpeak in the voltage spectrogram. Overshooting actionpotentials occurred solely during the depolarized levels. Thedistributions of the recorded voltage were either unimodal(with a prolonged tail) or bimodal. DC current injection intocells that showed bimodal distribution revealed that, in 37%of these cells, the voltage distribution was independent of theaverage membrane potential. In the remaining cells, changingthe holding potential significantly alters the voltage distribution,increasing the voltage difference between the twopeaks of the histogram upon hyperpolarization. This effecton the voltage distribution can only be accounted for if eachof the two peaks represents a different conductance state. Indeed,an average 54% change in input conductance betweenthe UP and DOWN states was calculated for 10 cells. Thesimilar dependence of the two states on the current injectioncan be explained by assuming that the location of the conductancechange that generates the UP and/or DOWN stateis spatially remote from the recording electrode. Hence theintegrative capabilities of a population of cortical neuronscan be independent of their state. In order to study the impact of the surrounding landscapeon exploratory behavior of rats, two experiments were conducted.In the first rats were tested in a square arena with additionalfree-standing (portable) corners, featuring the sameproperties as the arena corners. It was found that the routesof progression converged upon the added corners probablysince the added corners were distinct against the backgroundof the arena enclosure. This implies that the four arena cornersand walls were encoded as one geometric module, andthe distinctness of the added corners made them a targetof exploration. Thus, the impact of a corner extended beyondthe specific self-geometry and depends on the backgroundenvironment. In the second experiment rats wereintroduced into either a round or a square arena with variousarrays of free-standing corners that differed in spacing,orientation, and number. The rats were able to detectthe geometry of the enclosure, the array, and the landmarks:they favored the added corners particularly in the roundcompared with the square arena, and stayed at the interiorof the added corner regardless of their orientation in thearena. Only geometric changes in landmark array affectedrats' level of activity. It is suggested that the context and geometryof the environment affects the distinctness and themeaning of landmarks for the observer, which in turn resultsin a different distribution of activity. Altogether, the two experimentsillustrate that the impact of the environment onexploratory behavior of rats resembles that of environmentalelements in urban environments. We suggest that principlesinvolved in shaping the image of a city in urban planning maybe applicable for understanding how the physical structureof the environments shapes exploration and navigation inanimals. n = 11). Contrast sensitivity(CS) to Gabor patches (GP) was measured for a few spatialfrequencies  under monocular conditions.We also measured the monocular collinear facilitation. We found asignificant asymmetry in monocular CS; it was better in thehorizontal meridian. The facilitation was significantly differentbetween the two meridians regardless of the contrastthresholds of the single target. Our results show that neuralconnectivity in the normal visual cortex of adults is asymmetric,displaying “cortical astigmatism,” thus mirroring theearly optical asymmetry during the developmental period inchildhood.Maturation of neural connectivity is experience dependent insuch a way that the state of the visual input during the criticalperiod can be inferred fromthe visual functions in adults.In meridional amblyopia, the visual input during the criticalperiod was asymmetrical; hence, the perception in onemeridian was blurred, whereas the orthogonal one was normal.Consequently, in adults, the contrast sensitivity and thelateral interactions are dramatically reduced in the blurredmeridian, whereas they are practically normal in the orthogonalone. However, asymmetric visual input is common duringnormal development and children below four years of agetend to be astigmatic . However, this effectdecreases and usually disappears with increasing age. Herewe explored whether this visual asymmetry during the criticalperiod, shaped the development of the visual connectivityand induced cortical asymmetry that was retained duringadulthood in people with normal vision . We tested subjects withcorrected vision of 6/6 or better (Supported by a grant from the Israel Science Foundation. P < 0.0077), reflecting more mistakes whenthe odorants were not nameable. Reaction time (RT) measurementsrevealed a nostril-side main effect  = 5.1,p < 0.01), reflecting overall longer RT when the odor wasdelivered across nostrils then in both nostrils, and a nameabilityby side interaction  = 6.33,P < .004) implyingthat the nameability effect (longer RT for unnameable odors)was more pronounced when subjects were tested across nostrils(P < .015). These findings imply dual representations inOWM: when a verbal representation is available, it is equallyaccessible to both nostrils, but when an odor image is remembered,it offers preferred access to the nostril that generatedit.Olfactory working memory (OWM) maintains informationover short information over short time frames. Whetherthis involves