Paradoxically, interventions that decrease mitochondrial ROS levels in vivo delay onset of aging. To reconcile these findings, we used the mitochondria-targeted mass spectrometry probe MitoB to measure hydrogen peroxide within mitochondria of living mice. Mitochondrial hydrogen peroxide was the same in young mutator and control mice, but as the mutator mice aged, hydrogen peroxide increased. This suggests that the prolonged presence of mtDNA mutations in vivo increases hydrogen peroxide that contributes to an accelerated aging phenotype, perhaps through the activation of pro-apoptotic and pro-inflammatory redox signaling pathways.In mtDNA mutator mice, mtDNA mutations accumulate leading to a rapidly aging phenotype. However, there is little evidence of oxidative damage to tissues, and when analyzed  There was no difference in MitoP/MitoB ratio between young mutator mice and age-matched controls Fig. , even thols Fig. . There wols Fig. . (For thice Fig. . Therefoet al., Mitochondrial tissue content was similar for all the mice Fig. . The Mitin vivo may arise from disruption to mitochondrial function due to mtDNA mutations increasing superoxide production, which is suppressed in vitro by saturation with substrates and oxygen. As oxidative damage does not accumulate markedly in mutator mice, the mtDNA mutations may activate mitochondrial ROS production as part of subtle redox signaling pathways that contribute to accelerated aging. Increased apoptosis is associated with elevated mitochondrial ROS, consistent with greater cell death in mutator mice (Kujoth et al., et al., et al., et al., et al., et al., The increase in mitochondrial hydrogen peroxide with age in the mutator mice in vivo, and suggest that the ROS production contributes to the accelerated aging phenotype. Accelerated aging may occur through the activation of pro-apoptotic and pro-inflammatory redox signaling pathways in response to mtDNA damage. Whether these mechanisms drive aging in general, are specific to the mtDNA mutator mouse model, or are merely secondary consequences of aging are important questions to be addressed in future work.Our findings show that the presence of mtDNA mutations in mutator mice increases mitochondrial ROS levels with age


Very preterm birth  has been associated with an increased risk to develop cognitive and socio-emotional problems, as well as with increased vulnerability to psychiatric disorder, both with childhood and adult onset. Socio-emotional impairments that have been described in VPT individuals include diminished social competence and self-esteem, emotional dysregulation, shyness and timidity. However, the etiology of socio-emotional problems in VPT samples and their underlying mechanisms are far from understood. To date, research has focused on the investigation of both biological and environmental risk factors associated with socio-emotional problems, including structural and functional alterations in brain areas involved in processing emotions and social stimuli, perinatal stress and pain and parenting strategies. Considering the complex interplay of the aforementioned variables, the review attempts to elucidate the mechanisms underlying the association between very preterm birth, socio-emotional vulnerability and psychopathology. After a comprehensive overview of the socio-emotional impairments associated with VPT birth, three main models of socio-emotional development are presented and discussed. These focus on biological vulnerability, early life adversities and parenting, respectively. To conclude, a developmental framework is used to consider different pathways linking VPT birth to psychopathology, taking into account the interaction between medical, biological, and psychosocial factors. Very preterm birth  is common and represents up to 13% of all births . VPT infants are exposed to repeated procedural pain-related stress during a period of rapid brain maturation and physiological vulnerability, and several studies have shown an impact of these procedures on altered neurodevelopment and hypothalamic-pituitary-adrenal (HPA) programming Grunau, , includiA further important potential explanatory factor for impaired socio-emotional development in VPT individuals may involve the effects of early parental behavior. Life threating events in the perinatal period and the immature behavioral organization of preterm born infants may increase overall parental psychological distress and alter the interaction between child and primary carer, potentially interfering with the establishment of long-term positive parent-child relational patterns. Parental mental health has in fact been associated with children's early socio-emotional development, as it plays a pivotal role in protecting against the effects of early stress  and social withdrawal (CBCL) subscales and are described as being “not liked by peers,” “rather solitary, tend to play alone,” “too dependent.” Similar findings were reported in geographically diverse samples: social problems scores, as measured by the CBCL, were higher in four population-based cohorts of extremely low birth weight children  born in 1977–1987 compared to controls  symptoms of anxiety and depression show different life courses, with anxiety having a typical onset in childhood, compared to depression that mostly emerges in adolescence; (2) there are significant gender differences in prevalence of specific disorders, i.e., women are twice more likely to suffer from depression compared to men; (3) symptoms of anxiety and depression are highly comorbid, with anxiety often being a precursor to depression. Furthermore, in the preterm literature, anxiety and depression are often simultaneously investigated, which makes it difficult to disentangle the relative prevalence of dimension-specific symptoms , reflecting possible WM pathology, in right orbitofrontal cortex detected at term equivalent age in VPT infants was related to peer problems at 5 years, supporting the idea of the involvement of the orbitofrontal cortex in theory of mind, social cognition, and social regulation  and the Vineland scales  is a common finding. Convincing evidence exists to suggest that overall cognitive ability is reduced in preterm populations, and a recent meta-analysis describes a gradient effect of VPT birth on IQ, with an average estimated decline of 1.5 IQ points for each weekly decrease in gestational age for those born < 33 weeks of gestation  regulation and lower motor and cognitive functions at 8 and 18 months corrected age  or to target specific factors found to be precursors of socio-emotional and psychiatric difficulties in preterm born individuals.New findings on early markers of outcome will help us explain the cascade of socio-emotional behavioral difficulties often described in preterm born individuals, will provide a better understanding of their brain substrates and will open the way to new effective contributions to support child development.AM: Study conception and design, data interpretation and write up. CN: Study conception and design, data interpretation and write up.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


NAC genes, as well as the suitable promoters for minimizing the negative effects caused by over-expressing some NAC genes, should be considered.Abiotic stresses adversely affect plant growth and agricultural productivity. According to the current climate prediction models, crop plants will face a greater number of environmental stresses, which are likely to occur simultaneously in the future. So it is very urgent to breed broad-spectrum tolerant crops in order to meet an increasing demand for food productivity due to global population increase. As one of the largest families of transcription factors (TFs) in plants, NAC TFs play vital roles in regulating plant growth and development processes including abiotic stress responses. Lots of studies indicated that many stress-responsive NAC TFs had been used to improve stress tolerance in crop plants by genetic engineering. In this review, the recent progress in NAC TFs was summarized, and the potential utilization of NAC TFs in breeding abiotic stress tolerant transgenic crops was also be discussed. In view of the complexity of field conditions and the specificity in multiple stress responses, we suggest that the NAC TFs commonly induced by multiple stresses should be promising candidates to produce plants with enhanced multiple stress tolerance. Furthermore, the field evaluation of transgenic crops harboring  As sessile organisms, plants continuously suffer from a broad range of environmental stresses including abiotic and biotic stresses. Abiotic stresses such as drought, salinity, heat and cold, adversely affect plant growth and agriculture productivity, and cause more than 50% of worldwide yield loss for major crops every year Boyer, . FurtherArabidopsis and rice. These genes are generally classified into two types  from petunia NAM , NAC family has been found to function in various processes including shoot apical meristem , DREs (Dehydration-responsive elements), jasmonic acid responsive element and salicylic acid responsive element. Then the complex post-transcriptional regulation involves microRNA-mediated cleavage of genes or alternative splicing. NAC TFs also undergo intensive post-translational regulation including ubiquitinization, dimerization, phosphorylation or proteolysis  containing the CACG core-DNA binding motif has been identified in the promoter of the drought inducible EARLY RESPONSE TO DEHYDRATION1 (ERD1) gene in Arabidopsis , such as an Arabidopsis calmodulin-binding NAC with GCTT as core-binding motif G(T/C) (T/C/A) (T/C/A)  which can maximize the positive effects and minimize the negative effects caused by over-expressing some NAC genes. In summary, NAC TFs are the key components of the signaling pathway in stress response which carry out their function by interacting with both downstream and upstream partners (Figure As everyone knows, one of the most important aims for plant stress research is to provide targets for the improvement of stress tolerance in crop plants. With the forecast changes in climatic conditions leading to a more complex stress environment in the fields, we will face new challenges in creating the multiple stress-tolerant crops. Breeding such plants will depend on understanding the crucial stress-regulatory networks and the potential effects of different combinations of adverse conditions. Studies of multiple stress responses in s Figure . UnderstThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Major Depressive Disorder (MDD) is the most common psychiatric disease, affecting millions of people worldwide. In addition to the well-defined depressive symptoms, patients suffering from MDD consistently complain about cognitive disturbances, significantly exacerbating the burden of this illness. Among cognitive symptoms, impairments in attention, working memory, learning and memory or executive functions are often reported. However, available data about the heterogeneity of MDD patients and magnitude of cognitive symptoms through the different phases of MDD remain difficult to summarize. Thus, the first part of this review briefly overviewed clinical studies, focusing on the cognitive dysfunctions depending on the MDD type. As animal models are essential translational tools for underpinning the mechanisms of cognitive deficits in MDD, the second part of this review synthetized preclinical studies observing cognitive deficits in different rodent models of anxiety/depression. For each cognitive domain, we determined whether deficits could be shared across models. Particularly, we established whether specific stress-related procedures or unspecific criteria  could segregate common cognitive alteration across models. Finally, the role of adult hippocampal neurogenesis in rodents in cognitive dysfunctions during MDD state was also discussed. Described in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders  as “sigetc.) . These si.e., the deficits observed exclusively during depressed episodes and those occurring prior, between and after MDD episodes [The DSM-V clearly defines