Our current knowledge supports the view that catecholamines, atrial natriuretic peptide and insulin are the main physiological stimuli of exercise-induced lipolysis in humans. Emerging evidences indicate that contracting skeletal muscle can release substances capable of remote signaling to organs during exercise. This fascinating crosstalk between skeletal muscle and adipose tissue during exercise is currently challenging our classical view of the physiological control of lipolysis, and provides a conceptual framework to better understand the pleotropic benefits of exercise at the whole-body level.Exercise is a powerful and effective preventive measure against chronic diseases by increasing energy expenditure and substrate mobilization. Long-duration acute exercise favors lipid mobilization from adipose tissue, i.e., lipolysis, as well as lipid oxidation by skeletal muscles, while chronic endurance exercise improves body composition, facilitates diet-induced weight loss and long-term weight maintenance. Several hormones and factors have been shown to stimulate lipolysis  Physical exercise is one of the most effective lifestyle interventions to fight against many chronic diseases and in particular obesity and type 2 diabetes. Health benefits of exercise are achieved through an improvement of energy metabolism and glucose homeostasis. These benefits are sustained over the long term through an improvement of body composition induced by muscle hypertrophy and fat mass loss . Importa2max), is associated with a 5 to 10-fold increase in whole-body lipid oxidation compared to rest  and glucose as fuels to sustain muscle fiber contraction. When exercise is performed at high intensity and for a short duration, muscle cells primarily rely on glucose and muscle glycogen as fuels, which is mainly released from muscle and liver glycogen stores. However, if the exercise is performed at a moderate intensity and for a longer duration, FA will become the main source of energy to sustain muscle contraction. Indeed, FA oxidation in muscle is dependent of FA supply from different sources: FA released through lipolysis of triacylglycerols (TG) stored within WAT, from circulating very low-density lipoproteins-TG (VLDL-TG), from intramyocellular triacylglycerols (IMTG) and potentially TG stored within inter/intra-muscular adipose tissue (IMAT). The contribution of VLDL-TG to whole-body lipid oxidation varies from 5 to 10% at rest and seems to be marginal during exercise . Fatty a to rest . A large to rest . In thisin vitro in isolated adipocytes and whole-body resting FA oxidation in healthy individuals  on one side, and visceral WAT on the other side. Exercise mostly activates lipolysis in SCAT, as only 5–10% of circulating long-chain FA are released from visceral adipose tissue in lean subjects . Abdominin vitro , which enhances adipocyte lipolysis in vitro . Furtherexplants .White adipose tissue has also been described to produce soluble factors that may act in a paracrine/autocrine fashion to sustain lipolysis during exercise such as interleukin-15 (IL-15). It has been demonstrated that IL-15 can be produced by SCAT during a one h-cycling exercise, which is known to increase WAT lipolysis. In addition, resting IL-15 secretion correlates with SCAT lipolysis, and an infusion of IL-15 through microdialysis activates SCAT lipolysis in lean subjects while it suppresses lipolysis in obese subjects . However2max, eliciting the maximal reliance on fat as fuel oxidized in skeletal muscle   . As statctively) . HoweverThe contribution of FA to fuel the contracting muscle also depends on exercise duration. Studies from different groups have shown that FA oxidation gradually increases during a prolonged exercise bout while CHO oxidation decreases . This goFinally, the whole energy expenditure elicited by exercise has also to be taken into account when considering the contribution of FA burned in response to exercise, as a high percentage does not always reflect a large amount of FA burned if the energy expenditure elicited by the exercise bout is low. Exercise energy expenditure is linked to both exercise intensity and duration.Importantly, we and others have observed that exercise-induced SCAT lipolysis is lower in obese subjects than in non-obese subjects . This waThe relationship between exercise intensity and FA oxidation, and therefore FA release from WAT lipolysis, is not as straightforward as initially thought. The role of FA as nutrients during post-exercise recovery has been described in a recent review by Bente Kiens’ group . BrieflyIn summary, it appears critical to consider the post-exercise recovery period to fully assess the impact of different exercise modalities on FA utilization and thus body weight loss.Exercise training improves FA mobilization during an exercise bout. Indeed, it has been shown that FA appearance rate (Ra) in the blood is higher in endurance trained subjects compared to sedentary controls . Exercisin situ microdialysis experiments in SCAT of young overweight men, that 4 months of aerobic training improve both beta-adrenergic and ANP lipolytic responses (Furthermore, exercise training improves ANP responsiveness in obese subjects, but it is yet unclear whether this is due to an increase of ANP plasma concentration or to an increase of ANP receptors on the adipocyte cell surface . Indeed,esponses . Finallyesponses . Strikinesponses . This coesponses . The impesponses . Interesesponses .Finally, it has been observed that the exercise intensity which elicits the higher lipolytic rate is increased with exercise training . Thus, wAltogether, these data suggest that an exercise training program combining high-intensity and moderate intensity exercise bouts could optimize daily FA utilization and optimize body weight loss in overweight or obese individuals.Carbohydrates availability influences exercise-induced lipolysis. Indeed, glucose ingestion during an exercise bout reduces SCAT lipolysis and partially inhibits FA oxidation . ExercisNumerous review articles have described the impact of time of the day on exercise efficiency, but very few focused on lipid metabolism and WAT lipolysis . A few sMany studies have shown that calorie restriction is more efficient at reducing body weight than exercise training, and that combining exercise training with a caloric restriction intervention confers a slight additional benefit to achieve weight loss compared to calorie restriction alone . HoweverTherefore, even if combining exercise to a calorie restriction intervention does not achieve further weight loss than calorie restriction alone, exercise potentiates visceral fat mass loss and a sustained improvement of body composition , and preThere are many additional questions that remains to be answered to fully understand the impact of exercise on WAT lipolysis and body composition. Indeed, future studies should aim at identifying unknown lipolytic factors secreted during exercise, such as myokines and potentially micro-RNAs released in extracellular vesicles in response to muscle contraction . UnderstFinally, research efforts should also focus on refining exercise training modalities to achieve a maximal and sustained improvement in body composition, especially in overweight or obese individuals. Assessing the combination of time-restricted eating patterns with exercise training sessions performed during the fasting state could be an attractive approach to potentiate fat mass loss.Collectively, there is little debate that exercise training facilitates abdominal weight loss in overweight and obese individuals. Chronic exercise has largely demonstrated its ability to facilitate weight loss during calorie restriction and maintenance of long-term weight loss. A number of studies suggest that combining moderate and high intensity exercise can provide additional benefits on weight loss, at least in part, by favoring higher rates of energy expenditure during exercise and greater FA oxidation rates during post-exercise recovery. Although canonical lipolytic systems and hormones have been studied in detail during the past 30 years, more recent studies uncovered a muscle-adipose tissue crosstalk mediated by myokines regulating WAT lipolysis. However, much remains to be discovered. With the discovery that contracting muscles can produce myokines capable of remotely targeting organs, including WAT, our current knowledge will likely be challenged in the next few years.CL and CM wrote and revised the manuscript. IG, IH, and DL edited and revised the manuscript. All authors contributed to the article and approved the submitted version.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.