verbal representations or neural images of odorper se, is unknown. Also, the contribution of primary olfactorystructures versus higher-order brain systems is unclear.To address this, we set out to test OWM across nostrils.Considering the predominantly ipsilateral nature of olfactoryprojections, we hypothesized that nonverbal OWMimages would result in no effect of nameability and betteroverall performance within the same nostril, and in contrast,that verbal OWM images would result in a main effect ofnameability, and a possible left nostril advantage. Twentyonesubjects participated in a button-press delayed-matchto-sample task , with 10nameable and 10 unnameable odorants, chosen per subject.In 1/3 of the trials “sample” and “match” were presented inthe same nostril, 1/3 of the trials “sample” was presentedin one nostril, and “match” in the other, and in 1/3 of thetrials “sample” and “match” were delivered to both nostrils.Odorant order was randomized, and test side was counterbalanced.Presented results refer to trials where “sample” and“match” were the same. There was a nameability main effect = 8.75,  The endocannabinoid 2-arachidonoyl-glycerol (2-AG) wasshown to afford neuroprotection via CB1-receptor mechanisms.Recently a non-fCB1, non-CB2 endocannabinoid-likeN-arachidonoyl-L-serine (AraS) was found in the brain. Itis an endothelium-dependent vasodilator with antiapoptoticeffects, and was shown to stimulate Akt phosphorylation inhuman umbilical vein endothelial cells and suppress LPSinducedTNFalfa in macrophages. We here compared the effectsof this compound after traumatic brain injury (TBI) tothose of 2-AG.Mice were subjected to TBI and treated 1 h later with eitherAraS, 2-AG or vehicle. Neurobehavioral function of the injuredmice was assessed by the Neurological Severity Score(NSS), and lesion volume was evaluated by staining with2,3,5-triphenyltetrazolium chloride, that binds to viable mitochondria.In addition, the effect on the proliferation ofneural progenitor cells was assessed in-vitro by the size ofneurospheres isolated from embrional mouse brain tissue(E15) and grown for 4d, using the Image-Pro-Plus software.During 90d after injury the neurobehavioral outcome of themice treated with 2-AG or AraS was significantly better thanthat of the vehicle-treated mice. In addition, lesion volumemeasured 24 hours after trauma was smaller in the groupssubjected to either 2-AG or AraS compared to vehicle. Moreover,preliminary experiments showed that exposure of neurospheres,consisted of multipotential neural precursor cellsto AraS led to a 2 to 4-fold increase in the size of the treatedspheres after 4d as compared to untreated ones.The endocannabinoid-like AraS, similarly to the 2-AG, mayact as a neuroprotectant after TBI by reducing infarct volume,facilitating long-term function recovery and probablyalso by promoting proliferation of neural precursor cells. Thecellular mechanisms of these effects are currently being investigated.Supported by grants from AMRF/APNRR and from NIDA no.DA9289. The critical period for thermal control establishment inchicks spans between postnatal days three and five. Heat conditioningof chicks during that time frame enables them to bemore tolerant to heat later in life. This modulation is thoughtto be carried out by alteration of neuronal properties in thepreoptic anterior hypothalamus (PO/AH) which is probablyrealized by the subset of proteins which are expressed. Epigeneticmechanisms such as DNA methylation are emergingas important regulators of neuronal gene expression. Hencethe present study analyzed the patterns of methylation of thepromoter of a known regulator of neuronal plasticity, thebrain-derived neurotrophic factor (BDNF), during a 24 hourheat conditioning of chicks on the third postnatal day andduring 24 hours of thermal challenge a week later. The experimentslooked at the expression of the BDNF gene along withthe levels of DNA methylation of 6 different CpG positionson the BDNF promoter at different time points during heatconditioning and challenge (day 10). Our data show a transientincrease in BDNF expression during heat conditioningwhich peaked 6 and 12 hours into conditioning. Concurrently,there was a transient induction of methylation of twoCpG positions (the first and the third CpG location downstreamfrom the BDNF-ATG) and a reduction of methylationof one CpG position (1000 bp downstream from the BDNFATG),while the other positions did not show significantchange. Furthermore, our data demonstrate a significant differencebetween the levels of methylation of the BDNF promoterof conditioned compared to nonconditioned chicksduring a thermal challenge, which correlates with the differentlevels of BDNF in the two groups. These data suggest thatcomplex and dynamic changes in DNA methylation mightbe involved in the regulation of thermotolerance acquisitionand support the role of DNA methylation in the regulationof gene expression during neuronal plasticity. Sensation is an active process. When the sensors move, bothmotion and touch signals are crucial for sensory processing.Recently, we showed that whisker-motion and contact signalsare conveyed in parallel via the thalamus. Yet, it is unknownhow downstream brain areas process these signals to localizeobjects. Specifically, the function of secondary somatosensorycortex (S2), which receives massive thalamic projectionsfrom both whisker-motion and contact pathways, is