subtypes in major depression such as melancholic and atypical subtypes of MDD. Comparing different cognitive functions across MDD subtypes may help in the identification of neurocognitive patterns according to the specificity of MDD markers. Additionally, few studies aimed at delineating between trait- and state-like cognitive alterations, episodes . One metIn order for basic research to provide potential advances in this field, it is essential to use animal models that present behavioral, neurochemical and brain morphological phenotype reminiscent of some symptoms of MDD. Indeed, animal models exhibiting deficits in one or more of the relevant domains of cognition are useful to investigate mechanisms underlying impaired cognitive processes observed in MDD and their dependence on mood pathology. In rodents, many anxiety-depression models, including chronic early-life stress and adulthood models, have been validated for the study of anhedonic behaviors, modeling the negative mood symptomatology of MDD. It has been reported that adverse experiences during pregnancy or early stress life events in childhood could lead to an increased sensitivity to the effects of stress in adulthood life, directly enhancing vulnerability to depression ,9. RodenIn this review, the first part will be focus on clinical cognitive dysfunctions depending on the type and stage of the MDD illness. The second part of this work will gather preclinical studies observing cognitive deficits in different rodent models of anxiety/depression. For each cognitive domain, we will highlight which deficits can be shared, across models, and, whether specific stress-related procedures or non-specific criteria  can segregate common cognitive alteration. Finally, the role of adult hippocampal neurogenesis in rodents in cognitive dysfunctions during MDD state will be discussed.Cognitive abnormalities in many various cognitive domains have been reported among patients suffering from MDD ,20,21,22Further studies involving larger, homogenous cohorts of patients are needed to provide new understanding regarding this issue. Cognitive dysfunctions in elderly depressed people have been widely investigated, but no specific cognitive impairments have been observed due to the physiological decline of cognitive process with age and to potential neurodegenerative disorders appearing in late-life. However, late-life depression has been particularly associated with a slower speed in information processing, executive functions difficulties and working memory deficits ,38,39. AThe Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Asberg Depression Rating Scale (MADRS) are clinician-administered assessments of depressive symptoms that are the most frequently used methods in depression clinical trials. However, neither of these scales evaluates cognition in any depth and both rely on a clinician’s subjective opinion based upon a patient’s report. In the HAM-D, a single item assesses psychomotor functioning, whereas a single item on the 10-item MADRS assesses concentration .The number of studies investigating cognition performances in depressive disorder has grown during the last decade, reflecting the interest in cognition as a therapeutic target . Given tThrough a review highlighting the nature of cognitive assessment instruments used in MDD trial, the California Verbal Learning task (CVLT), the Trail Making Test (TMT-A), the Wechsler Memory-Scale (WMS) and the Wechsler Adult Intelligence Scale (WAIS) were listed as the most frequently used in clinical studies . Among cAttention processing monitoring: the Digit Span test and the Continuous Performance test,Processing speed: the Trail Making Test-Part A, the Digit symbol test and the Finger Tapping test,Executive functions and verbal memory: the Stroop Color Word test, the Trail Making Test-Part B and the Wisconsin Card Sorting Test,Memory functions: the Rey Auditory Verbal Learning Test, the Wechsler Memory Scale and the California Verbal Learning taskClassified by cognitive domains, some of the most familiar used tests in the MDD context are as follows ,45: AtteDespite the variety of accessible methods, there is still a lack of harmony regarding the practical use of appropriate instruments or batteries to assess cognitive functions in major depression. The development of a validated and standardized cognitive battery to use in a specific manner in MDD clinical trials is necessary to improve both assessments and treatments of MDD patients.The course of MDD pathology is characterized by a first-episode of major depression either followed by a complete remission or break periods without any mood-related symptoms and recurrent episodes separated by short time periods between relapse. In order to better visualize the progression of cognitive symptoms associated with depressive symptoms, Although many studies found that a wide range of antidepressant treatments were able to improve both mood and cognitive-related symptoms in MDD ,47,48, oAlthough description of cognitive alterations in the context of mood disorders has been extensively analyzed in the literature ,28,31,53Although many studies found that a wide range of antidepressant treatments were able to improve both mood and cognitive-related symptoms in MDD ,47,48, oThe proportion of MDD patients that encountered recurrence episodes is estimated at 50%–60% . CognitiOtherwise, evidence suggesting that rDD was associated with negative biases and increased sensitivity to negative events. While first-episode MDD patients can show an impairment in emotional cognitive function ,32, rDD Taken together, rDD are characterized by a proportional aggravation of cognitive disturbances compared to first-episode MDD . This prMany questions about cognitive deficits associated with MDD pathology remain unanswered: could cognitive impairments be a premature behavioral marker of susceptibility to depression and be used as a prevention tool? Are residual cognitive dysfunctions in remitted patients a risk factor for relapse? New discoveries in this field could significantly improve therapeutic care in MDD patients. Relieving cognitive dysfunctions may be a necessarily step to treat major depression.Most of clinical studies investigating cognitive dysfunctions in MDD patients did not detail the heterogeneous condition of depression symptomatology. Melancholia and atypical disorders are the main subtypes in depression. Specifically, melancholic depression can be distinguish from non-melancholia by a set of physical symptoms occurring during clinical depressive episodes such as anhedonia and/or lack of reactivity to usually pleasurable stimuli, observable psychomotor retardation, weight loss, worsening of symptoms in the morning hours and early morning awaking DSM-V, ,61,62). ,62. 61,6After two decades of research, increasing evidence suggests that melancholic patients exhibit greater cognitive dysfunctions than non-melancholic patients but no qualitative review focusing on cognitive impairments in melancholic subtype has been written yet. Conducted in small cohorts of patients, the oldest studies mainly focused on psychomotor and motor coordination performances such as Finger tapping task, fast walk, finger-thumb apposition, hands movements, foot tapping, finger-copying task or reaction time tasks. In accordance to the CORE concept, psychomotor performances were diminished in melancholic patients compared to non-melancholic patients ,68,76.The major finding emerging from the variety of cognitive domains tested is that all studies assessing attentional processes and more globally executive functions invariably showed deficits in one or several associated tasks in melancholic patients compared to non-melancholic patients ,72,74,75As mentioned previously, cognitive abnormalities in MDD patients can persist even after clinical remission ,54,77,78There is substantial evidence showing that perception in patients with MDD is characterized by blunted responsiveness to emotionally positive information as well as an increased tendency to perceive emotionally neutral visual information as negative . HoweverTaken together, the majority of studies agreed on both generalized and specific cognitive impairments in the melancholic subtype, characterized by a greater degree of these alterations compared to non-melancholic patients. Specifically, melancholic patients were distinguished by specific impairments in decision speed and positive emotion processing ,73,74,75Although subtyping depressive patients can be a useful tool in identifying specific profiles in depressive symptomatology, its clinical utility regarding predictive antidepressant drug efficacy must be hampered by recent exploratory  or transper se facilitates this form of reward-related learning. The interrelationship between specific components of motivational dysfunction and specific cognitive systems in the context of depression remains to be studied in order to allow for a greater understanding of mood disorders [Even though, anhedonia and dysfunctional reward processing are unspecific to MDD, and may be observable in other psychiatric disorders , this isisorders .Cognition is a complex brain function that involves processes including attention, processing speed, learning and memory, working memory, verbal fluency and executive functions. However, some of these cognitive domains cannot be modeled in Rodents because of the higher cognitive demands specific to Humans, particularly in executive functions such as planning, problem solving, multi-tasking or decision-making and verbal fluency.Collective efforts from preclinical researchers and clinicians are currently in progress to improve the translation of fundamental research tools into clinical application in Psychiatry. For example, the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative was introduced to identify tasks with construct validity across species to improve the “translational-ity” of behavioral tests from rodents to non-human primates and humans ,90. MoreDespite this growing awareness for translational research across species, classical learning and memory behavioral paradigms remain widely used in fundamental research and in the context of anxiety-depression. Among them, few have a strong translational value from rat to non-human primates to humans . In addition, fear extinction conditioning is the only task that presents a direct translational assessment from rodents to humans. Except these paradigms, the vast majority of preclinical assessment tools does not exhibit particular translational features. In exchange, they offer the advantage to be very well-validated through literature history, thus allowing relevant comparisons between studies using the same cognitive task.i.e., object location recognition, passive avoidance), confirming that a unique categorization of a cognitive task into a specific domain of memory is not always appropriate.Finally, some of the behavioral tests appear several times in different cognitive domains  can vary to evaluate the various components of episodic-like memory (What? Where? When?). The spontaneous nature of this task, exploiting the curiosity of rodents and their propensity for novelty seeking, confers to recognition tests many advantages, especially in an anxiety-depression context. Unlike many others learning or memory paradigms, no positive (food reward) or negative  reinforcements are needed, minimizing other psychological parameters that could influence performances during the task . HoweverMany preclinical studies have investigated the performances of anxiety-depression models on object recognition memory . The novStudies using prenatal stress or early-life stress procedures showed either impairing ,112,113,On the contrary, object recognition memory is predominantly impaired in chronic stress procedures applied during adulthood, such as social defeat, UCMS or the CORT model. This alteration is indicated by a diminution of the discrimination index (DI) ,129,130,Although the novel object recognition test is widely used in laboratories, place recognition (the “Where” component) and temporal ordering (the “When” component) tasks can