Biological plasticity is ubiquitous. How does the brain navigate this complex plasticity space, where any component can seemingly change, in adapting to an ever-changing environment? We build a systematic case that stable continuous learning is achieved by structured rules that enforce multiple, but not all, components to change together in specific directions. This rule-based low-dimensional plasticity manifold of permitted plasticity combinations emerges from cell type–specific molecular signaling and triggers cascading impacts that span multiple scales. These multiscale plasticity manifolds form the basis for behavioral learning and are dynamic entities that are altered by neuromodulation, metaplasticity, and pathology. We explore the strong links between heterogeneities, degeneracy, and plasticity manifolds and emphasize the need to incorporate plasticity manifolds into learning-theoretical frameworks and experimental designs. Plasticity is ubiquitous in the brain, with lines of evidence suggesting that changes can occur in any component that governs brain physiology . HoweverTheoretical and computational frameworks that consider neurons as simplified computational units with synaptic plasticity as the substrate for learning  have a lA well-formed example of structured multiscale plasticity manifolds is the theta-burst pairing (TBP) protocol in hippocampal pyramidal neurons . The cytAs biological plasticity invariably recruits the activation of biochemical signaling cascades, the molecular scale forms the lynchpin in the emergence of plasticity manifolds. The strength and dynamics of signaling species, including cytosolic calcium, activate a specific subset of downstream signaling cascades –44. OnceThe rules associated with plasticity manifolds should not be generalized across different cell types or different contexts. For instance, activation of group 1 metabotropic glutamate receptors results in depression of synaptic strength combined with an enhancement of intrinsic excitability  in CA1 pDegeneracy is the ability of disparate combinations of structural components to perform the same function  and provHow do systems  expressing degeneracy switch from one valid solution to another toward maintaining functional homeostasis in the face of perturbations? We argue that plasticity manifolds provide a structured substrate for multiple components to change together, thereby seamlessly traversing the valid solution landscape . DegenerDegeneracy also expresses in the emergence of plasticity manifolds, manifesting as the ability of distinct structural components to yield the same plasticity profile , definedPlasticity manifolds are dynamic entities, whereby the rules binding the specific components that undergo conjunctive plasticity could themselves change. A prominent behaviorally relevant route to alter plasticity rules is neuromodulation, a well-established substrate for altering brain states, functional connectivity, and behavior ,72–74. MThe molecular substrates modified by the implementation of the changes that are imposed by a plasticity manifold could alter the plasticity profiles of synapses and neurons. The consequent changes to the rules governing conjunctive changes in several components, including the directions and strengths of such changes, constitute metaplasticity of plasticity manifolds. The mechanistic basis for such metaplasticity could be through changes in synaptic or neuronal properties or through alteration to specific signaling molecules ,69,75,76From the continual learning perspective, one of the several routes to avoid catastrophic forgetting of prior learning ,78–80 isPlasticity manifolds are recruited and altered by pathological conditions ,81–94. AThe primary implication for the existence of multiscale plasticity manifolds is their ability to sustain stable continual learning in the face of widespread biological heterogeneities, by recruiting disparate components toward efficiently adapting to an ever-changing environment. Learning-theoretical frameworks should incorporate plasticity manifolds, including the synergistic interactions between distinct forms of multiscale plasticity, as a substrate toward stable continual learning . Such frExperimental designs and technical advances should strongly focus on simultaneously measuring plasticity across cell types in multiple brain regions , rather How do learning-theoretical frameworks and experimental designs account for plasticity manifolds? As the cell type–dependent signaling pathways form the substrate for plasticity manifolds, addressing this requires the entire set of regulatory components in a cell, involving genes, mRNAs, proteins, and metabolites, which has been called the regulome . It is iTogether, learning-theoretical frameworks should build and assess experimentally constrained multiscale models of plasticity manifolds, which are driven by cell type–specific regulomes. Toward achieving stable continual learning, these frameworks should strive to harness (i) the tremendous multiscale computational power of molecular signaling networks, active dendritic structures, and neuron-glia networks spanning different brain regions and (ii) the flexibility and the robustness offered by degeneracy, parametric variability, and neuromodulation . The phe


The dietary pattern in industrialized countries has changed substantially over the past century due to technological advances in agriculture, food processing, storage, marketing, and distribution practices. The availability of highly palatable, calorically dense foods that are shelf-stable has facilitated a food environment where overconsumption of foods that have a high percentage of calories derived from fat (particularly saturated fat) and sugar is extremely common in modern Westernized societies. In addition to being a predictor of obesity and metabolic dysfunction, consumption of a Western diet (WD) is related to poorer cognitive performance across the lifespan. In particular, WD consumption during critical early life stages of development has negative consequences on various cognitive abilities later in adulthood. This review highlights rodent model research identifying dietary, metabolic, and neurobiological mechanisms linking consumption of a WD during early life periods of development  with behavioral impairments in multiple cognitive domains, including anxiety-like behavior, learning and memory function, reward-motivated behavior, and social behavior. The literature supports a model in which early life WD consumption leads to long-lasting neurocognitive impairments that are largely dissociable from WD effects on obesity and metabolic dysfunction. Indeed, evidence from both humans and preclinical rodent models described herein indicates that habitual consumption of a WD during early life developmental periods can lead to long-lasting neurocognitive dysfunction even independent of obesity and severe metabolic dysfunction  report that the highest sources of energy for 2- to 18-year-olds were grain desserts, pizza, and soda, which are low in beneficial nutrients, but high in solid fats and/or added sugars . More refunction . Thus, iTo study the link between WD patterns during early life periods and neurocognitive development, rodent models are often used to target discrete periods of development during which dietary components can be administered with rigorous control and with objective quantification of the amount of calories consumed. The perinatal period in rodents, lasting from gestation to weaning , is a time during which maternal exposures can have lasting effects on cognitive processes. Indeed, the perinatal developmental stage is a critical period for neuronal programming of regions involved in learning and memory, such as the medial prefrontal cortex (mPFC) and the hippocampus (HPC) . AlthougIn laboratory rodents, several different dietary manipulations have been used to model aspects of the WD. A rodent “high fat diet” model typically involves increasing the amount of fat  while reducing the amount of carbohydrates compared to low fat and high carbohydrate standard rodent control diets. However, the carbohydrate content of a common rodent high fat diet is predominantly comprised of simple sugars, vs. the complex polysaccharide-based carbohydrate content of a typical rodent control diet (with the exception of some low-fat control diets that are high in sucrose). Another common rodent WD model is a cafeteria diet, which is a free-choice diet with combination of highly palatable, energy dense foods  that are commonly consumed by humans. Modeling the obesogenic environment omnipresent in modern Westernized cultures, these diets are provided in the home cages and are therefore easily accessible to the animals. Relative to a control group on a healthy diet, rodents exposed to these WD models may, but do not always, display one or more of the following outcomes associated with metabolic syndrome and obesity: increased caloric intake, body weight gain, increased adiposity, hyperinsulinemia, hyperglycemia, glucose intolerance, and inflammation contributing to hepatosteatosis .While commonly referred to as “diet-induced obesity” (DIO) models in the literature, rodent WD models lead to differential metabolic and body weight outcomes based on species , strain, sex, and/or age and duration of dietary consumption. For example, the same dietary manipulation may lead to obesity and metabolic dysfunction in adult male rats, but not in adolescent female rats. Thus, in this review we will refer to these dietary models as “WDs” and not DIO, and we further define a WD as a rodent model with access to either a diet high in fat , a diet with carbohydrate consumption coming predominantly from monosaccharides  or disaccharides (sucrose), or more commonly, a combination of the two (as in the examples described in the previous paragraph).Herein we review insights from carefully controlled rodent studies that inform on the impact of WD consumed during early life developmental stages on various cognitive domains, including anxiety-like behavior, learning and memory function, reward-motivated behavior, and social behavior . A seconWhile anxiety can be an adaptive emotional response to stressful situations, excessive and/or chronic anxiety can have detrimental health effects in humans and manifest as a clinical anxiety disorder . In humaA dietary influence on anxiety may be indicative of lasting changes to brain structures involved in anxiety-like behavior. Briefly, anxiety-like behavior is mediated by a network of brain regions  that is Studies on the effects of perinatal exposure to WD suggest increased anxiety-like behavior in offspring . For exaWhile an obesogenic phenotype is not necessary for the development of anxiety-like behavior, the duration of the maternal diet may be an important factor. For instance, if a cafeteria diet is provided to rat dams strictly during lactation only (PN 1–21), the male offspring do not display anxiety-like behavior in the EPM during adulthood . This ocIn addition to the effect of perinatal WD exposure on anxiety-like behavior, studies suggest that maternal WD consumption throughout gestation and lactation may impact the HPC and amygdala, brain regions that are strongly linked with anxiety. For example, WD-associated anxiety-like behavior is accompanied by increased expression of 5HT-r1a and GABAa alpha2 receptor subunit in the ventral HPC , as wellWhile the majority of the studies described above found anxiogenic effects (increased anxiety) as a consequence of perinatal WD exposure, some have reported mixed results in various anxiety measures . For exaIn contrast to the anxiogenic effects associated with perinatal WD exposure described above, maternal exposure to a WD may be anxiolytic (decreasing anxiety) for the offspring in the presence of perinatal stress. For example, rat offspring that underwent maternal separation, which normally induces anxiety, did not display increased anxiety-like behavior in the OF test if the dams consumed a WD  from gestation to postpartum day 21 . These rSimilar to perinatal exposure, adolescent consumption of WD can lead to increased anxiety-like behavior. For example, adolescent male rats that consumed a cafeteria diet consisting of 45% fat, a 15% weight by volume (w/v) sucrose solution, and standard chow during adolescence displayed increased anxiety-like behavior in the EPM during adulthood . Similarper se.Similar to effects associated with perinatal WD, anxiety-like phenotypes are observed independent of weight gain and obesity outcomes caused by adolescent WD consumption. For example, rats that consumed a cafeteria diet consisting of 45% fat, a 15% w/v sucrose solution, and standard chow during adolescence had significantly increased caloric intake and body weight , but conWhile weight gain may be less relevant to the development of anxiety-like behavior associated with adolescent WD consumption, WD may be contributing to anxiety-like behavior by affecting neurobiological processes in the HPC, the nucleus accumbens (ACB) and the mPFC. For example, Ferreira and colleagues  found thWhile many studies show that WD consumption during adolescence generally promotes anxiety-like behavior, it should be noted that there are instances where an elevated anxiety phenotype did not develop after consumption of WD. For example, brief exposure (11 days) to a 41% fat diet initiated at adolescence (PN31) had no impact on anxiety-like behavior in the EPM . In maleSimilar to effects associated with perinatal WD, consumption of WD during adolescence in rodents may reduce anxiety in circumstances associated with early life stress (ELS), fostered by either maternal separation, restraint, social isolation, or a disrupted nest anywhere from PN 2–28. For instance, in male rats, consumption of a high sucrose WD during social isolation from PN 21–28 resulted in reduced anxiety-like