poorlyunderstood. Here, neuronal activities from S2 in responseto object touch were recorded using artificial whisking inanesthetized rats. We found that high proportion of neurons(41%) in deeper layers  of S2 (S2-L46)show significant selectivity to object location, in distinctionwith the superficial layers (layers 2/3) of S2 (20%). Similar tothe latter, small fractions (<23%) of neurons in three thalamicnuclei  and three layers  of the primary somatosensory cortex (S1) displayedsignificant selectivity to object location. We further investigatedthe dynamics of responses in all these somatosensorysites during whisking in free air and against objects in variouslocations. Comparison of the dynamics of location-selective(S) cells with those of nonselective cells revealed several differences.Among these differences was a lack of a slow-wavedynamics in S cells, different response dynamics during retraction,and a weaker response of S cells to the first cyclein VPMdm and S1-L4. Comparison of response dynamicsacross nuclei revealed two major patterns of cortical dynamics,one evident in S2-L46 and S1-L5a and another in S2-L23 and S1L4. The analysis so far thus suggests that corticalprocessing of active touch is done in parallel in at least twostreams, that processing of object location involves severalbrain sites, among which a significant processing of objectlocation is performed in the deep layers of S2. In the last decade a large amount of electrophysiological researchhas focused on high frequency brain activity in humans,and specifically on the “induced gamma response”(iGBR). This response is a typical increase in the gammaband (>30 Hz) peaking around 250 milliseconds post stimulus,following the presentation of a visual stimulus. The iGBRwas hypothesized to represent the neural synchronization involvedin various cognitive functions such as binding andconsciousness. The iGBR is calculated by averaging single trials’spectral data, circumventing phase cancellation due tointer-trial latency jitter Our study is the first attempt to lookat gamma responses in single trials. Subjects performed a visualparadigm in which all subjects demonstrated a prominentiGBR. In each subject many of the single trials exhibita gamma increase at a similar latency, topography and frequenciesas the average iGBR. Examination of the EEG datashows that each gamma increase is characterized by a sharppeak in the filtered data (30–100 Hz) of central channels. Inaddition, a prominent peak with an opposite polarity appearsat the EOG channels placed around the eyes. In a simultaneousrecording of eye position (using an eye tracker device) itwas found that these gamma increases are frequently accompaniedby an eye movement. As a further analysis, trials weresorted according to eye movements in the relevant time window.Averaging across the third of trials with the strongest eyemovements, the iGBR was exceptionally high. In contrast,when the average was performed across a third of trials showingthe least eye movements, the iGBR was eliminated. Therelation between eye movements and gamma power was furtherdemonstrated when sorting by gamma power and examiningthe eye movements. These findings show a strong relationbetween iGBR and eye movements, challenging prevailingmodels of the neural origin of the scalp recorded iGBRand the related cognitive processes. Learning new sensorimotor tasks involves plastic changes inresponses of the primary motor cortex (M1) and the Premotorarea (PM). We have shown such changes accompanyingboth the learning process and the consolidation into longterm memory that follows learning. Since contextual informationhas been shown to affect the learning of various sensorimotortasks, we investigated the effect of context on neuronalresponse in the motor cortices. In order to do so, we simultaneouslyrecorded neuronal activity from 32 electrodesin M1 and Premotor cortices of two behaving monkeys. Ineach session, the monkeys performed first a center-out taskand then, they had to learn a novel arbitrary associationstask (where they had to learned a color-direction association),and then they performed a second block of the centerouttask. We compared neuronal responses during trials featuringthe same movement direction and target color, eithermade during the center-out task or during the arbitrary associationtask . Also, we compared the two center-out blocks toeliminate effects of passage of time. We found that about 65%of the neurons showed significant difference in responseswhen the very similarmovements made in different contexts.Differences included both firing rate change and change inresponse pattern. These differences could not be accountedfor by any change in movement parameters. These resultsdemonstrate that the motor cortices are liable to contextualmodulation, and broaden our knowledge on motor corticesdynamics. Brain machine interfaces extract relevant information, likethe velocity of the intended movement, from recorded neuralactivity. However, while the recorded neural activity is inthe form of spike trains, most decoding algorithms are basedon the binned spike counts. The bin-width (BW) is usuallydetermined by trial and error or based on previous experience.Here we investigate the effect of the bin-width onthe signal-to-noise ratio (SNR), and on the ratio SNR/BW.The latter is shown to be related to the capacity of the neuralchannel under different