help to refine the degree of evaluation of episodic-like memory. The place recognition task examines the animal’s ability to discriminate between an object that was moved during the delay between the acquisition and the retention phase and an object that remained stationary, adding a spatial component to the task. On the other hand, temporal ordering task consists in presenting a set of two identical objects during a first acquisition session. After a defined interval, another set of two new identical objects is presented to animals for exploration. During the retention session, animals have to discriminate between the “old object” from the first acquisition session and the “recent” object from the 2nd session. An intact temporal order memory is observed when an animal has spent more time with the “old” object . versus adult chronic stress procedures . Inmpaired: ,121.via the temporal ordering task. Only works in maternal separation were performed, once again presenting discrepancies in the results. One study showed no effect of MS procedure on temporal order memory [Very few studies evaluated the “when?” component of episodic-like memory r memory , while ar memory . At thiset al. [Independently of the nature of task, antenatal and early post-natal procedures were the only models in which an improvement in episodic-like performances was observed ,115,117.et al. ,135, andet al. .Taken together, except an overall impairment in all discrimination tasks observed in adult chronic stress procedures, results are too inconsistent in pre/perinatal manipulations to extract relevant advances in the area of episodic-like memory. Further investigations focusing on place and temporal recognition may contribute to progress in the discovery of fundamental mechanisms underlying episodic-like memory in rodents in a pathological context. Finally, efforts should be intended to integrate episodic memory in clinical neuropsychological tests performed in MDD patients to fully assess cognitive functions.In humans, the concept of working memory refers to the ability to get and temporarily store specific information during a variable delay in which the stimulus is absent, and to return the message when requested by the context. Clinically, the majority of neuropsychological tests assessing working memory relies on verbal tasks such as the Digit Span task  ,75. In rAs illustrated in et al. provided a full characterization of cognitive consequences in PNS-rats [Bidirectional findings are observed when analyzing early chronic stress life procedures effects on working memory. Indeed, while prenatal stress mostly impaired alternation tasks and spatial working memory ,140,141,PNS-rats  in whichRegardless of the nature of the task, a robust altered effect in unpredictable chronic mild stress animals was found on working memory. Indeed, all of the preclinical studies demonstrated either a decrease in alternation behavior ,152,153 Interestingly, several studies initially focused their attention on neonatal maternal separation and chronic CORT procedures independently before combining these two methods (MS + CORT) to assess their behavioral effects in delayed alternation tasks ,142,144.Finally, working memory performances in social defeated animals varied, in delay- and species-dependent manners. In the T-maze alternation task, mice displayed a decrease in alternation rate as soon as the 5-seconds delay  whereas Taken together, chronic environmental stress procedures lead to a decline in working memory whether it was applied during gestational or adulthood periods. On the contrary, early maternal separation or chronic corticosterone regimen do not cause any damaging effects separately, but demonstrated conflicting delay-dependent effects when associated. Socially-defeated animals displayed species and delayed-dependent behaviors in working memory. Other non-spatial behavioral paradigms evaluating working memory with operant tools are currently in development such as Delayed Match to Sample, Delayed non-Match to Sample Delayed , but so versus omissions) and the speed with which the animal responds (time reaction). Complexity in the task can be increased by varying the stimulus light or inter-trial interval duration for example, assessing in this case parameters such as premature or perseverative responses (nose poke that occurs prior to light presentation or repeated nose pokes in a previously lit aperture), giving further information on impulsive behavior  can contribute to the apparition of depressive symptoms as well as cognitive deficits , PND35 (juvenile) and PND56 (young adult). Their results highlighted that enhanced behavioral effects generated by MS procedure do not emerge until adolescence .The attentional set-shifting task (ASST) is a paradigm used to assess cognitive flexibility in anxiety-depression models. Probably less employed than reversal tests because of its complexity to set up, this task refers to animal’s ability to recognize and to adapt their behavior to various changing rules or environmental circumstances. In the most common version of rodent ASST, rodents are trained to dig for a food reward and make a simple discrimination based on both odor and digging medium. During the test, at each stage, rats are required to attend to one of two perceptual dimensions (odor or digging medium), and to shift between stimuli dimensions in order to learn the rule to successfully retrieve the food reward. The ability to extract knowledge from different stimuli dimensions suggests that animals are capable of using some aspects of higher-order cognitive functions present in human executive functioning ,188.Although the nature of parameters varies according to the study , an alteration in cognitive flexibility has been observed across anxiety-depression models ,175,178.Studies performed in rats highlighted interesting differences in performance between chronic stress procedures. The first work studying the consequences of MS on cognitive flexibility showed that maternally-separated rats displayed weaker overall performances in the ASST compared to control animals, as indicated by significant deficits in compound discrimination (SD), reversal 1 (REV1) and extra-dimensional set-shifting (ED) . These tDespite the complexity of assessment instruments and interpretation, cognitive deficits in attention and executive functions are shared across all anxiety-depression existing rodent models, strengthening clinical findings in MDD patients. Developing further preclinical behavioral tools to explore other aspects of executive functions than cognitive flexibility is obviously the next challenge in the field.via rodent models. It is now well known that long-term exposure to a chronic stress can induce deleterious changes in hippocampal structure, including in the neurogenesis process, thus deteriorating some aspects of spatial behavioral experience [Spatial memory is one of the most documented types of memory in laboratories, thanks to the development of various spatial behavioral paradigms through decades  maze, Barnes maze, Y-maze, novel object recognition location). This particular form of reference memory has already been the target of a bibliographic review focusing on the consequences to chronic stress effects on spatial learning and memory performances, but mostly limited to chronic restraint stress or social exposures in several species . To our perience ,190.Historically, the three main mazes, mentioned in The vast majority of studies uses latency to reach the platform in MWM and BM tasks as a parameter to measure learning across training days. However, latency is sensitive to motor and motivational factors that are likely to be modified by chronic stress procedures, leading to possible critical issues for the interpretation of data. Consequently, it is essential to control distance and speed performances, to confirm that the observed reduction in latencies across trials or days is correlated to a spatial learning alteration and not to motor, exploratory or motivational factors related to an anxiety-depression phenotype. Two hypotheses can be proposed concerning the lack of spatial learning detrimental effects following early-life stress. It is likely that specific spatial learning neuronal networks and pathways may not be influenced by these chronic stress procedures at this young age, inducing no damaging effects in adulthood either. However, spatial learning performances being tested at the adult age, brain maturation occurring during adolescent and young adult periods, during which stress procedures are no longer applied, could be sufficient to compensate cognitive learning dysfunctions that might have been induced during previous prenatal or perinatal period. It is also remarkable that impairment in spatial learning phase after adulthood anxiety-depression procedures is almost systematically associated by impairment in retention performances, suggesting that all the spatial abilities were impacted here ,208,209.Impaired probe trial performances in twenty-two studies ,209,211,Had no effect in nine studies ,200,211,Enhanced retention performances in five studies ,199,203.Among studies that assessed spatial retention memory, consequences of anxiety-depression phenotypes are more ambiguous, so that categorization according to the type and the nature of stress models appears inconceivable. According to the Overall, almost 2/3 of cited studies displayed impairment in spatial reference memory, highlighting the vulnerability of retention ability in a low mood pathological context, independently from the anxiety-depression model. In early-stress life procedures (PNS and MS), factors that contribute to the high variability in results are multiple and rather easy to identify. For example, in PNS studies, the period and duration of stress procedure can affect the behavioural performance. One study examined the effects of three separate prenatal stress periods on spatial learning and memory retention in male rats: (1) before pregnancy stress during 10 days, (2) early pregnancy stress  to GD10) and (3) late pregnancy stress (GD11-GD21) . PreconcInterestingly, some of the studies in which spatial learning was not affected in anxio-depressed animals revealed impairments in retention trial ,198,201.Studies using chronic unpredictable restraint (CUR) stress provide other pieces of information. A recent study investigated whether a recovery period between chronic stress application and spatial tests may impact behavioral responses. For that purpose, one group of rats received behavioral testing immediately after a 21 days-CUR procedure, whereas another group of animals was given 21 days to recover from chronic stress before assessing spatial performances. Immediately-stressed rats displayed a learning spatial impairment, while there was no impact on spatial learning in rats that benefited from a recovery period . FocusinInterestingly, administration of CUR in female rodents failed to alter spatial learning and memory performances, whether they had a recovery period or not. This comment is in line with all the other studies that have been conducted in female mouse or rat, because they did not report any changes in spatial learning and retention behaviors following different chronic stress procedures ,141,207.Up to now, the vast majority of clinical studies using neuropsychological tests in MDD focused on cognitive deficits such as executive functions, attention, processing speed, working memory, verbal and visual learning and memory or psychomotor performances. Clinical emotional assessment remains paradoxically one of the less documented type of memory studied in MDD. Only few reports concentrate their research specifically on cognitive biases associated with mood disorders . HoweverEmotional memory (associative memory in rodents) refers to a non-declarative type of memory, implicit memory, characterized by the impossibility to reach the memory through a conscious process. Emotional memory is necessary for individuals to learn to predict a danger and adapt their behavior accordingly. In their natural environment, rodents respond to danger in a