behavior in the OF and EPM tests at PN 28 relative to animals that received standard chow and animals that received stress without the WD . SimilarWhile the underlying mechanisms for the anxiolytic effects of WD consumption in cases of ELS are incompletely understood, WD consumption, either during or following ELS, resulted in rats consuming more food , gainingThe development of anxiogenic or anxiolytic behavior in association with early life WD exposure is likely dependent on whether or not the WD is accompanied by ELS . More spThe process of learning and remembering information is perhaps as well-studied as it is persistently mysterious. In rodent models, memory is typically assessed based on an observable behavioral change that is attributable to prior experience, and a variety of behavioral tasks are commonly implemented depending on the type of memory being studied. Common tests of recognition memory that involve passive reinforcement  are the Novel Object Recognition (NOR), Novel Place Recognition (NPR), or Novel Object in Context (NOIC). The latter two of these tasks, which involve contextual-based associations, relies on the function of the HPC and interactions with the perirhinal and prefrontal cortices, whereas object recognition memory relies on the function of the perirhinal cortex, and is independent of the HPC when conducted without a temporal or contextual component .Spatial memory, or memory based on the location of visuospatial cues in the environment, is commonly assessed via the Y-Maze Spontaneous Alternation task, Morris Water Maze (MWM), the radial arm maze, and the Barnes Maze. These tasks require allocentric navigation, are hippocampal-dependent, and involve either escape from aversive reinforcement , appetitive reinforcement , or passive reinforcement (Y-Maze Spontaneous Alternation task) . Other mExposure to western dietary factors through maternal nutrition has long-term consequences for learning and memory function, even when the animals are maintained on standard, low-fat chow after weaning . For exaIn contrast to conditioned odor aversion and NOR, other types of memory may not be as vulnerable to perinatal WD consumption. Spatial memory retention in the MWM task, for example, is actually enhanced in male rats after perinatal exposure to a 60% kcals high-saturated-fat or high-trans-fat diet . In suppIn addition to the type of learning and memory being evaluated, one major difference between the aforementioned studies that found effects of perinatal WD on various types of memory vs. those that did not is the ratio of fat and sugar content of the WDs. Those that found no effect of perinatal WD exposure on hippocampal-dependent memory utilized diets that were extremely high in fat , whereas those that found impaired odor-based avoidance memory utilized a more moderate WD with regard to fat calorie % . In order to have higher fat content in rodent diets, normally this is achieved by reducing the carbohydrate content, which in a WD is typically predominantly sugar. For instance, a 45% kcals fat WD would have higher sugar content  than a 60% kcals fat WD containing ∼7% kcal sucrose. In fact, studies investigating the effects of perinatal WD on spatial learning and memory that used a more moderate WD with regards to fat content  showed that male rats had impaired spatial memory retention in the MWM task, but this was only the case when the animals were maintained on the WD into adulthood as opposed to animals that had their WD replaced with standard chow after lactation . In anotThe ratio of sugar and fat in the diet is also a critical variable for WD effects on metabolism and neuronal outcomes. For instance, odor memory impairment induced by perinatal exposure to a 45% kcals fat WD is associated with dendritic atrophy in the BLA and the CA1 region of the HPC during adulthood  as well In studies that found that learning and memory processes were not impaired following exposure to a perinatal WD, in some cases there were still long-term effects on metabolism and on the brain. For example, despite showing better spatial memory retention, male rat offspring of obese dams on a 60% kcals fat WD exhibited increased neuroinflammation and microglial activation in the HPC . Lack ofIn some cases, the detrimental aspects of the perinatal WD exposure on brain and behavioral outcomes are reversed during adulthood after dietary intervention. For example, the oxidative stress, lipid peroxidation, and decreased BDNF protein levels in the HPC observed following perinatal 57% kcals fat WD exposure were normalized in adulthood when animals were weaned on healthy chow , correspEvidence from multiple studies suggests that adolescent consumption of a WD containing a high % kcal from fat impairs hippocampal-dependent learning and memory in rodents, and that these effects even occur following acute exposure. For example, short-term feeding  of a WD containing 60% kcals from fat in male mice impaired spatial memory in the Y-maze alteration task and object recognition memory impairment in the NOR task during adolescence . SimilarWhile the aforementioned short-term WD exposure studies suggest that the diet significantly impacted memory, these impairments were likely independent of metabolic effects, as the short duration on the diet was insufficient to promote weight gain  or aberrad libitum access (for 1+ month) to this diet after weaning promotes deficits in spatial learning in the MWM task  for 2 hrs daily throughout adolescence did not result in spatial memory deficits , ad libiMWM task , the NOLMWM task , the radMWM task , and theMWM task  in adultMWM task  and enhaMWM task , as asseMWM task . AdolescMWM task . AlteratMWM task . InteresMWM task , 2013. IMWM task . SimilarMWM task . SwitchiMWM task . These dMWM task . These fIn addition to memory impairment, long-term feeding of a WD also leads to significant disruptions in metabolism and neurobiological systems associated with memory control. While short-term feeding of a WD during adolescence does not promote weight gain, long-term feeding from adolescence to adulthood typically promotes weight gain in male rodents . AdditioGiven that rodent WDs high in fat are often also high in sugar, it is important to investigate the contribution of dietary sugars to the effects on learning and memory. Common obesity-promoting diet compositions from Research Diets consist of the 45% kcal HFD, which contains 17.5% of kcal from sucrose, the 58% kcal HFD, which contains about 13% of kcal from sucrose, and the 60% kcal HFD, which contains about 7.5% of kcal from sucrose. Interestingly, the effects of sugar alone have been shown to impact learning and memory independent of weight gain when given during the adolescent period . Furtherad libitum access to the experimental diet, some studies have examined the effects of intermittent access to a sugar solution during adolescence on learning and memory function. Results of these studies suggest that intermittent sugar access similarly conferred lasting impairments in learning and memory function later in life , males that consumed sugar performed worse in tasks with small spatial separations, whereas females performed worse in tasks with large spatial separations  did not impact NPR performance, however the rats were only able to perform place recognition correctly during the proestrus phase of the estrous cycle, a stage that contains higher levels of circulating estrogens . Taken tMetabolically, female mice exhibit similar deficits to males in response to a 45% kcal from fat WD from adolescence to adulthood, having significant weight gain relative to controls despite comparable caloric intake . HoweverWith regard to underlying neurobiological mechanisms for how high sugar diets during adolescence impact memory function, memory deficits induced by free access to the 11% w/v sugar solution in adolescence are associated with increased plasma insulin and pro-inflammatory cytokines such as interleukin 6 and interleukin 1β in the dorsal HPC . MoreoveCafeteria diets are often obesogenic when consumed by rodents during adulthood, however, whether or not adolescent consumption of cafeteria diets in rodents promotes cognitive impairment is still controversial. For example, adolescent male rats on a cafeteria diet consisting of a variety of high fat and high sugar palatable food options, standard chow, and a 15% (w/v) sucrose solution weighed more and had greater adiposity compared with rats maintained on chow and water alone. The cafeteria diet-fed rats also exhibited impairments in hippocampal-dependent spatial learning and memory in the MWM, but not object novelty detection or fear acquisition, during adulthood . In contAdolescent exposure to WD factors contributes to memory impairments, even in the absence of weight gain . While oConsumption of palatable food such as a rodent WD engages hedonic- and reward-associated neural systems, and therefore it is not surprising that early-life WD consumption can have lasting impacts on these systems and associated behaviors . AlteratDopaminergic projections from the ventral tegmental area (VTA) to the ACB are involved in motivated behavior, especially Pavlovian cue-reward associative learning . On the Perinatal exposure to a WD can dysregulate reward-motivated behavior, even when offspring are reared on a standard chow diet . For exaWD consumption by dams through an extended perinatal period that includes several weeks of pre-conception, gestation, and lactation yields long-lasting effects on reward-motivated behavior. For example, male and female rats born to dams that received hydrogenated vegetable fat (3 g/kg), a trans-fat, by oral gavage during the extended perinatal period preferred a morphine-associated context in CPP during late adolescence (PN 41+) to a larger degree than control female offspring . SimilarEven when WD exposure is initiated at the beginning of gestation, reward functions can be disturbed in the offspring. For example, when dams are fed a WD from gestational day 1 until end of lactation, male pups show a transient enhanced fat preference at PN25 that normalizes by PN95 . Female Similar to the effects described in the earlier sections on anxiety, learning, and memory, an obesogenic phenotype is not required for there to be differences in reward-motivated behavior associated with perinatal WD consumption. While some studies observed that a perinatal WD increases body weight and adiposity and promotes disturbances in metabolism  in offspring at weaning  and as aEffects on reward-mediated behavioral outcomes associated with perinatal WD exposure may be driven, in part, by altered striatal dopamine signaling. Studies have shown that the ventral striatum, which contains the ACB, is important for encoding food-related reward value and that dopamine is released in response to food-associated cues  whereas When perinatal WD feeding is extended from 3 weeks prior to conception until end of lactation, hyper-responsiveness to cocaine and amphetamine occurs in a context of reduced basal striatal and VTA dopamine levels, but enhanced ACB deltaFosB expression following cocaine exposure relative to control offspring . In addiSimilar to perinatal exposure, adolescent consumption of WDs also impacts reward-motivated behavioral outcomes. For example, adolescent access to a WD, where 40–45% of total kcals are derived from fat, alters diet preference for fat and carbohydrates  and incrad libitum feeding body weight) in a progressive ratio test, where reinforcement during training was based on a random interval, but not random ratio, schedule  had no impact on CPP acquisition for cocaine in adulthood, although this result may have been confounded by the rats being placed on significant water restriction (20 min access per day) during behavioral training and testing  is not required for these effects to occur. For instance, rodents displaying altered reward-motivated behavior following adolescent access to sugar either with a 5% w/v sucrose solution, sucrose pellets, or with a 40% kcals sugar diet had similar body weights relative to controls . These ocontrols . Animalscontrols  or did ncontrols , with lecontrols  with onecontrols . Even thcontrols . AltogetSimilar to perinatal WD exposure, adolescent WD consumption influences reward-motivated behaviors, in part, via alterations mesolimbic dopamine, cannabinoid and opioid signaling. For example, WD-exposed rodents that showed increased locomotor sensitization to amphetamine displayed a concomitant sensitized mesolimbic dopamine response as reflected by increased bursting activity of dopaminergic neurons in the VTA and increased ACB c-FOS expression  in response to amphetamine administration. The WD-fed rats also showed increased dopamine release and tyrosine hydroxylase and D2R expression in the ACB . On the Both perinatal and adolescent WD exposure in rodents has lasting effects on reward-motivated behavior in adulthood . PerinatWhile perinatal and adolescent WD exposure can impact reward-motivated behavior, an obesogenic phenotype, as indicated by increased body weight and a perturbed metabolism, is not required for these effects to occur in rodents. Neural connections involving dopamine, opioid, and other neuropeptide systems between the VTA, mPFC, ACB, and various structures embedded within the brain reward circuitry regulate motivated behavior . DependiIn both humans and rodents, it is well known that dietary choices are influenced by social factors . One mecin utero up until PN 40 had increased play behavior (number of play attacks initiated) during adolescence (PN 37) compared to rats that received a control diet for the same duration  for 7–8 days starting at PN 27–28 or prolonged intermittent access to a WD  diet for 2 h daily from PN 28–56 promoted deficits in social recognition memory, measured by the time spent exploring a novel rat vs. a familiar rat . Moreovead libitum from weaning onwards in male mice did not result in social avoidance behavior in adulthood when tested using a social interaction test after social defeat stress , as measured by resident-intruder interactions (spending less time in submissive postures and having a longer latency to submit to the resident) . Resiliet stress . Togethet stress  and the t stress .While some of the animals that showed deficits in social recognition memory after having consumed a WD during adolescence did not show differences in body weight , fastingSimilar to the consequences of perinatal WDs on social behavior, adolescent WDs may affect social behavior by impacting the PFC. For instance, social memory deficits were associated with impaired long-term potentiation in the mPFC and reduced protein levels of oxytocin in mPFC tissue. These deficits were reversed by administration of oxytocin systemically or the selective oxytocin receptor agonist, -oxytocin in the mPFC , which sThe studies reviewed here suggest that consumption of a WD during early life periods of development impair social-based memory and alters play behavior , but also that these same diet exposures may be protective against social defeat stress . These eIn this review, we present behavioral and neurobiological evidence from preclinical rodent models highlighting that consumption of  a WD during critical periods of development can lead to neurocognitive dysfunction later in adulthood. In particular, we highlight the detrimental effects of WDs high in fat (particularly saturated), sugar, or a combination of the two on the following cognitive domains: anxiety-like behavior, learning and memory function, reward-motivated behavior, and social behavior .During the perinatal period, exposure to WDs results in impairments in each of these cognitive domains in rodents when tested during adolescence and/or adulthood. For example, increased anxiety-like behavior is associated with prenatal/perinatal WD exposure unless the rodents were also subjected to early life stress, where prenatal/perinatal WDs ameliorates anxiety-like behavior. Additionally, WD exposure during the perinatal period impairs episodic memory and conditioned odor aversion learning and extinction but has no effect on contextual or cued fear conditioning. Furthermore, effects on reward-motivated behavior are also common after prenatal/perinatal WD exposure, including addictive-like behaviors to drugs of abuse, increased impulsivity, reduced behavioral flexibility, and reduced motivation to work for food reward despite increased consumption when the rewarding food is made freely available. Finally, prenatal/perinatal WD exposure reduces social memory and prosocial behavior in rodents. Importantly, these effects are often seen despite the progeny being maintained on a standard, low-fat chow after weaning. Further research is necessary to evaluate whether behavioral effects are specific to a certain stage within the prenatal/perinatal period, as some studies found certain effects were specific to late gestation or lactation.Long-term access to WDs during adolescence increases anxiety-like behavior in adulthood, although this effect may not be long-lasting given that anxiety-like behavior is not seen in rodents that had the WD removed for an extended period of time. Similar to what occurs after prenatal/perinatal WD exposure, adolescent WD exposure is protective against the development of anxiety-like behavior when consumed during periods of early life stress. Both acute and chronic consumption of WDs has deleterious effects on learning and memory processes, including impaired spatial and episodic memory, cued fear learning and extinction, aversive memory, and reversal learning. With regards to reward-motivated behavior, WD exposure during adolescence shifts dietary preferences in adulthood towards a diet similar to what the animal was exposed to during adolescence. Additionally, adolescent WD exposure increases impulsive responding for food rewards, reduces motivation for food rewards, and increases drug-seeking behavior. WD consumption during adolescence also impairs social memory and affects social interaction behavior in adulthood, yet reduces stress induced by social defeat. Altogether, the literature indicates that adolescent exposure to WDs promotes enduring cognitive impairments but may also mitigate stress responses. More research is necessary to determine whether similar effects are observed in female rodents, and whether sex hormones are a critical variable.In many instances, behavioral deficits associated with early life WD exposure occurred independent of obesity-associated outcomes such as increased body weights, adiposity measures, hyperphagia, or negative metabolic outcomes. Further, in many cases the neural substrates associated with each cognitive domain are impacted by WD exposure during development, such as increased oxidative stress, inflammation and microglial activation, as well as altered neurotransmission, neurotrophic signaling, synaptic plasticity, and reduced neurogenesis. What remains to be understood is whether or not these cognitive deficits can be reversed given some type of intervention  and whether or not these cognitive consequences have transgenerational effects.Evidence reviewed herein establishes that WD exposure in rodents during the perinatal and/or adolescent period promotes long-term deficits in anxiety-like behavior, learning and memory, reward-mediated behavior. While this review focused on rodent studies, similar changes in behavior in humans have been reported, where healthier diets are positively associated with better cognitive outcomes . The rodAll authors contributed to the idea for the manuscript. LT and LD-S wrote and edited the manuscript. SK and EN edited the manuscript, provided vital input to shape the manuscript, and contributed to the writing. All authors approved the final manuscript. The figures were created using BioRender.com by LT, and reviewed by all authors.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.


A 38-year-old male presented with a three-week history of bilateral lower extremity choreiform movements. History included sleep abnormalities, rushed and unintelligible speech, with delusions two to six months prior to presentation. He also developed mild dysphagia, staring spells, and anterograde amnesia. On examination, he had pressured speech, asynchronous cycling movements of the bilateral lower extremities persisting during sleep, occasional ballistic movements of the upper extremities, and ataxia. Magnetic resonance imaging (MRI) of the brain showed high cortical signal change in bilateral parieto-occipital cortices with evidence of medullary olive hypertrophy bilaterally. Electroencephalography showed generalized slowing without periodic spikes. Cerebrospinal fluid was positive for protein 14-3-3 and real-time quaking-induced conversion. Genetic testing was positive for autosomal dominant prion protein gene (PRNP) genetic mutation. The patient passed away three months after discharge.This case provides previously undescribed imaging and movement abnormalities in a patient with familial Creutzfeldt-Jakob disease (CJD), and suggests that CJD should not be removed from the differential in patients with these atypical findings. Human transmissible spongiform encephalopathies are a group of disorders that cause rapidly progressive dementia, and ultimately death, due to aggregation of misfolded prion proteins. This class of neurodegenerative conditions is usually sporadic but may also be inherited or acquired . PatientA number of variants of CJD have been defined based upon focal neurologic findings reflecting predominant involvement of individual brain regions. Examples of these include forms with mainly visual (Heidenhain variant) , cerebelA 38-year-old man with no past medical history presented with a three-week history of abnormal lower extremity movements. Six months prior to presentation, he developed insomnia and would sleep for 3-4 hours each night. He sought medical attention and was prescribed trazodone, which was stopped after a week due to morning headaches. Two months later, his speech became abnormal, noted to be rushed and unintelligible after the first few words. He then developed unsteadiness and was taken to the hospital where he was diagnosed with posterior reversible encephalopathy syndrome (PRES) and discharged on antihypertensives. Two months prior to presentation, he developed delusions, and worsening hypersomnia. Three weeks before his admission, he developed involuntary “stepping” movements of the bilateral lower extremities. This movement persisted during sleep and caused him significant fatigue. Other symptoms included mild dysphagia, brief staring spells, and anterograde amnesia. There was no reported history of fever, weight loss, recent travel, sick contacts, animal bites, drug use, or new medications. He worked in construction but was recently laid off due to his unsteadiness and speech abnormalities. Family history was significant for delusions and hallucinations in his mother who died at an early age due to an unknown illness.Examination was notable for pressured speech, delayed recall of two out of three items, saccadic intrusions with square wave jerks on extraocular motion testing, alternating stepping movements of the bilateral lower extremities, and rare ballistic movements of the upper extremities Video .Gait testing was deferred as he could no longer ambulate at the time of presentation.During his hospital stay, magnetic resonance imaging (MRI) of the brain showed high cortical signal change in bilateral parieto-occipital cortices with hypertrophic olivary degeneration Figures -3.Video electroencephalogram showed generalized slowing without periodic spikes. Organophosphate levels were mildly elevated. The infectious, inflammatory, and neoplastic workup was negative. Cerebrospinal fluid was positive for both protein 14-3-3 and real-time quaking-induced conversion. Genetic testing was positive for the autosomal dominant prion protein gene (PRNP) genetic mutation essentially confirming the diagnosis of familial CJD (fCJD). The patient’s family was counseled extensively on the poor prognosis of the disease and they opted for palliative care. The patient passed away three months after discharge. The family declined autopsy.Abnormal voluntary and involuntary movements are important findings to assist in the identification of patients with possible CJD. Myoclonus, cerebellar signs, pyramidal/extrapyramidal signs, and akinetic mutism are all components of the Center for Disease Control (CDC) diagnostic checklist . MyoclonSeveral MRI abnormalities have been previously reported in patients with sporadic CJD. Among them, cerebral cortical or subcortical high signal changes, and high signal intensity in the caudate nucleus and putamen are common enough to form part of the diagnostic criteria . Other nLess common variants of CJD have been described based on specific imaging findings. Visual abnormalities such as visual hallucinations, visual field deficits, cortical blindness, visual agnosia, and defects in visuospatial and color perception are characteristic of the Heidenhain variant ,15. ThesIn the case presented earlier, there is clear involvement of the inferior olivary nuclei without basal ganglia involvement. The inferior olivary nuclei form part of the dentato-rubro-olivary pathway (Guillain-Mollaret triangle). Lesions in this pathway classically produce palatal myoclonus, in which there are rhythmic and stereotypic clonic jerks of the soft palate at a frequency of 1-3 Hz . OccasioIn this patient, there was no evidence of palatal myoclonus. However, there were repeated, stereotypical, alternating flexion-extension movements noted at bilateral hips and knees, with each limb jerking at a frequency of about 2 Hz. Similar to symptomatic palatal myoclonus, these movements did not terminate during sleep . In one Hypertrophic olivary degeneration has not been previously described in fCJD. The accompanying lower extremity movements have also never been described in fCJD. We suspect that the lesions were related to our patient’s prion disease as prion protein has been frequently found in this location, and he had no lesion in the Guillain-Mollaret triangle to explain the etiology of this finding. There was no report of olivary abnormality on his brain MRI obtained at a different facility four months earlier to suggest that this lesion was chronic. Furthermore, we postulate that his abnormal lower extremity movement disorder could be related to this imaging finding as there were characteristics that overlapped with symptomatic palatal myoclonus. A theoretical explanation of these movements utilizes the connection of the Guillain-Mollaret triangle with the rubrospinal tract. The rubrospinal tract forms part of the lateral motor system and is thought to have predominantly flexor, or anti-extensor effects ,20. GiveThe limitations of this report include the fact that no pathologic specimen was available to confirm prion protein deposition in the olives. Also, the patient’s movement disorder did not include upper limb myoclonic movements during his hospital stay, which would beg the question of why the lower limbs would be selectively affected in a rubrospinal pathology. Additionally, due to the paucity of similar cases, a strong causal link cannot be made between the abnormality of the inferior olives and these movements.The diagnosis of CJD remains challenging due to the large variability in the clinical presentations. It should be one of the differential diagnoses considered in patients who present with subacute movement disorder, rapidly progressive cognitive changes, and imaging findings of hypertrophic medullary olives. More cases of fCJD need to be reported to assist in building a more comprehensive profile for this disease.