assumptions. Furthermore, whilethe SNR increases with the BW, the update rate decreases,suggesting that the ratio SNR/BW should be considered asa relevant criterion. The SNR is estimated under the assumptionthat the neural spike trains are realization of doublystochastic Poisson processes–the simplest point processesthat can encode stochastic signals. Analysis of neural spiketrainsrecorded during BMI experiments from different corticalareas, indicate that the mean SNR/BWhad a broad peakaround 100 milliseconds—the bin-width that was selected bytrial and error. However, detailed analysis indicates that theSNR/BW of different neurons peak at different bin-widths.In particular, the SNR/BW of M1 neurons peak at shorterbin-widths, while that of PMd neurons peak at longer binwidths.Supported by Fund for Promotion of Research at the Technion,DARPA, NIH, NSF. Recent experiments with Brain Machine Interfaces indicatethat the extent of neural modulations increases abruptlyupon starting to operate the interface. In contrast, neuralmodulations due to the trajectory profile remain relativelyunchanged. Furthermore, the enhanced modulations subsidewith further training, mirroring the trend in task performance,which degraded upon starting to operate the interfaceand improved gradually with training. Here we investigatethe hypothesis that the enhanced modulations reflectinternal representation of trajectory errors, which resultsin corrective commands in the short term and adaptivemodifications of internal models in the long term. Asimplified unidimensional model is analyzed to demonstratethe observed transient enhancement in neural modulationsduring the operation of Brain machine Interfaces. Identifyingthe source of the transient enhancement in neural modulationwould provide insight into adaptive motor controland facilitate the improvement of future Brain Machine Interfaces.Analysis of the model yields the conditions underwhich it is stable, reduces the motor error and acquires thecorrect inverse internal model/feedforward controller. Simulationsof both skilled and BMI operations, using parametersand signals from experiments, yield results with similarcharacteristics as those observed in experiments in regardsto both tracking performance and to neuronal modulationlevels. Our model gives rise to the hypothesis thatmotor neurons are tuned both to preferred desired directionsand preferred error directions, further more, it stressesthe importance of adequate tuning to error directions withoutwhich the model is not stable and unable to reducethe motor error by feedback control or to adapt the correctinternal inverse model that will perform as feedforwardcontroller.Fund for Promotion of Research at the Technion. The translocator protein (TSPO) can be found in conjunctionwith the mitochondrial 32 kDa voltage-dependent anionchannel (VDAC) and the 30 kDa adenine nucleotide transporter(ANT). The VDAC and ANT form the core elementsof the mitochondrial permeability transition pore (MPTP).Opening of the MPTP can start the mitochondrial apoptosiscascade. Furthermore, the TSPO has been suggested toact as an oxygen sensor. Oxygen related mechanisms induceprominent clinically relevant changes in cancer cells and tumorbiology through the control of gene expression. Therefore,we studied the levels of TSPO and apoptosis in gliomacells under hypoxic conditions. To do this, we applied eitheran environment with 1% oxygen (hypoxia) or addedCoCl2 to the medium . Treatmentswith 1% oxygen resulted in an increase in the levelsof TSPO (Western) and an increase in TSPO binding density.Furthermore, 1% oxygen levels resulted in an increase inapoptosis levels (50%). Adding CoCl2 (0.25 mM) to the cellsalso resulted in an increase in apoptosis levels (40%). However,the binding density of TSPO was unchanged with applicationof CoCl2. We also found that under treatment withCoCl2, the amount of P53 is decreased, suggesting a deregulationof the cell cycle. Stabilization of HIF1-α level indicatedthat in our model CoCl2 (0.25 mM) treatment indeedmimics hypoxia conditions. Our results indicate that reducedoxygen levels affect both TSPO levels and apoptosis, whileCoCl2 only affects apoptosis. Other preliminary results, fromTSPO knockdown with siRNA, suggest however that CoCl2also induces apoptosis via TSPO. These results suggest thatTSPO as an oxygen sensor may play a role in the inductionof apoptosis levels due reduced oxygen levels. This mayhave implications for our understanding of the involvementof TSPO in pathological conditions such as ischemia andcancer.Research support: WK, LV, ML, and MG . We develop a robust linear classification framework for inferringmental states from electrophysiological (MEG andEEG) signals. The framework is centered around the conceptof temporal evolution of regularized Fisher Linear Discriminantclassifier constructed from the instantaneous signalvalue. The value of the regularization parameter is selectedto minimize the classifier error estimated by cross-validation.We build upon the proposed framework to develop a featureselection technique. We demonstrate the framework and thefeature selection technique on MEG data recorded from 10subjects in a simple visual classification experimente showthat using a very simple adaptive feature selection strategyyields considerable improvement of classifier accuracy overthe strategy that uses fixed number of features.We develop a robust linear