species-specific manner by a typical freezing behavior triggered to avoid detection from possible predators. Freezing is defined as a cessation of all movements, except breathing. This instinctive behavioral response is used in preclinical studies to assess associative learning and memory. In anxiety-depression models, this type of memory is evaluated using classical conditioning tasks , based on negative reinforcers, and being dependent on the hippocampal brain structure ,217. BasFindings presented in Nature showed that the activation of positive memory could reverse depression-like behavior. Optogenetic reactivation of dentate gyrus cells previously active during a positive experience can rescue stress-induced depression-related behaviors [A recent study published in ehaviors . This woehaviors . Here, oWhen the conditioned stimulus is repeatedly presented without the presence of the unconditioned stimulus, it corresponds to the extinction phase. Consequently, freezing behavior decreases over time because the context is no longer associated with the danger. In anxiety-depression models, assessment of extinction fear remains less investigated than fear conditioning. Among studies evaluating this aspect of associative memory, no consistent findings were described, suggesting in stressed-animals either conserved fear extinction performances ,218,219 The step-through passive avoidance test is a hippocampus-dependent memory task conducted in two sessions. The apparatus is divided in two chambers separated with a guillotine door: one illuminated, transparent “safe” compartment and one darkened, opaque “shock” compartment. During the first testing day, animals are put into the lighted compartment, in which they are expected to enter freely into the dark compartment. Once the animal has entered into the dark compartment, one inescapable foot shock is delivered. 24 h later, the animals are placed in the light compartment again for a retention test, with free access to the dark compartment without any shock. The latency for the subject to enter into the dark chamber is recorded . The pasAlmost all the preclinical studies in the passive avoidance test found a significant decrease in latency to enter into the dark compartment in chronically-stressed animals compared to controls , highligTo conclude, despite some conflicting results across chronic stress models, preclinical studies appear to replicate some of the associative deficits observed in MDD patients, underlining a propensity for stressed-animals to remember negative stimuli and difficulties to associate aversive events to a specific context. Moreover, alterations in fear extinction remind symptoms observed in PTSD patients. Further efforts are needed to identify measurable relevant parameters in associative memory behavioral paradigms that can lead to a greater interpretation.Interestingly, some recent studies revealed that dorsal and ventral poles of the dentate gyrus of the hippocampus were functionally distinct ,240. A lIn humans, magnetic resonance imaging (MRI) studies revealed that first-episode MDD patients had smaller hippocampi than healthy subjects and these data correlated to neurocognitive alterations . In addiAdult neurogenesis occurs in two regions of the mammalian brain: the subgranular zone of the dentate gyrus (DG) and the subventricular zone (SVZ). It is now well established that adult neurogenesis process is intimately involved in mood and cognition regulations as well as in antidepressant drug response. Although adult hippocampal neurogenesis was shown to be necessary for antidepressant action in chronic-stress animal models ,244, altMore specifically, various approaches have allowed studying the role of the DG-CA3 circuit in pattern separation. Recently, a study showed that in animal models where neurogenesis is altered  or ablated (x-irradiation), a decrease in reactivation of CA3 but not of DG neurons priory activated by fear exposure was observed in a time dependent manner . These rThe presence of cognitive alterations in mood disorders, including MDD, strongly suggests that brain structures implicated in emotional and cognitive functions are linked. However, questions of how cognitive and depressive symptoms are related to each other and how to distinguish specific biological mechanisms attributable to cognitive or emotional functions in a MDD context remain opened. Moreover, the fact that most of antidepressant drug treatments failed to treat the cognitive dysfunctions observed in MDD, despite the remission of mood-related symptoms, confirms that independent neural circuitry underlying cognitive functions and depressive symptoms may be engaged. It is now well accepted that patients with depression suffer from associated cognitive dysfunctions, such as negative or distorted thinking, difficulty concentrating, indecisiveness, reduced reaction time or memory loss. However, whether these cognitive deficits are specific to a clinical subtype of MDD in Humans  or to a specific chronic stress procedure in animal models of the disease  remains to be further determined. The use of translational anxiety/depression animal models will substantially improve our understanding about these cognitive alterations.In this review, we provided an overview of clinical findings regarding the nature of cognitive dysfunctions in depressed patients from the first episode to recurrence according to the subtype of MDD. Then, we have summarized available data indicating the type of cognitive functions  affected in different anxiety/depression animal models.Clinical evidence indicates an overall cognitive decline in MDD patients persisting even after remission and during recurrent episodes. Among MDD subtypes, melancholic patients were identified to experience more pronounced cognitive deficits, suggesting a different pattern of cognitive impairment from those found in non-melancholic patients. Among all the cognitive alterations, executive and attentional functions deficits seem to be a constant hallmark in MDD patients, since it is present in all stages of the MDD course and in melancholic patients. Through the study of different anxiety/depression animal models, it appears that these executive and attentional deficits are conserved in rodents regardless of the chronic stress procedure. About the other types of memory, results are more heterogeneous according to the chronic stress methods used. This review points out the limit of rodent models, since heterogeneity in the results was observable within models and/or within a same type of memory. Numerous factors such as sex, protocol details, species, strain, environmental conditions, and the nature of the test promote this variability. Besides, animal models cannot fully replicate all of the cognitive deficits observed in human MDD, but rather only reflects different etiologies or aspects of the disease. Overall, among all the suggested models, adulthood-induced chronic stress models (the UCMS and the CORT model for example) seems to show greater similarities with the cognitive symptoms observed in MDD patients, key advantages compared to pre or perinatal chronic stress procedures. Unfortunately, cognitive condition in MDD patients tends to receive less attention than other depressive-related symptoms, particularly when it comes to consider the therapeutic strategy. Indeed, finding therapeutic strategies that treat both depressive and cognitive-related symptoms remains one of the main challenges in this field. Up to now, clinical reports about the efficacy of classical antidepressant drugs are relatively inconsistent ,51,185.


PubMed, Scopus, and psycINFO databases in February 2014. Search strings used were: exercise (and) animal model (or) rodent (or) rat (and) traumatic brain injury (or) cerebral ischemia (or) brain irradiation. Studies were selected if they were (1) in English, (2) used adult animals subjected to acquired brain injury, (3) used exercise as an intervention tool after inflicted injury, (4) used exercise paradigms demanding movement of all extremities, (5) had exercise intervention effects that could be distinguished from other potential intervention effects, and (6) contained at least one measure of cognitive and/or emotional function. Out of 2308 hits, 22 publications fulfilled the criteria. The studies were examined relative to cognitive effects associated with three themes: exercise type (forced or voluntary), timing of exercise (early or late), and dose-related factors . The studies indicate that exercise in many cases can promote cognitive recovery after brain injury. However, the optimal parameters to ensure cognitive rehabilitation efficacy still elude us, due to considerable methodological variations between studies.The objective of the present paper is to review the current status of exercise as a tool to promote cognitive rehabilitation after acquired brain injury (ABI) in animal model-based research. Searches were conducted on the  Physical exercise has long been known to be effective in the treatment and prevention of many physical conditions such as type 2 diabetes, hypertension, obesity, dyslipidemia, and cardiovascular disease –3. FurthPhysical exercise after acquired brain injury (ABI) has received attention as a cost-effective, noninvasive, and practicable rehabilitation tool. Preclinical research has shown that post-ABI exercise can increase cerebral growth factor levels –21, reduIn this paper, the preclinical research investigating the effects of post-ABI exercise on cognitive recovery will be systematically reviewed. Within brain injury rehabilitation, several factors  have been shown to be of importance for promoting brain plasticity mechanisms and enhancing recovery outcome . Such fa PubMed, Scopus, and PsycINFO databases, providing a total of 2308 hits. Articles were then selected using the following inclusion criteria:In English.Animal model based.Employing adult animals .Animals were subjected to acquired brain injury (ABI) in their adult life, either through mechanical injury, neurotoxic injection, irradiation, or induction of cerebral ischemia. after cerebral injury (habituation to the exercise apparatuses prior to injury was accepted).Exercise was used as an intervention/treatment toolThe exercise regimens consisted of a general motor activation of all of the animals' extremities . Sole training of a single muscle group or extremity  was not included.The effects of the exercise intervention could be clearly distinguished from effects of nonexercise interventions if such were also investigated.Studies contained at least one measure of cognitive and/or emotional function after (or during) exercise treatment. Studies solely investigating motor abilities  or neural/molecular mechanisms were excluded.Relevant research studies were found using the search terms “exercise (and) animal model (or) rodent (or) rat (and) traumatic brain injury (or) cerebral ischemia (or) brain irradiation,” all in all 9 search strings. The searches were performed in February of 2014 on theTwenty-two research articles fulfilled the above inclusion criteria. Examination of the references in these articles did not uncover further publications that fulfilled the inclusion criteria.Of the 22 papers, 14 used rats, five used mice, and three used gerbils as their experimental subjects. All used male animals except two see . RegardiExperimental groups fell into four types of exercise: nonmotorized running wheel exercise (nine studies), motorized treadmill exercise (11 studies), motorized running wheel (one study), swimming in a circular pool (one study), and swimming or running wheel exercise (one study).Cognitive measures applied in these studies were spatial learning/retention paradigms administered in a water maze (12 studies) or in a Barnes maze (one study), visual discrimination and retention in a water maze (one study), object recognition tests (three studies), an object location test (one study), conditioning based learning paradigms (seven studies) , open field tests (three studies), and tail suspension tests (two studies). Some studies used more than one test.Within animal model based research, exercise is often differentiated into voluntary or forced paradigms. In voluntary paradigms, the animals are given a choice between movement and inactivity while having access to the exercise apparatus. In forced exercise, activity levels are controlled by external factors. Exercise in a nonmotorized running wheel allows animals to exercise at their own accord, while motorized treadmill running/running wheel exercise and swimming exercise do not offer such movement autonomy. The following section examines whether the type of exercise (voluntary or forced) exerts differential effects on cognitive recovery after ABI.Nine studies included experimental groups subjected to voluntary (running wheel) exercise.