Plant organellar RNA metabolism is run by a multitude of nucleus-encoded RNA-binding proteins (RBPs) that control RNA stability, processing, and degradation. In chloroplasts and mitochondria, these post-transcriptional processes are vital for the production of a small number of essential components of the photosynthetic and respiratory machinery—and consequently for organellar biogenesis and plant survival. Many organellar RBPs have been functionally assigned to individual steps in RNA maturation, often specific to selected transcripts. While the catalog of factors identified is ever-growing, our knowledge of how they achieve their functions mechanistically is far from complete. This review summarizes the current knowledge of plant organellar RNA metabolism taking an RBP-centric approach and focusing on mechanistic aspects of RBP functions and the kinetics of the processes they are involved in. Arabidopsis thaliana; Selaginella uncinata  chloroplasts, at least 139 nuclear-encoded RBPs from the PPR  polymerases triggers exonucleolytic degradation , which iKD values have been measured, recombinant P-class PPRs bind to their cognate RNA in the picomolar–nanomolar range. For example, the equilibrium KD values of PPR10 and HCF152 are 10 and 40 pM, respectively  proteins, which are known for their propensity to form protein–protein interactions. However, some TPR proteins have evolved to bind RNA, including members of the half-a-tetratricopeptide (HAT) subfamily . MoreoveThe immediate outcome of the action of helical repeat proteins, the most abundant P-class PPR proteins, is the baffling complexity of transcript isoforms, which exceeds bacterial and nuclear transcript heterogeneity. The production of shorter, often monocistronic, forms from longer precursor RNAs has long been assumed to be beneficial for protein production. Chloroplast operons contain genes with very different functions, and separating individual cistrons was speculated to contribute to adjusting individual transcript amounts and improving translation. The results of experiments with in vitro translation systems supported this idea, where the translational output of some mRNAs was strongly influenced by the processing state of the UTRs . HoweverThe half-lives of chloroplast transcripts, determined by blocking transcription and measuring RNA quantities over time, is in the range of hours or even days . Noninvarps12 mRNA halves, supporting the trans-splicing of rps12  family of RBPs is more specialized, with all but 1 member involved in RNA splicing in chloroplasts and mitochondria . The besF intron . In vitrF intron . Whetheri mutant .trans-splicing  proteins or the DUF794 protein family  of mRNAs is common in mitochondria and chloroplasts, although the functional impact of this is not yet clear  genes, which block their expression and restore pollen production and plant fertility by reducing their deleterious effects  genes (orf29 in Arabidopsis (Rfo/PPR-B protein was demonstrated to suppress the expression of the CMS transcript (orf138) by impeding its translation via ribosome blockage rather than by inducing its cleavage  genes . MoleculL) genes . HoweverL) genes . PRORP rbidopsis , but thebidopsis . The secbidopsis . The Rfocleavage .Rf gene candidates in rye and barley were found to encode members of the mTERF family , specific genomic loci constantly spawn novel family members , suggestf interacts with and induces the degradation of MCA1, an RNA stability factor for the petA mRNA encoding cytochrome f  make an excellent “chassis” for synthetic biology due to their small, well-understood genomes, and prodigious production potential . Most chpsbD mRNA  efforts that have been put into cataloging the numerous RBPs involved need to be complemented by equivalent efforts at understanding the processes mechanistically. There are several particular areas that we would encourage researchers to focus on. Our understanding of the kinetics of RNA maturation in organelles is still rudimentary. A much better understanding of the rates of the different processes (and the rate-limiting steps within them) are needed to discover which have regulatory potential. New labeling techniques that can provide high-throughput pulse-chase analysis appear to offer a way forward . With reThe following materials are available in the online version of this article.. Gene and RBP numbers of selected species, supports Fig. 1.. PPR proteins involved in plant organellar RNA splicing, supports Chapter 4.1koad049_Supplementary_DataClick here for additional data file.


We systematically reviewed genetic studies employing single-cell transcriptomics (scRNA-seq) or spatial genomics in Alzheimer’s disease (AD) research to highlight potential molecular mechanisms and explore what changed from previous findings. An overview of molecular imbalances in AD and differences in their mechanisms across sex, period of onset, age, and immunity are presented. Our study provides evidence for continuing research to identify common causes and possible solutions to ameliorate AD. scRNA-seq and spatial transcriptomics have the advantage of providing more in-depth results, which is vital for identifying crucial factors for AD-modifying investigations.The devastating effects of Alzheimer’s disease (AD) are yet to be ameliorated due to the absence of curative treatment options. AD is an aging-related disease that affects cognition, and molecular imbalance is one of its hallmarks. There is a need to identify common causes of molecular imbalance in AD and their potential mechanisms for continuing research. A narrative synthesis of molecular mechanisms in AD from primary studies that employed single-cell sequencing (scRNA-seq) or spatial genomics was conducted using Embase and PubMed databases. We found that differences in molecular mechanisms in AD could be grouped into four key categories: sex-specific features, early-onset features, aging, and immune system pathways. The reported causes of molecular imbalance were alterations in bile acid (BA) synthesis, PITRM1, TREM2, olfactory mucosa (OM) cells, cholesterol catabolism, NFkB, double-strand break (DSB) neuronal damage, P65KD silencing, tau and APOE expression. What changed from previous findings in contrast to results obtained were explored to find potential factors for AD-modifying investigations.  Alzheimer’s disease (AD) is one of the major causes of death in older people and the seventh leading cause of death in the United States . It affeAD is a heterogenous aging disorder that affects cognition, and metabolic imbalance is one of its hallmarks. Therapeutic trials in AD are limited because they do not account for heterogeneity . HoweverMethods that utilize both scRNA-seq and spatial mapping can capture the transcriptome topography in an unbiased fashion based on their tissue position before homogenization . While pImprovement in functional genomics discovery is one of the highlights of these two methods. Three unique marker genes  differentially expressed between AD and normal conditions were recently discovered with spatial transcriptomics . Their dIdentify common causes of molecular imbalance in AD;Highlight potential molecular mechanisms.This paper accesses the evidence base by systematically scoping the literature for genetic studies employing scRNA-seq or spatial genomics in AD research to identify potential molecular mechanisms. It provides synthesized information for continuing research to discover possible solutions to ameliorate AD. The overarching aim is to:The remaining sections of the paper will discuss the eligibility criteria, search strategy, evidence synthesis, and quality appraisal of the selected studies. This will be followed by an overview of molecular imbalances in AD and differences in their mechanisms across sex, period of onset, age, and immunity. Next, a narrative synthesis of potential molecular mechanisms of AD will be discussed with respect to the findings and what has changed in contrast to previous findings.This study was registered in PROSPERO (CRD42022385085). Primary studies from any country that used human biological samples to study molecular mechanisms in AD and employed single-cell sequencing or spatial genomics were reviewed. Only original publications in English from peer-reviewed journals were included. The PCC framework suggested by the Joanna Briggs Institute (JBI) was used in defining the eligibility criteria seen below .P—Population: Humans with Alzheimer’s diseaseC—Concept: Molecular mechanismsC—Context: Single-cell transcriptomics and/or spatial genomics. All articles reviewed reported molecular mechanisms in AD and applied genomics methods. Articles from grey literature and/or studies involving only non-human samples or other types of dementia or other neurogenerative diseases were excluded.The search was conducted in Embase and PubMed databases and covered the periods between 1960 and 2022. PubMed is one of the most popular biomedical and genomic databases accessed online from the National Center for Biotechnology Information (NCBI) platform. Similarly, Embase is another comprehensive pharmacological and biomedical bibliographic database hosted on Elsevier. All searches were conducted the same day, prior to 27 October 2022. The key categories searched were Alzheimer’s disease, single-cell transcriptomics and/or spatial genomics, and molecular mechanisms. These key search terms and their synonyms were identified using PROSPERO MeSH thesaurus qualifiers. The search strategy yielded a total of 93 hits. Thirty duplicates were removed after initial matching by PubMed ID and digital object identifier (DOI). Out of the 63 articles remaining, 46 were excluded for not fully meeting the selection criteria after screening by title and abstract. Eight articles were not included because they did not meet the eligibility criteria, leaving nine articles. The screening process is presented in To create a descriptive summary of the results with respect to the study objectives, data were extracted from the selected studies under these headings: author name and year, methodology adopted, study aims and sample type, key findings, category, and potential molecular mechanisms, as seen in The critical appraisal was performed using the Critical Appraisal Skills Programme (CASP) checklist with a modified set of questions appropriate for the study . Table 2Did the study address a clearly focused question?Did the authors address the research aims and objectives?Were the concept and context of the study measured and relevant?Have the authors identified all necessary confounding factors?Were the methods used sufficiently described in detail?Were the results presented in a reproducible way?Could the results have