classification framework for inferringmental states from electrophysiological (MEG andEEG) signals. The framework is centered around the conceptof temporal evolution of regularized Fisher Linear Discriminantclassifier constructed from the instantaneous signalvalue. The value of the regularization parameter is selectedto minimize the classifier error estimated by cross-validation.We build upon the proposed framework to develop a featureselection technique. We demonstrate the framework and thefeature selection technique on MEG data recorded from 10subjects in a simple visual classification experiment. We showthat using a very simple adaptive feature selection strategyyields considerable improvement of classifier accuracy overthe strategy that uses fixed number of features. Social interaction depends on our ability to create, store andretrieve memories for human faces. Learning new faces isunique not only due to the special nature of face processingbut also because it requires forming detailed neural representations.To date few studies have investigated the neuralmechanism involved in learning new faces. In the presentstudy subjects studied a series of faces and were then testedon their memory for them when presented again interspersedamong new faces. Both famous and nonfamous faces wereused, in separate blocks, in order to compare memory forfaces which subjects have prior experience with and new faceswhich subject have no previous representation for. EEG wasrecorded and we focused primarily on two electrophysiologicalmeasures of neural activity: theta-band activity (4-8Hz) which has been associated with successful encoding andretrieval of memories and Gamma-band activity (>30 Hz)which has been linked to activating a neural representationmatching an incoming stimulus. We compared activity duringthe test phase in response to correctly remembered faces(hits) with correctly categorized new faces (CR). Theta activitywas similar for both famous and nonfamous faces andwas larger for hits than for CRs. In contrast, Gamma activitywas larger for famous faces than for nonfamous faces.Hits elicited smaller Gamma amplitudes than CR, which isin line with previous studies demonstrating a reduction inGamma activity for repeated stimuli and has been attributedit to a “sharpening” of the cortical representation activatedby the stimulus. This study demonstrates that both Thetaand gamma activity play a role in retrieval of memories forfaces, and suggests that whereas Theta activity is related tomnemonic processing irrespective of pre-experimental familiaritywith the stimuli, Gamma activity is involved in theactivation of neural representations and is modulated by recentexposure to the same stimulus. The formation of neuronal networks is governed by a limitednumber of guidance molecules, yet it is immensely complex.The complexity of guidance cues is augmented by posttranslationalmodification of guidance molecules and theirreceptors. We report here that cleavage of the floor plateguidance molecule F-spondin generates two functionally opposingfragments: a short-range repellent protein depositedin the membrane of floor plate cells, and an adhesive proteinthat accumulates at the basement membrane. Their coordinatedactivity, acting respectively as a short-range repellantand a permissive short-range attractant, constricts commissuralaxons to the basement membrane beneath the floorplate cells. We further demonstrate that the repulsive activityof the inhibitory fragment of F-spondin requires itspresentation by LRP receptors ApoER2, LRP2/megalin andLRP4, which are expressed in the floor plate. Thus, proteolysisand membrane interaction coordinate combinatorialguidance signaling originating from a single guidance cue. In our previous study, we found that the filling-in processis impaired in patients with depression, as evident by theirreporting less target present than the control group. We suggestedthat this deficit is due to an abnormal balance of theexcitation and inhibition between neurons. However, it is stillpossible that the response criterion in these subjects is moreconservative, due to general indifference. In this study, weused a forced choice task ,and a static presentation (no limitation of informationprocessing time) to minimize the attentional effect. We measuredthe contrast threshold of a Gabor target that was presentedat the left or the right side of the screen (1.2° each side)between two flankers (12 cpd), separated at 7 distances from0 to 12 lambda. The short distances test contrast discriminationand the far distances contrast detection. We found thatthe function of the control group is similar to the standardfunction, found when using 2 temporal alternative forcedchoice (2AFC), showing suppression in 0 and 1 lambda andfacilitation at the far distances. On the other hand, the depressedsubjects performed like the control subjects only atthe far distances, whereas at the short distances (contrast discrimination),the expected suppression is absent and is replacedby facilitation. Since suppression in contrast discriminationtasks is explained as largely due to response saturationof neurons, we suggest that high levels of inhibition preventthe neurons from reaching saturation. High levels of inhibitionreduced the level of excitation, which in turn will lead toan impaired filling-in process in depressed subjects.Supported by the National Institute of Psychobiology in Israel.