β-HSD4 (enzymes involved in DHA metabolism), Sir2 , iPLA2 (molecules involved in membrane homeostasis), p-TrkB (BDNF receptor), and lower levels of 4-HHE (marker for lipid peroxidation) in the groups subjected to either exercise or the DHA diet (compared to controls) and a further increase/decrease in the combined group. The combined group also showed increased STX-3  and brain derived neurotrophic factor (BDNF) levels. The study indicates that early initiated voluntary exercise and/or the DHA diet can positively affect cognitive recovery after TBI, possibly through counteracting membrane damage and coordinating DHA metabolism.Wu et al.  subjecteContrary to these results, Griesbach et al.  found thAlso finding detrimental effects, Crane et al.  subjecteThe conflicting results of the two first studies are somewhat surprising, as they use similar models and setups. Discrete differences, for example, in the duration of the exercise protocol, could potentially account for these divergent findings. While the studies by Griesbach et al.  and CranInitiating exercise a little later after injury, Luo et al.  subjecteβ levels (a proinflammatory marker) increased in the early exercise group in week 5 after CCI and levels reduced in the late exercise group in postinjury week 9 (both compared to the nonexercised CCI-group). There were also increased levels of IL-6 (a proinflammatory marker) and IL-10 (an anti-inflammatory marker) in the late exercise group in week 9. Cortical  Galectin-3 and C1qB levels  were increased in the early exercised animals, while they were reduced in the late exercised group together with levels of gp91phox and p22phox (membrane components of NADPH oxidase enzyme). Late exercise increased hippocampal CREB gene expression, BDNF, and IGF-1 (insulin-like growth factor 1) levels and increased neurogenesis and cell survival in the late exercise group (but not in the early exercise group). The study concludes that the improved cognitive performance in the group subjected to late exercise is possibly due to a more optimal coordination/balance of microglia expression and increased growth factor levels.However, in another study by Piao et al.  startingSimilar to studies initiating exercise immediately after ABI, starting a voluntary exercise paradigm one week after injury produces conflicting results, suggesting that the exercise type (voluntary versus forced) is not the only factor determining the efficacy of exercise.As already mentioned, Griesbach et al.  found imα (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6)) were elevated in the irradiated groups (compared to shams). Levels of IGF were increased in the irradiated, exercised animals compared to irradiated, sedentary animals. Levels of BDNF and VEGF  were decreased in all irradiated animals (both exercised and nonexercised). However, running partially restored VEGF-levels in the irradiated, exercised animals. The study shows that later-initiated voluntary running can prevent memory decline at a later stage in irradiation-exposed animals.Wong-Goodrich et al.  subjecteShowing similar positive recovery effects of late-initiated voluntary exercise after brain irradiation, Winocur et al.  irradiatWhile three studies found cognitive improvement in animals starting exercise 25 days after injury or later , 43, 44,Five studies , 42–44 fAll in all, the above research shows a somewhat mixed picture of using voluntary exercise in cognitive rehabilitation after ABI. Later starting points (from 14-days post-injury) appear to have the most consistent effects on cognitive recovery. However, further research is needed to determine if exercise interventions can be administered too late to produce cognitive improvements. Moreover, caution should be taken in making general recommendations based on such a limited and methodologically diverse set of studies. The results indicate that the voluntary aspect of exercise is not the sole determinant of effect; other variables such as starting point and duration may also play a significant role.Fourteen studies have looked into the effects of forced exercise on cognitive recovery after ABI.Itoh et al.  subjecteCechetti et al.  looked aShih et al.  subjecteIn another study investigating the effects of different exercise intensities, Shen et al.  subjecteWhile the above studies suggest that early forced exercise can promote cognitive recovery, these results are not unchallenged. Hicks et al.  found thThe findings of Hicks et al.  were echInvestigating emotional parameters, de Araujo et al.  exerciseSome studies have opted for exercise initiation two days after injury. After inflicting bilateral CCAO in gerbils, Sim et al.  found thChen et al.  exposed Positive recovery effects of second day postinjury initiation were also found by Kim et al. . Using eChen et al.  comparedStarting exercise on the fourth day after injury, Shimada et al.  subjecteTwo studies have begun forced exercise 1 week after ABI or later. The previously mentioned study by Luo et al.  comparedThe studies of forced exercise, like those of voluntary exercise, show a somewhat conflicting, pattern of outcome. Though only one study shows detrimental effects (in one group) on anxiety-related behavior, the above studies generally show that especially early forced exercise can lead to improvement in animals exposed to low or moderate intensity exercise. One may therefore ask whether exercise needs to be maintained at a certain intensity level in order to produce cognitive gains. Neither of the two studies using swimming exercise produced cognitive recovery effects. However, more studies are needed to determine whether this is a result of the type of exercise or protocol related issues. Unfortunately, only two studies investigated effects of exercise starting later than a week, leaving us with limited knowledge about the effects of forced exercise initiated at a later stage.As already described, the above research varies in the time points of exercise initiation. Of the 22 studies included in this overview, we find that 16 studies had experimental groups starting exercise from postinjury days 0–4, while eight studies had experimental groups starting exercising at the earliest from postinjury day 7.Examining common traits or dissimilarities of the early intervention groups with positive or no effects does not render a clear picture. Almost all early initiation studies with positive effects of exercise on cognition use forced exercise paradigms. However, as early initiation voluntary exercise studies are much fewer in number, this might be a paradigm bias. Moreover, the studies vary on most parameters including types of injury and animal as well as exercise duration and intensity.The three studies showing groups with adverse effects , 40, 52 Later initiation studies are fewer and with starting points spanning from 1 week to almost 4 months after injury; it is difficult to obtain a coherent picture. Studies with groups starting 7 to 9 days after injury , 41, 57 It is quite surprising that we know relatively little about the cognitive effects of exercise starting relatively late post-TBI. In clinical rehabilitation settings exercise is often initiated in later recuperation stages, when patients are stabilized and able to perform physical activities. It therefore seems clinically relevant to further investigate the potential effects of late-initiation exercise.Exercise dose encompasses many variables including total length of intervention (how many days), session duration (how many minutes), distribution (how often), distance moved (how far), and intensity (how fast).In the 22 studies included in this review, the total length of intervention varied considerably, ranging from 1 day to almost 4 months. Regarding individual session durations, most of the voluntary exercise studies gave the animals unlimited access to the running wheels, that is, 24 hour access. The forced exercise paradigm sessions lasted between 5 min and 1 hour; eight of those studies used 30 min session durations. By and large, the animals exercised/or had access to exercise apparatuses on a daily basis throughout the intervention period except in two studies that distributed the intervention somewhat differently , 51, as Average group distances and/or intensities are not stated in all studies see . This inFour studies explicitly examined the cognitive effects of different exercise intensities , 55, 58.Interestingly, in the case of the Chen et al. study , the modAll in all, the substantial variations in exercise protocols among the studies make it difficult to make general dose recommendations. While it does appear that dose, duration, and intensity are important factors for cognitive recovery, more systematic research looking into these aspects and how they interact with other variables such as starting point is needed to elucidate this further.While many neural mechanisms behind the effects of exercise are being investigated, special attention has been given to neurotrophic factors, in particular BDNF. BDNF is highly expressed in the cortex and hippocampus and is involved in many neural processes including neuronal differentiation and survival, as well as axonal path-finding . FurtherIn relation to exercise type, a special focus has been placed on the connection between exercise and the release of stress-hormones, as forced exercise is believed to be more stressful than voluntary exercise. However, studies dealing with this topic show somewhat inconsistent results. Griesbach et al.  found thSeveral studies using forced exercise after TBI have found BDNF-elevations , 63–65, Thus, it appears that forced exercise does lead to elevated stress-hormone levels. When it comes to impact on BDNF-levels, the picture is more unclear. It seems that the type of exercise (voluntary or forced) cannot solely account for variation in neurotrophic factor levels, but other factors such as timing and intensity are also key players. How stress-hormones and neuroplasticity-related proteins are affected by exercise, how they interact, and, importantly, what consequences this has for functional recovery remain to be resolved. As discussed above, though the efficacy of forced exercise on cognitive parameters is inconclusive, detrimental effects on cognition are practically unseen. This poses the question of whether elevations in stress-hormones during physical activity are necessarily harmful when it comes to the recovery of cognitive functions.Like exercise type, some research indicates that starting point affects BDNF-levels after ABI. Early exercise initiation (defined here from day 0–6 postinjury) has been shown to elevate BDNF-levels in several studies , 63, 65;These studies indicate that both early and later initiated exercise regimens can increase BDNF-levels in some cases. Whether such BDNF-elevations are part of the neural processes mediating cognitive recovery is still unclear. Griesbach et al.  did not Initiating exercise at later points, Griesbach et al. , 42 founIt seems that the relationship between BDNF-responses and cognitive recovery outcome at different exercise initiation points is still largely unresolved. Currently, there are a limited number of studies investigating this, underlining a need for additional research.Not many studies have investigated the relationship between BDNF-levels and exercise intensity in post-ABI exercise. Shih et al.  and ShenThe above studies provide some information as to the effects