occurred by chance?Can the result be applied to the population of interest?Were all outcomes important to the population of interest?Do the results of this study fit with other available evidence?Are there implications of this study for practice?The CASP checklist questions included:As seen in The results of the study are presented in To understand the fundamental molecular mechanisms involved in AD pathogenesis, Varma et al.  found seNonetheless, alterations in neuronal apolipoprotein E (APOE) expression and olfactory mucosa (OM) cells also lead to sex-specific molecular differences in AD. In a female-only study conducted by Zalocusky et al.  to find Dysregulation of BA synthesis and cholesterol catabolism may point to early features of dementia because the same pathway is entangled in neuropathological changes before onset of dementia . This evIndeed, new treatment targets for AD prevention could be accelerated by understanding the mechanisms in young carriers of APOE4 who are yet to establish neuropathology. E4 carriers have been reported to display decreased cerebral glucose metabolism, which is a popular hallmark of early-onset AD . The entAnother primary risk factor and important variable in understanding AD is aging . DSBs acNonetheless, as neurons age and mature in the developing brain, tau mRNA expression increases . The onsThe five important drivers of immune system molecular imbalance underlying AD from the selected studies were DSB neuronal damage, neuronal APOE expression, functional alterations of triggering receptor expressed on myeloid cells 2 (TREM2), absence of microglia in amyloid plaques, and defective mitochondria protease (PITRM1). Excitatory neurons with late-stage DSB damage were found to be linked with AD pathology and the immune response; these neurons are usually marked with antiviral immune activation in resemblance to a phenotype associated with virus-infected neurons and senescent cells . In addiThe differences in molecular characteristics of individual neurons under pathophysiological and normal conditions are driven by neuronal APOE expression . A link The functional alteration of TREM2—an innate immune system receptor expressed in microglia— and the Defective mitochondria in AD are drivers of immune response reactions . scRNA-sPrevious studies have used TREM2 activation tool, anti-TREM2 Ab, to observe cellular functions and visualize signals but not for TREM2 activation . While tFurthermore, previous histological reports have suggested that OM cell alteration is an early symptom of AD; what changed was the cell type-specific functional alterations in OM that past reports did not reveal. Genes such as MT-ATP8 and MT2A, previously found in AD to be expressed in the frontal cortex and skin fibroblasts respectively, were also highly expressed in AD OM cells ,34. MT2AWith respect to APOE expression, results show that it is more elevated in E4 than in E3 astrocytes, and scRNA-seq analysis by Farmer et al.  have ideA list of 2031 new genes previously unconnected with amyloid plaques containing microglia and highly enriched in AD were found by Grubman et al.  after apDespite the limitations of spatial transcriptomics, it is continuing to prove its importance. A previous study  showed NIdentifying molecular level mechanisms in AD is limited due to the lack of data and difficulty in obtaining samples from the brains of patients . HoweverIn early-onset AD, the key to better management is early detection, which is quite challenging due to misdiagnosis ; therefoThe accumulation of deficits and distinct changes in gene expression and tissue regulation have been reported in several aging-related studies ,21,22,44The loss of TREM2 and PITRM1 function may give rise to AD-like pathological features ,23. TREMIt is important to consider the hallmarks of underlying immune system molecular mechanisms in AD pathogenesis. The APOE pathway is related to DNA damage and repair; together with MCH-I, APOE expression is a crucial factor driving immune response and variability within individual neurons . LikewisTaken together, the results across all four categories show that the reported causes of molecular imbalance are alterations in BA synthesis, loss of PITRM1 and TREM2 function, disruption of OM cells, dysregulated cholesterol catabolism, DSB neuronal damage, NFkB and P65KD silencing, tau expression, and neuronal APOE expression. Potential molecular investigations may evaluate the impact of altering BA signaling and synthesis, sex-specific role of LRP1 regulation, AD-specific changes in OM cells and the entorhinal cortex, regulatory mechanisms initiating tau gene transcription, microglial TREM2 activation, and PITRM1 mechanistic links between mitochondrial disorders and neurological proteinopathies. Evaluating these molecular imbalances could reveal crucial factors for AD-modifying investigations and targeted treatments.


In reality, plant hairs perform much more extensive functions. Plants, especially their leaves, are extensively fed on by many insect herbivores  or ‘entertainers’ (performers). If you must call out any of those people, it will get tricky and confusing as the human population will be divided into two subpopulations. Just imagine how much the sense of personal, cultural, familial, and historical connections and importance we would be missing. Just like this imaginary world, trichomes of plants were almost exclusively denoted either as glandular or non-glandular. Previous trichome nomenclature literature from specifically 1940 to 2000 (Solanum (nightshades)). Firstly, Solanum lycopersicum L.) trichomes that were recognized and named based on their morphological features. Later, th century  and adaxial (upper side) leaf surfaces of all species at a similar age were captured using a Desktop Scanning Electron Microscope (DSEM) using a methodology developed by Recently,  Solanum . Our resThrough this detailed examination, three broad three categories were identified: stellate (star-shaped) non-glandular trichome (without glands), simple (without branches) non-glandular trichome (without glands), and glandular trichome (without branches but with gland/s on the tip of hair). Further, each of these broad categories was finely divided and relevantly named into different types by looking at subtle differences between trichomes. For example, stellate non-glandular trichome (SNT) is a generic name for star-shaped trichomes but with the deeper investigation and careful observation, we could divide stellate non-glandular trichome into SNT with short central ray , SNT with long central ray , bifurcated SNT (two branches originating from a common base), multitangulate (having branches at multiple angles), multiradiate (having multiple branches) SNT, porrect stellate  and porrect-geminate SNT (similar to porrect-stellate but consists of two whorls of branches one over the other).broad name => finer associated features => its sketch => its density on leaf surface => dimensions”.Such thorough categorization was done for two other broad categories as well. Moreover, even if the two trichomes were identical in shape, precise differences in morphology were provided by density and dimension parameters. Additionally, we found some peculiar trichomes types which were very rare or not reported before. With all the data in hand, we came up with two huge tables  simple non-glandular trichomes have the most diverse types followed by glandular trichomes and compound non-glandular trichomes, and (ii) every species has a unique combination of trichome types and associated density and dimensions on each side of the leaf.In total, we characterized and named hundreds of trichomes to the finest scale, possibly for the first time. Along with well-defined names and features, our study provides details of the density and dimensions of each trichome type. Overall, it can act as a new catalog of trichomes as it showcases the tremendous variety seen in the Solanum, leads us to their functional consequences- especially how the variation in density and dimensions of trichomes can be further examined for their correlation with herbivores’ feeding (Dicyphus errans (Hemiptera: Miridae) traction force on leaf surface and the trichome density and length. Clearly, there is a need for more in-depth studies which explore the capabilities of plant hair such as defense, considering their physical and chemical properties .These interesting findings and the overall diversity of trichomes in  feeding . For exa feeding  or/and b feeding . HoweverIn the case of glandular trichomes, the entrapping of herbivore by release of sticky substances is an additional advantage other than their hinderance capability for the herbivore. In plants with more than one type of glandular trichome types releasing such sticky substances, the shape and size of those trichomes play an important role as well in measuring precisely, which kind of trichome is more effective in hindering herbivores . FurtherThe extensive categorization of trichomes of various species can help us answer some evolutionary questions such as ‘Can the branching pattern of the trichomes explain their functional diversity across the members of each family?, ‘why some species exclusively have glandular or non-glandular trichomes?’, ‘what selection forces decide the combination of different trichome types in a species?’, ‘what mechanisms drive this process, and does a combination of abiotic and biotic stressors play a differential role in deciding trichome traits?’, to mention a few. For example, Spodoptera cosmioides (Lepidoptera: Noctuidae), and found three genotypes in which antixenosis is mediated by trichome density and leaf color. By using In recent years, many studies have explored the role of non-glandular trichomes in providing physical resistance herbivores  and the Taken together, now trichomes do not have to be vaguely categorized only as glandular or non-glandular type, unlike the unnatural and misshaped fictional human world of entertainers and observers. Earlier trichomes were originally believed to be evolved for abiotic stresses, but now have much more diversification and functional importance to offer. This study can help and guide phylogeneticists and ecologists to explore the path to find their importance even further. Furthermore, the specific importance that might be associated with each trichome type can be investigated to help entomologists look into their potential for integration in integrated pest management programs, and plant breeders to breed hardy plant varieties.SW designed and wrote first draft. RK revised and added tables and figures. SW and RK did further revisions. All authors contributed to the article and approved the submitted version.