of exercise on cognition in the brain injured individual. They also stress some of the parameters that are important for the efficiency of this intervention. However, there are still many unresolved issues.Voluntary and forced exercise paradigms vary on parameters of choice of movement and, potentially, level of stress-hormone activation. The studies included in this review also reveal other differences between the two exercise paradigms. Most of the voluntary paradigms allow animals access to the exercise apparatus in their home environment, while the forced paradigms require moving and handling of the animals to initiate (and sometimes prompt) exercise. Whether such environmental differences can affect the outcome in terms of cognitive recovery will have to be clarified in the future.In all but two of the studies using voluntary exercise, animals were housed individually either permanently or during intervention. Most of the forced exercise studies do not report housing conditions; however those that do have animals pair or group housed. Some studies have looked into the effects of social deprivation and exercise in animals. Stranahan et al.  found thFurthermore, there are considerable differences in relation to exercise dose and duration. Animals in the voluntary paradigms have 24-hour access to the exercise apparatuses (except in one study) and can administer their treatment when they choose and in the intensity and duration that they prefer. This is a marked difference from forced exercise paradigms that mainly offer single exercise bouts of limited duration (up to 1 hour) under controlled running speeds. These differences underline that paradigms of voluntary and forced exercise vary on many variables that can affect the cognitive  outcome.Epidemiological research shows that premenopausal women have decreased risk of stroke compared to age-matched males as well as to postmenopausal women . Animal The type and severity of injuries in the above studies are quite different. Some types of injury cause more focal tissue damage; others are more wide-spread and diffuse in nature. Some injuries are unilateral, while some affect both hemispheres. The studies using cerebral ischemia models inhibit blood flow for varied time periods. The studies using traumatic brain injury models  use different techniques, impact velocities, and depths of compression. The models inducing injury by irradiation use different doses and afflict different cerebral areas. As different types of brain injury and injury severities can cause different injury patterns, both in terms of tissue responses as well as their spatial and temporal occurrence , this caAnother issue relates to the genetic make-up of the experimental animals. Much research has shown that the same brain injury method can induce significantly different cerebral  responses depending on the rodent strain/stock used –90. EvenThe applied cognitive tests are generally brief, limiting our knowledge to mainly short-term learning effects. Potential long-term effects of exercise have not been examined in any of the studies, leaving us with little knowledge as to whether the observed cognitive effects are lasting or transient. Furthermore, the majority of studies use tests that motivate learning through avoidance, that is, the ability to avoid an unwanted stimulus (escaping water or a previously presented painful stimulus). Testing animals in nonavoidance based tasks would help to clarify whether the outcome is related to the treatment or the method of testing.Another discussion related to the cognitive tests pertains to the individual test protocols and setups. While many of the studies used spatial acquisition tasks in a water maze, the individual testing protocols were very varied, in terms of both number of acquisition trials and sessions. Such differences could potentially affect the learning outcome if some animals were to be trained more intensively than others . FurtherPostinjury depression and anxiety are common after brain injury . As alreIt is known that depression can lead to cognitive impairment. However, whether these impairments are primarily psychosocially or neurobiologically founded, transient or enduring, is still debated . Though In this review we have examined the effects of exercise on cognitive measures after acquired brain injury in animal models. Although there is cause for optimism in using exercise as a rehabilitation tool in the treatment of cognitive sequelae after ABI, research in this area is still fairly limited. Overall, there is evidence that exercise in some cases can improve cognitive recovery. However, what distinguishes these cases from others that do not produce effects (or have adverse effects) remains unclear. Considerable variations in models and experimental protocols, including differences in animal strains, injury type, exercise type, post-injury starting point, dose-related differences, and cognitive measures, should presently warrant caution in making general protocol recommendations. More research is needed to clarify these issues as well as the potential long-term effects of postinjury exercise.


Sex differences are known to exist in adipose and immune functions in the body, and sex steroid hormones are known to be involved in sexually dimorphic biological and pathological processes related to adipose-immune interaction. However, our knowledge of proteins that mediate such differences is poor. Two novel obese mice models, Mito-Ob and m-Mito-Ob, that have been reported recently have revealed an unexpected role of a pleiotropic protein, prohibitin (PHB), in sex differences in adipose and immune functions. This discovery points towards a role of pleiotropic proteins and their potential interplay with sex steroid hormones in mediating sexually dimorphic adipose-immune interaction. Mitochondrial functions encompass the anaplerotic tricarboxylic acid cycle and energy production, but these functions are often finely tuned to serve specific roles in different cell types or tissues. Examples are lipogenesis in white adipocytes, thermogenesis in brown adipocytes, insulin secretion from pancreatic β cells, and cytokine production from immune cells. Thus, mitochondrial proteins involved in fundamental aspects of mitochondrial biology are uniquely placed to perform pleiotropic functions and provide an opportunity to simultaneously manipulate two different functions in two different cell types or tissues. However, to the best of our knowledge, a potential use of such pleiotropic protein in manipulating two different functions in two different cell types have not been discussed earlier.It has been more than 25 years since McClung et al.  have disaP2 gene promoter [aP2 gene is known to primarily expressed in adipocytes but also expressed in monocytic macrophages and dendritic cells among various immune cell types  [Recently, Ande et al. –11 have promoter , 11. Becnophils) –14. Overnophils) . A similnophils) –11. Withnophils) . Intrigunophils) , 11, 15.nophils) . The devnophils) .Phb2 knockout mice [Similar to Mito-Ob and m-Mito-Ob mice, an increase in body weight after puberty has been observed in the female heterozygous out mice . In thisout mice . Moreoveout mice . These eout mice .HCC is sexually dimorphic in humans and rodents with higher prevalence in males, an effect that depends on sex steroids , 22. TheWhat is the mechanism of PHB-induced sex differences in adipocyte and immune cell functions?Does PHB mediate sex-specific functions?What is relationship between PHB and sex steroids in mediating sex dimorphic functions?In summary, the discovery of PHB in mediating sex differences and adipose and immune functions and consequently in adipose-immune interaction raises important questions related to the role of PHB in the biology of sex differences such as the following:It is anticipated that a better understanding of the role of PHB in sexually dimorphic functions in the body may lead to the discovery of novel ways to modulate adipose and immune functions and contribute to the development of more effective, gender-responsive, and personalized medicine.


Forest dynamics encompass changes in stand structure, species composition, and species interactions with disturbance and environment over a range of spatial and temporal scales. For convenience, spatial scale is defined as individual tree, neighborhood, stand, and landscape. Whether a given canopy-leveling disturbance will initiate a sequence of development in structure with little change in composition or initiate an episode of succession depends on a match or mismatch, respectively, with traits of the dominant tree species that allow the species to survive disturbance. When these match, certain species-disturbance type combinations lock in a pattern of stand and landscape dynamics that can persist for several generations of trees; thus, dominant tree species regulate, as well as respond to, disturbance. A complex interaction among tree species, neighborhood effects, disturbance type and severity, landform, and soils determines how stands of differing composition form and the mosaic of stands that compose the landscape. Neighborhood effects  operate at small spatial extents of the individual tree and its neighbors but play a central role in forest dynamics by contributing to patch formation at stand scales and dynamics of the entire landscape. Dominance by tree species with neutral to negative neighborhood effects leads to unstable landscape dynamics in disturbance-prone regions, wherein most stands are undergoing succession; stability can only occur under very low-severity disturbance regimes. Dominance by species with positive effects leads to stable landscape dynamics wherein only a small proportion of stands undergo succession at any one time. Positive neighborhood effects are common in temperate and boreal zones, whereas negative effects are more common in tropical climates. Landscapes with positive dynamics have alternate categories of dynamics stabilized by high-severity and low-severity disturbance regimes. Contrary to prevailing ecological theory, systems with positive neighborhood effects can have similar levels of compositional stability across tree, stand, and landscape scales. Neighborhood effect theory can help explain responses of landscapes to large-scale land clearing and novel effects brought on by factors such as invasive species and deer overabundance. This article covers forest dynamics in the context of landscape ecology and patch dynamics theory. Forest dynamics as related to biological legacies, land use, herbivory, tree diseases, carbon storage, biogeochemistry, forest health, and climate change are covered elsewhere.Forest dynamics encompass changes in stand structure, species composition, species interactions with disturbance type and severity, and disturbance interactions with landform, over a range of spatial and temporal scales6, emergent properties at large spatial extents from interactions among individuals7, resilience, and increasing stability/slower dynamics at landscape than at stand scales9, as well as the forestry concepts of disturbance severity, stand development, and succession10. However, here neighborhood effects are added to the traditional tree-stand-landscape hierarchy, and stability is examined from the viewpoint of species composition rather than age-class distribution of disturbance patches. This changes the properties of landscape mosaics; four categories of landscape dynamics emerge from a neighborhood effect point of view and they include some seemingly strange elements, such as high stability at small and large spatial extents, and two different types of shifting mosaic steady states. In addition, neighborhood effect theory shows how species not only respond to disturbance but also sometimes regulate disturbance.This review is rooted in classic concepts of landscape ecology, including hierarchical patch dynamicsThe article starts with a review of forest development and succession, which sets the stage for discussions of species-disturbance interactions, integration of neighborhood effects into cross-scale dynamics, and categories of