Stroke is a disease with high morbidity and disability, and motor impairment is a common sequela of stroke. Transcutaneous auricular vagus nerve stimulation (taVNS) is a type of non-invasive stimulation, which can effectively improve post-stroke motor dysfunction. This review discusses stimulation parameters, intervention timing, and the development of innovative devices for taVNS. We further summarize the application of taVNS in improving post-stroke upper limb motor function to further promote the clinical research and application of taVNS in the rehabilitation of post-stroke upper limb motor dysfunction. Stroke is a highly morbid and disabling disease that places a significant burden on healthcare globally , 2. As tVagus nerve stimulation (VNS) is an invasive stimulation technique that requires the surgical placement of a stimulation device inside the patient's body and was first approved by the US Food and Drug Administration (FDA) as a treatment for intractable epilepsy . In receAs basic science and clinical trials related to taVNS have been conducted, the issue of studying its optimal stimulation parameters becomes increasingly important . The optOnly one study used a fixed current intensity of 0.5 mA , while oAs to the setting of pulse width, the main choices in stroke clinical motor disorder treatment are 0.1 ms , 20, 27 Recovery of motor function in clinical stroke patients is often accompanied by rehabilitation. Therefore, it is crucial to determine the optimal timing of taVNS treatment in conjunction with rehabilitation. At present, there are no relevant reports regarding taVNS intervention timing in clinical rehabilitation protocols. Given the potential of taVNS to improve motor function in stroke patients, it is important to identify the most effective timing and sequencing of taVNS treatment.Although there are no studies regarding the optimal timing of intervention when taVNS is applied to post-stroke patients, we can still summarize the current trends in intervention timing from the available clinical studies. Two current clinical studies regarding taVNS intervention for post-stroke upper limb motor dysfunction did not highlight a specific temporal relationship between taVNS and conventional rehabilitation , 27. RehA previous review classified the types of taVNS devices , which cCurrent clinical studies of taVNS for improving post-stroke upper limb motor function mostly use open-loop devices , 25–29. In this closed-loop system, different biofeedback signals should be selected based on the disease being treated. These biofeedback signals must meet the conditions necessary to trigger the closed-loop system and do not interfere with other functions. At present, the most suitable closed-loop taVNS system for motor function rehabilitation in stroke patients is motor-activated auricular vagus nerve stimulation (MAAVNS), which uses electromyography (EMG) to detect muscle movements to trigger taVNS stimulation , 40, theThis technique has been successfully applied to improve neonatal oral motor coordination . It can In addition, a device under development attempts to use vibrotactile stimulation instead of electrical stimulation , also thIn terms of assessing the clinical efficacy of taVNS interventions for post-stroke motor dysfunction, most of the relevant clinical studies have used several evaluation indicators see . Among tIn a prospective study, 13 patients suffering from ischemic stroke for at least 3 months with residual upper limb dysfunction were subjected to a 6-week repetitive upper limb training task combined with a taVNS intervention . The parAt present, a total of two studies have used rehabilitation robotic training instead of conventional rehabilitation combined with taVNS to intervene in post-stroke motor dysfunction , 29, oneThere are several kinds of side effects, including skin redness, nausea, vomiting slight pain and light-headedness. In the two studies of taVNS combined with conventional rehabilitation training, three participants had skin redness , 26. In Current studies have difficulty in harmonizing the accompanying treatments used in different researches. In fact, it is understandable that for each patient the therapist should determine the appropriate individual treatment protocol. For the researchers this also makes it more challenging to control for variables. However, the available studies show that the effect of taVNS on stroke is significant regardless of treatment timing and accompanying treatments , 28, 29.In current clinical studies  still oCurrently available clinical studies of taVNS interventions for post-stroke motor function are focused on upper extremity motor function, and no clinical studies related to lower extremity motor function have been conducted. The subject selection was mainly in ischemic stroke patients, with only three studies recruiting both hemorrhagic and ischemic stroke patients , 28, 29,Overall, taVNS is a very promising technology that has a wide range of applications in a variety of diseases. As a new technique, the therapeutic efficacy of multiple rehabilitation methods in combination with taVNS for post-stroke movement disorders has been initially confirmed. It is a future research direction to increase the follow-up time and explore the best treatment pattern for patients with different etiology and disease courses.


This edition of the World Journal of Surgery addresses an issue of global humanitarian, economic, and even political importance . It has Although acute pain has obvious implications in terms of resource utilization and humane treatment, it is chronic pain resulting from surgical procedures that has the greater impact on quality of life and economic activity. A significant proportion of the harm associated with chronic pain is its’ treatment; the opioid epidemic in the USA and worldwide illustrates the dangers of managing chronic pain with medications designed to relieve acute pain . No stanThis holds true especially in inguinal hernia surgery, an area where the confluence of three nerves and their surgical handling are associated with a significant incidence of debilitating chronic post-inguinal surgery pain (CPIP) .starts the fire becomes the focus of prophylactic interventions, and rescue plans are readily accessible, with all relevant parties on high alert.Preventing CPIP remains a challenge. Experienced surgeons may suspect that an individual, highly anxious patient may be at higher risk of CPIP, but clinical practice often confounds even the most astute clinician. Identifying at-risk patients is thus a key component in managing this entity. Understanding that a hot, dry summer increases the risk of forest fires contributes to enhanced vigilance. Preventing the spark that Surprisingly, pre-emptive analgesic strategies aimed at reducing chronic post-surgical pain, and CPIP, have shown inconsistent results . RegionaPeri-operative risk factors for CPIP have been enumerated and validated in small series. Model predictive ability remains too weak to provide consistent for reliable use; none the less open repair of recurrent hernias in young females with high pre-operative pain scores seems to confer the highest risk . Intra-oGeneric pain scores have existed for decades, the most validated include the numeric rating scale (NRS). Obvious shortcomings include the absence of dynamic measures and the ‘single snapshot’ nature of the pain evaluation. Consequently, specific pain assessment has been developed for specific pain-inducing phenomena. Examples include the ‘PIC’ Score, a focused, inverse pain assessment tool for rib fracture patients’. Pain on movement, cough strength and inspiratory effort—all are linked to the need for enhanced analgesic interventions.Clear associations between the severity of post-operative pain and the development of chronic post-surgical pain have been demonstrated.Person-centered, precision medicine-based approaches to CPIP prevention are awaited; genotype mapping may soon help identify patients at risk of CPSP. However, phenotypic identification of particular patient patterns in the PACU will remain a key tool.Widder and colleagues therefore need to be congratulated for developing the first acute post inguinal hernia repair pain score. This may provide a small part of the puzzle, and allow aggressive, targeted interventions immediately post herniorrhaphy. We encourage the launch of a prospective and multi-institutional study to validate the scoring tool described.Surgical techniques have been developed to address this common clinical condition; three main procedures are recommended and used frequently, the open surgical approach (Lichtenstein) and two minimal invasive techniques: extraperitoneal (TEP) and Transperitoneal (TAAP) inguinal hernia repair, but unfortunately previous studies have demonstrated mixed results, in relation with high risk of recurrences, post-operative complications and CPIP. It is important to take in consideration as a clinician, that post- operative pain that develop after a hernia repair procedure, will cause a significant number of patients to suffer CPIP long-term, and even permanently.Outstanding challenges therefore remain; including what the most effective management of acute pain post-surgery should be.


Cells and tissues display a remarkable range of plasticity and tissue-patterning activities that are emergent of complex signaling dynamics within their microenvironments. These properties, which when operating normally guide embryogenesis and regeneration, become highly disordered in diseases such as cancer. While morphogens and other molecular factors help determine the shapes of tissues and their patterned cellular organization, the parallel contributions of biophysical control mechanisms must be considered to accurately predict and model important processes such as growth, maturation, injury, repair, and senescence. We now know that mechanical, optical, electric, and electromagnetic signals are integral to cellular plasticity and tissue patterning. Because biophysical modalities underly interactions between cells and their extracellular matrices, including cell cycle, metabolism, migration, and differentiation, their applications as tuning dials for regenerative and anti-cancer therapies are being rapidly exploited. Despite this, the importance of cellular communication through biophysical signaling remains disproportionately underrepresented in the literature. Here, we provide a review of biophysical signaling modalities and known mechanisms that initiate, modulate, or inhibit plasticity and tissue patterning in models of regeneration and cancer. We also discuss current approaches in biomedical engineering that harness biophysical control mechanisms to model, characterize, diagnose, and treat disease states. Organisms achieve and maintain multicellularity by promoting cooperation and mediating conflict within groups of cells, thus prioritizing the collective over its units . How do Plasticity is a property of cells that enables phenotypic changes without genetic mutation and is typically activated as a response to signals and cues within tissue microenvironments , 9, 10. When cellular plasticity subverts key safeguards and becomes unrestrained, as is the case with cancer, tissue architecture can become irreversibly unstable as cells proliferate uncontrollably, invade foreign tissues, and contribute to widespread dysfunction and increased mortality . The supTissue patterning involves the integration of repeatable elements within the structure of an organism, including pigmentation and body segmentation. Originally predicted by Turing , the disCancer is defined by its highly plastic state and disorganized patterning, imperfectly mirroring normal morphogenetic processes –38. SomeIn addition to biochemical signaling and molecular pathways, there are at least three biophysical modalities that allow cells to share information with each other and their surrounding microenvironments: biomechanical, bioelectrical, and bioelectromagnetic –47 Tabl. These sThe ability for a tissue or organ to regenerate is dependent on many factors present in the post-injury microenvironment, including biomechanical properties of the ECM such as stress, strain, shear flow, stiffness, and topographical cues . In mammECM composition refers to the molecular network of proteins and proteoglycans that make up the natural scaffold of the tissue microenvironment. Modification of the ECM composition as part of the injury response can either promote or inhibit regeneration. Cells interact with surrounding ECM components through various surface receptors leading to activation of downstream intracellular pathways. Following injury in regeneration-competent species such as zebrafish, mechanical waves across tissues signal the position of wounds  and pro-The presence of excessive collagen and fibrinogen changes the composition of the injury microenvironment which elicits important cellular responses including alterations in plasticity and phenotype. For example, following injury to the liver, manipulating the microenvironment to decrease laminin and total ECM concentration leads to increased hepatocyte differentiation to promote liver regeneration . AlthougAs with normal cell types, tumor cells interact with and are regulated by the surrounding tissues, cells, and ECM, which are collectively known as the tumor microenvironment (TME) . The phyThe secondary microenvironment of colonized metastatic sites represents another important feature of cancer that is influenced by biophysical properties. It has long been noted that certain cancers are more likely to metastasize to specific organs and that this may be related to physical bottlenecks like anatomical proximity and circulation patterns , 72. In In contrast to their normal counterparts, cancer cells can abnormally alter the TME to promote their survival and progression , 76. TumOne major difference between scar tissue and regenerative-competent tissue is ECM stiffness, where scars are defined by fibrotic regions of disorganized, rigid collagen polymers . IncreasThe stiffness of the ECM can affect the plasticity of many cell types via mechanoreceptor-mediated mechanisms. Regulation of stemness has been linked to changes in actin force . For exaMus musculus , biomechanical signals , proton concentrations , photons , and other energy sources , or chemical or UV crosslinking . To mimiThe use of decellularized ECM from the organ or tissue is an alternative means by which in vivo biophysical properties such as 3D architecture, stiffness or composition can be retained. Once decellularized, this ECM can then be digested and resuspended into a hydrogel or seeded directly with the cells of interest and maintained in culture to study the effects of the ECM properties on cell phenotype and plasticity. Decellularized ECM can also be used to drive the differentiation of seeded cells for transplantation back into the body. One of the most commonly used reconstituted ECM substrates is Matrigel, which is naturally secreted by Engelbreth-Holm-Swarm mouse tumor cells. Interestingly, at microscopic scales, this material displays marked mechanical heterogeneity with punctate regions of increased stiffness relative to the bulk , consist+/K+ channels hyperpolarize colorectal cancer cells in vitro with downstream proapoptotic effects and cell cycle arrest [Investigators are now exploring the possibility of inhibiting tumor growth by targeting ion channels. Blockades of serotonin-gated Nae arrest . Similare arrest . Regenere arrest . As druge arrest , the posWhile voltage-gated calcium channels can be markedly underexpressed across several types of cancer including brain, lung, kidney, and breast , it was 2+ gradients and endothelial nitric oxide synthase expression [Localized electrical stimulation of the wound site by implanted EM field generators—also known as electroceuticals—is an emerging technology with promising effects on regeneration. Building on seminal experiments in the 1970s, platinum and silver-wired electrodes coupled to embedded resistors were recently implanted within the stumps of amputated rat limbs to deliver low-voltage DC stimulation to enhance regeneration . The stipression .Materials can also be used to focus or amplify endogenous bioelectric signaling for tissue engineering purposes. Indeed, recognizing the role of the microenvironment on electrical signal propagation, neural stem cell differentiation was modulated within custom scaffolds by increasing the electrical conductivity of the substrate , polystyrene sulfonate or “PEDOT:PSS”) to build models of the central nervous system in vitro .2+, Na+, K+) in cells and, in turn, downstream signaling cascades to proliferate and differentiate mesenchymal stem cells [To model electrotaxis in vitro, there is a growing number of researchers developing devices to generate electric fields to modulate tissue dynamics . While iem cells . EM fielem cells , 295.An emerging alternative to classic anti-cancer drugs is the use of tumor-treating fields. Non-ionizing radio frequency (RF) radiation has been used to locally heat cancerous tissues (> 45 °C) for direct ablation or sensitization to other treatments; however, because needles must be inserted directly into the tumor, applications are limited, the effect is highly localized, and the technique is invasive . AlternaPhotobiomodulation is gaining attention as a technique to program tissue plasticity and patterning. All cells express light-sensitive molecules, from enzymes  to light-gated ion channels , and G-protein coupled receptors  . Even am2) exposures triggered significant bone regrowth and re-patterning due to activation of mitogen-activated protein kinase (MAPK) and β-catenin pathways and downstream osteogenic gene expression of BMP-4 and RUNX-2 [Healing and repair can be stimulated by photobiomodulation by triggering inflammatory activations including the release of interleukins, tumor necrosis factor (TNF), and several growth factors . Infrared RUNX-2 . Skin red RUNX-2 . Similard RUNX-2 . As clind RUNX-2 . Neverthd RUNX-2  and perid RUNX-2 . Similard RUNX-2 .2) light with wavelengths of approximately 660 nm may exacerbate tumor growth and contribute to poor differentiation of cytoarchitecture. Therefore, there is a timely need to identify the determinants of photobiomodulation responses and the isolation of therapeutic applications which may be used to non-invasively control tissue dynamics.While cancer cells emit light signatures that are diagnostically relevant , 315, thConsistent with their shared molecular pathways, regenerative and cancerous tissues display common biophysical regulators of plasticity and patterning (or mispatterning). With mechanical forces, it seems that, in general, increased ECM stiffness promotes cancer cell induction, tumor growth, and metastasis while inhibiting regenerative potential in favor of scar formation. While it may be tempting to plot cancer and regeneration at opposite points on a continuum, they share several bioelectric signatures including a significantly depolarized resting membrane potential. Both systems, which involve cell migration toward different ends, are responsive to electric field gradients that guide outgrowths. Differentiation, cell division, and migration are also regulated by ambient and applied light in both regeneration and cancer. As discussed, tissue patterns associated with embryogenesis and recapitulated during regeneration may be stabilized by gap junctional networks, where disruptions result in teratogenic phenotypes or malignancies. Perhaps most clear is the previously underestimated interaction between molecular and physical modalities within the extended microenvironment, where mechanical, electrical, or electromagnetic signaling converge upon gene expression and factor release with feedbacks to modulate the environment in turn. Top-down biophysical control mechanisms are intrinsically linked to the ECM composition, structural topography, and cytoarchitecture of the microenvironment. Recognition of this is evidenced by parallel trends in regenerative medicine and oncology toward the modulation of tissue microenvironments to program physiological outcomes bypassing the micromanagement of individual cells. Our review of the literature suggests that biophysical phenomena are receiving increased attention as determinants of cell state and fate; however, there is a need to further integrate molecular and biophysical factors in consideration of their meaningful interactions.While traditional cell culture methods provide conditions to isolate individual variables to better understand cell signaling, the interconnectedness of several molecular and biophysical signaling modalities demands the development of model systems with increased physiological relevance. Three-dimensional cell culture techniques incorporate customizable ECM structures in vitro, enabling the assessment of cell–substrate interactions which are central to biophysical signaling. Current tissue engineering applications in animal models are beginning to enable such integration. Indeed, by combining topographical alignment, chemical cues, and electric fields, it was recently demonstrated that myofibroblast could be differentiated from dermal fibroblasts and tuned to enhance wound healing with pronounced matrix reconstruction . The fulAs 3D tissue cultures have become more accessible tools, it has become possible to recapitulate the relationships between matrix geometry and bioelectricity or the impact of tissue orientation on electromagnetic field effects within tractable and scalable platforms. Novel questions can now be addressed: Are long-range bioelectric signals impacted by the polarization of ECM polymers? Can optical signaling be disrupted by ECM composition? Can tumorigenic microenvironments be remodeled by combinations of biophysical signaling patterns? In addition to enabling unprecedented experiments, 3D tissues also permit the integration of implantable materials for enhanced translation of engineered biophysical interventions. To fully harness the potential of biophysical control over tissue plasticity and patterning, 3D tissue culture systems can be used to systematically disentangle determinant factors in ways that were previously impractical when restricted to the use of animal models of cell culture with monolayers. Once the physicochemical complexities of living systems are better understood, the full spectrum of cellular communication will become available to bioengineers in search of means to medically restore or stabilize form and function in the clinical setting.