landscape dynamics. Throughout the article, spatial scales and disturbance severity, as defined in3. A sequence of developmental or successional stages can occur by themselves or together. A stand-leveling event such as high-intensity fire, windthrow, or clearcut logging may reset development or succession (or both) to the early stages.Stand development is directional change in structure over time, whereas succession is directional change in species composition, where early-successional species are replaced by late-successional species10: (1) stand initiation, lasting from the time of canopy disturbance until a new canopy of young trees forms. These are often even-aged stands, or at least even-aged from time of release in cases where advanced regeneration was present. On sites with severe environments, recruitment of new trees may take decades, so that new stands may be unevenly aged by the time of canopy closure. (2) Stem exclusion, lasting from the time of canopy closure through the density-dependent process of self-thinning. (3) Demographic transition , begins when tree crowns and resulting gaps formed when trees die are large enough so that trees adjacent to a gap cannot fill them by lateral crown expansion; new cohorts of trees can grow into the overstory. (4) Multi-aged stage , reached when stage 3 has progressed to the point where only a few individuals from the original even-aged cohort remain, and the canopy has trees of widely varying ages; this stage lasts until another disturbance resets stand development. If the initiation stage was dominated by shade-intolerant, early-successional species, then secondary succession driven by tree species of moderate to high shade tolerance entering the stand may occur along with stand development. However, stand development sequences entirely dominated by late-successional, shade-tolerant species also occur11.Development occurs in four stages2) in stage 2 and early stage 3 to a wide variety of sizes in late stage 3 and stage 4 (50 to 400 m2); the larger gaps present in these later stages of development lead to opportunities for mid-tolerant species  to maintain or increase their presence in the forest13. The light level of the entire stand may be higher in old multi-aged stands, with gaps of widely ranging age and size because side light from numerous gaps can penetrate into the forest around gap edges, so there is no ‘interior zone’ not impacted by gaps14. In addition, partial disturbances that remove 20% to 50% of the canopy, but do not reset the stand to the initiation stage of development, have a large influence on forest dynamics in areas with wind-and-gap types of regimes, and stands hit by such disturbances have relatively high light levels for a few decades after disturbance15.During stages 3 and 4 of development, gaps may be filled with small even-aged cohorts of saplings that themselves undergo self-thinning, just like the entire stand did during stages 1 and 2, so that the development process is mirrored in many places at smaller spatial extents. Gap sizes also commonly change from mostly small  species with canopy-stored seed banks, which have several seasons of seeds on hand at any given time, survive disturbance as seeds, and are adapted to high-intensity crown fires on dry sites1, (2) shade-tolerant, late-successional species growing on mesic sites with a seedling/sapling bank in the understory that can respond to overstory wind disturbance19, and (3) shade-intolerant or mid-tolerant species with thick bark and foliage held high above the ground, which survive as mature trees adapted to surface fire regimes20. Type 1 forests are maintained at an early-successional stage by fire, and lack of fire or a novel disturbance type  may never activate the seed bank, leading to recruitment failure and succession to another species. A mismatch for type 2 could be a severe disturbance killing almost all mature trees, seedlings, and seeds. Type 3 forests are usually maintained at a mid-successional stage by fires and could have mismatches caused by a fire that is more severe than normal, killing the mature trees and allowing an earlier-successional species to take over, or lack of fire, allowing late-successional species to dominate21.Traits that determine how a given tree species survives disturbance interact with disturbance type and severity to determine whether a given disturbance will perpetuate the existing species composition or initiate an episode of succession22, is a form of mature-tree persistence that is not common in temperate and boreal forests, although the author has noted that yellow birch  and cottonwood (Populus deltoides) are exceptions. Stump and root sprouts are a common form of persistence in aspen (Populus spp.), birch (Betula spp.), and oak (Quercus spp.) species in temperate and boreal forests23.Sprouting from stumps, root systems, or trunks with broken crowns is a type of survival that is often underappreciated and can allow adaptation to various disturbance types. Crown sprouting, such as occurs in tropical forests after hurricane damageBetula papyrifera) and black spruce (Picea mariana) in North America can dominate early post-fire stands as well as old multi-aged stands25. This contrasts with progressively higher species turnover across successional gradients as mean annual temperature increases from temperate to tropical forests.Successional status in boreal species can be quite confusing; owing to the low richness of the regenerating species pool, one species can fill more than one successional role. For example, paper birch , and arrive at their resistance by various combinations of traits28.Tree species have a surprising ability to regulate disturbance frequency and effects by producing fuel structures at stand and landscape scales that promote high or low fire intensity and rate of spread. Tree susceptibility to wind is a function of wood strength, wood flexibility, tree growth form , and ability to streamline in the wind or to shed branches to reduce pressure caused by wind. Species resistant to wind tend to be late-successional, with some exceptions such as bur oak (29. Examples (Pinus banksiana) in the North American boreal forest31, growing on dry sites at high canopy densities with repeated high-intensity crown fires at intervals greater than necessary to reach seed-bearing age but shorter than needed for later-successional species to invade. A second example includes eastern hemlock (Tsuga canadensis) and sugar maple (Acer saccharum) that grow on mesic sites not conducive to fire but that reproduce well after treefall events caused by wind at a variety of spatial extents32. A third example is white pine (Pinus strobus) growing on dry-mesic sites with thick bark and low canopy bulk density that favor surface fires in mature stands.Although it is inevitable that any quasi-equilibrium that may exist at the landscape scale will be disrupted at some point, species have a tendency to ‘lock in’ a certain disturbance regime on a certain landform for multiple tree generations—during this time, disturbance and tree traits are in sync—or perhaps out of sync only for a small proportion of stands across the landscapexamples  include 33. Superimposed on this is additional patch variability caused by the fact that succession is a spatial process; waves of disturbance-sensitive species can move out from surviving populations at disturbance edges and refuges within disturbance perimeters4. Thus, the spatial distribution of landform features at a ‘meso-scale’  determines the magnitude of the effects of disturbance size, and landscape resilience to large disturbances2. For fire-sensitive species that can survive fires in swamps or lakeshores, the distribution of such refuge areas across the landscape could cause large variance in the time taken for fire-sensitive, late-successional species to reach stands across the landscape. If one such refuge exists on every 10 ha, for example, then late-successional, fire-sensitive balsam fir  could reach the understory of most jack pine forests within several decades, even within a large 100,000-ha fire perimeter. If no such refuges exist, then succession in the middle of a large burn may not take place because of simple lack of availability of late-successional species. In general, refuges from disturbance are frequent on forested landscapes, and overall disturbance size matters much less than one would think by looking at fire perimeter maps. Landscape heterogeneity can provide sites with coarse sandy or rocky soils that serve as permanent seed sources for early-successional species on a landscape otherwise dominated by late-successional species 32. In addition, landform heterogeneity can divide the landscape into patches (or landscape subsections) with different disturbance regimes, levels of connectivity with other nearby occurrences of the same forest type, and different types of dynamics. In mountainous regions, elevation, aspect, and shape of valleys and ridges create patches that dry out more or less frequently, influencing the frequency, intensity, and direction of movement of fire and wind disturbance, and restricting species movements in response to disturbance. Repeating patterns of lakes, swamps, and rocky ridges can have similar effects in the vast, relatively flat boreal forests of central North America.Species mosaics can form because of landform-disturbance-tree species interactions, even within one large disturbance patch . This co3. At the landscape scale, one can examine the proportion of stands in various stages of succession and development as a result of disturbance history1, as well as proportions of the landscape that may represent different successional pathways due to site type differences—a given landscape is likely to have different successional systems on soils with different water-holding capacity and nutrient status or on subsections of the landscape with different disturbance regimes as mentioned above34. At the stand scale, one can examine changes in tree size distributions and species due to development and succession35.The hierarchical tree, stand, and landscape concept has been commonly employed to understand forest dynamics38. These neighborhood effects can be positive (conspecific regeneration favored), neutral (no effects on abundance of conspecific regeneration), or negative. Neighborhood effects can be mediated by overstory-understory effects within mid- to late-successional forests or disturbance-activated effects such as seed rain from serotinous seeds or sprouting after fire in early-successional forests. It appears that tropical systems have many species with negative neighborhood effects due to disease impacts on seedlings39. These disease feedbacks are uncommon in the temperate zone, although red pine (Pinus resinosa) is an exception40. In temperate and boreal biomes, there are many species whose seedlings do better near conspecific adults, although neutral species are also common41.A fourth scale, neighborhood , is also needed to explain forest dynamics. Neighborhood effects are an additional mechanism of patch/stand formation. Trees alter the success of their own regeneration under their own canopy and those of adjacent trees through leaf-litter chemistry and physical characteristics, degree of shade and season(s) of shade cast by a given species, seed rain, sprouting, and disease dynamics3. In effect, strong positive neighborhood effects make the dispersal distance for the pre-disturbance species to recolonize the disturbed area effectively zero—as either seedlings or seeds are present immediately after disturbance throughout a disturbance patch. With positive neighborhood effects, disturbance patches can cross stands dominated by different species, so their boundaries are independent of patch boundaries created by neighborhood effects. Furthermore, patches dominated by different species with positive neighborhood effects act together to influence dynamics of disturbance at larger spatial extents (details below). Thus, neighborhood effects operate at the scale of adjacent trees (0.01 to 0.05 ha) but can create much bigger patches (1 to 10 ha or more) and influence landscape-scale dynamics  have a better memory of pre-disturbance composition at neighborhood and stand scales, over a wider range of disturbance severities, than forests dominated by neutral or negative neighborhood species. In essence, predicting forest dynamics without taking neighborhood effects into account amounts to assuming that neighborhood effects are neutral in all cases, and this would therefore be a neutral theory of forest dynamics. Neighborhood effect theory is a more general case that encompasses negative/neutral and positive dynamics.The neighborhood effect theory of forest dynamics was proposed by41.The theory also predicted that alternate states of composition  can occur after disturbances of similar severity on landscapes dominated by tree species with positive neighborhood effects, depending on the history of composition. A contrasting continuous response was predicted for forests with neutral neighborhood effects. These predictions were shown to be valid in several case studies9. Other characteristics are mostly opposite; A has mostly late-successional stands and is stabilized by low- to moderate-severity disturbance regimes such as gap dynamics, stand-leveling windthrow, and surface fires, whereas B has mostly early-successional stands and is stabilized by moderate- to high-severity disturbance. Severe disturbance beyond the threshold resets succession in A, whereas in B a lack of disturbance needed to maintain early-successional status allows succession to occur. Note that both A and B landscapes can have mosaics of stands with differing species composition if more than one species with strong positive neighborhood effects is present.The third major prediction of the theory was the existence of four landscape dynamic categories that emerged from a scaled-up impact of neighborhood effects . The cat39 and low chance of fire or other severe disturbance (in the absence of human land-clearing), can likely persist as category C landscapes for centuries, or as long as the climate is stable.Category C landscapes have neutral to negative neighborhood effects and low- to moderate-severity disturbance regimes. Tree species can replace each other after small, low-severity disturbances like gap formation, and there is no memory of species composition at individual tree and neighborhood scales. There can be stability at stand to landscape scales for C landscapes, although in temperate and boreal forests, C-type dynamics are very likely to be ephemeral and wiped out by large-scale disturbance or replaced by species with A-type dynamics. However, tropical rain forests, with their negative density-dependent relationships between mature trees and seedling densityPseudotsuga menziesii), white pine, and red oak (Quercus rubra), with examples described inCategory D landscapes are unstable at all spatial scales, as species with neutral neighborhood effects allow composition to change continuously with disturbance severity. A sequence of disturbances of equal severity and uniform temporal spacing would be needed to keep composition the same—an unlikely scenario except perhaps for frequently burned savannas. These are often forests with mixed-severity fire regimes in forest types like Douglas fir .The theory predicts limitations and (possibly unanticipated) exaggerations of management effects at stand to landscape scales. Landscape dynamics category can be changed by human actions. A very severe disturbance at the landscape scale can override the pre-disturbance memory of the entire landscape and cause a switch from A to B landscape dynamics and initiate widespread succession , or the artificial exclusion of severe fire can cause the opposite switch, from B to A (accelerated succession mentioned above or fire suppression in some pine forests48, possibly removing neighborhood effects that operate through leaf-litter effects, while overabundant deer could eliminate the seedling layer49 that is crucial to positive overstory-understory effects. Either of these could destabilize the hemlock and maple mosaics common in eastern North America that were maintained by positive neighborhood effects.The theory predicts how certain human-induced environmental changes will affect succession and development. Novel ‘disturbances’ and processes may be able to knock out positive neighborhood effects, leading to changed dynamics. For example, the European earthworm invasion is resulting in loss of the organic horizon in North American forests41, which may end when a large infrequent disturbance occurs17. However, the basic tree-trait and survival mechanism interactions with disturbance as an arbiter of whether the pre-disturbance species will persist after disturbance, or whether succession will be reset, need to be reassessed in light of the cross-scale impacts of neighborhood effects and landform effects. Landform and soil-type effects can create mosaics of stand types within single disturbance patches, whereas neighborhood effects can cause different stand types to separate even within one uniform soil type, and neighborhood effects also cause interactions of groups of positive or neutral species with disturbance to form different categories of landscape dynamics. Thus, the tree-stand-landscape hierarchy is not as straightforward as it may first appear because of the complex cross-linkages among levels and ability of tree species to extend their influence very strongly to stand and landscape scales via neighborhood effects that modify disturbance dynamics (Tree species have a surprising level of control over disturbance dynamics because some tree species can ‘lock in’ disturbance and species interactions on certain landforms to create periods of stability in composition at the landscape scaleynamics . From anUnfortunately, not enough is known to parameterize the neighborhood effect cusp catastrophe model and predict the actual threshold disturbance severity for a state change, and this is due to difficulties in developing universal measures of disturbance severity and neighborhood effect strength. For now, the theory can be used in a semi-quantitative sense with disturbance severity and neighborhood effect categories. A breakthrough is needed in understanding of disturbance severity and how to measure it, as well as disturbance severity versus disturbance type effects, which are frequently confounded.


Multiple sclerosis (MS) is a frequent, highly debilitating inflammatory demyelinating disease, starting to manifest in early adulthood and presenting a wide variety of symptoms, which are often resistant to pharmacological treatments. Cortical dysfunctions have been demonstrated to be key components of MS condition, and plasticity of the corticospinal motor system is highly involved in major MS symptoms, such as fatigue, spasticity, or pain. Cortical dysfunction in MS can be studied with neurophysiological tools, such as electroencephalography (EEG) and related techniques  or transcranial magnetic stimulation (TMS). These techniques are now widely used to provide essential elements of MS diagnosis and can also be used to modulate plasticity. Indeed, the recent development of non-invasive brain stimulation techniques able to induce cortical plasticity, such as repetitive TMS or transcranial direct current stimulation, has brought promising results as add-on treatments. In this review, we will focus on the use of these tools (EEG and TMS) to study plasticity in MS and on the major techniques used to modulate plasticity in MS. Multiple sclerosis (MS) is usually described as an inflammatory demyelinating disease involving mainly the white matter. However, axonal loss  and cortNeurophysiological examinations are thus of primary importance in the clinical care of MS. They allow both the investigation of corticospinal sensorimotor mechanisms involved in the disease, using electroencephalography (EEG), electromyography (EMG), and transcranial magnetic stimulation (TMS), and also allow clinicians to directly act on deficient cortical circuits to improve subjects’ condition, using non-invasive brain stimulation (NIBS), such as repetitive TMS (rTMS), theta burst stimulation, transcranial direct current stimulation (tDCS), or using peripheral nerve stimulation, such as transcutaneous electrical nerve stimulation (TENS).In this review, we will focus on the importance of neurophysiological tools to study and modulate plasticity in MS to help treat major symptoms of the disease.EEG represents an important exploratory tool in clinical neurophysiology practice in general and in particular in the care of MS, especially using multimodal evoked potentials (EPs), such as somatosensory evoked potentials (SEPs), auditory evoked potentials (AEPs), or VEPs. These measurements allow indeed a quantitative assessment of the system function targeted by the examination.Apart from the evoked activity, cortico-thalamo-cortical loops can be studied using induced EEG activity in relation to internal or external events. In particular, event-related desynchronization/synchronization (ERD/ERS) of the sensorimotor mu (8–12 Hz) and beta 13–25 Hz) rhythms is strongly related to the cortical motor control –22. ERD  Hz rhythBeta ERD was abnormally increased in the fronto-central regions in fatigued MS subjects, compared to non-fatigued subjects or controls . The stuLong-latency reflexes (LLRs) are muscular responses elicited by electrical stimulations of mixed nerves during slight contraction of the targeted muscle. In particular, LLR-II would be the most reliable  and woulTMS was initially used in MS to measure central motor conduction time (CMCT) to evaluate the effects of demyelination on neuronal conduction. CMCT is indeed significantly prolonged in MS –48. MoreTMS can also be used as a non-invasive tool able to interfere temporarily with a specific cortical activity in order to investigate its particular role. To this aim, single pulse TMS has been used to investigate the role of ipsilateral motor/premotor cortex hyperactivity during a simple reaction time task in MS . The autNon-invasive brain stimulation techniques are relatively new tools for modulating cortical excitability to provide symptomatic treatments in a large range of neurologic and psychiatric diseases. Among them, rTMS and tDCS have been widely studied and proven effective in conditions, such as Parkinson’s disease, stroke, or dystonia –62. SincCortical plasticity can indeed by induced in MS. Subjects with moderately severe stable MS showed the same rapid-onset motor plasticity than healthy subjects, despite motor impairment and central nervous system injuries . The autOne of the first applications of NIBS in MS has been to reduce spasticity. Indeed, rTMS is able to modulate the presynaptic inhibition of the soleus Ia afferents mediating the stretch reflex , 67. CenNIBS techniques have also been used to treat fatigue in MS. Indeed, cortical involvement in fatigue mechanisms was demonstrated through impaired intracortical inhibition , dysfuncAnother application of NIBS in MS has been neuropathic pain. Central neuropathic pain is influenced by functional changes at the supra-spinal level, in various components involved in pain perception. In particular, the thalamic nuclei, limbic system, sensorimotor, and insular cortices function in a hyperactivated state. A lack of intracortical inhibition would also be involved in central neuropathic pain . Based oThese studies demonstrated that neuromodulation of cortical plasticity using NIBS can have diverse applications to benefit people with MS. NIBS over M1 might reduce spasticity and neuropathic pain through an increase in corticospinal excitability , 70, 86,Transcutaneous electrical nerve stimulation is used in the treatment of acute or chronic pain symptoms . TENS usA variety of neurophysiology tools can significantly help in the investigation and reinforcement of neuroplasticity in MS. Importantly, the development of NIBS techniques is bringing new possibilities for add-on treatment strategies. Thus, the combination of these tools could help personalize treatments for people with MS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.