Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure.

Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs.

[Exercise for the promotion of mental health : Putative mechanisms, recommendations, and scientific challenges]. / L'exercice physique pour la santé mentale : mécanismes, recommandations, recherches futures.

The idea of applying various forms of physical activity for the betterment of physical health and the reduction of chronic medical conditions is ubiquitous. Despite evidence of successful applications of physical activity for improvement of mental health dating back to antiquity, it has until recent years remained unconventional to consider exercise as an intervention strategy for various mental health conditions. The past two decades, however, have seen a relative explosion of interest in understanding and applying various programs and forms of exercise to improve mental health. Here, our purpose is to provide a comprehensive and updated overview of the application of exercise as a strategy for improving mental health. In the present paper we first summarize contemporary research regarding short- and long-term impacts of exercise on mental health. Then an overview of the putative mechanisms and neurobiological bases underpinning the beneficial effects of exercise is provided. Finally, we suggest directions for future research as well as a series of concrete recommendations for clinicians who wish to prescribe physical activity as part of patient mental health management.

Mitochondrial cannabinoid receptors gate corticosterone impact on novel object recognition.

Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB1) receptors associated with mitochondrial membranes (mtCB1). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB1 receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB1 receptors in noradrenergic neurons to impair NOR consolidation, mtCB1 receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.

Age-dependent effects of estradiol on temporal memory: A role for the type 1 cannabinoid receptor?

This study investigated in male mice how age modulates the effects of acute 17ß-estradiol (E2) on dorsal CA1 (dCA1)-dependent retention of temporal associations, which are critical for declarative memory. E2 was systemically injected to young (3-4 months old) and aged (22-24 months old) adult mice either (i) 1 h before the acquisition of an auditory trace fear conditioning (TFC) procedure allowing the assessment of temporal memory retention 24 h later or (ii) during in vivo electrophysiological recordings of CA3 to dCA1 synaptic efficacy under anesthesia. In young mice, E2 induced parallel dose-dependent reductions in memory and synaptic efficacy, i.e. an impairment in TFC retention and a long-term (NMDA receptor-dependent) depression of dCA1 synaptic efficacy as assessed by field excitatory postsynaptic potentials. In contrast, E2 tended to improved TFC retention whilst failing to change synaptic efficacy in aged mice. Age-dependent effects of E2 treatment were confirmed by immunohistochemical analyses of TFC acquisition-elicited dCA1 Fos activation. Thus, such an activation was respectively reduced and enhanced in young and aged E2-treated mice, compared to vehicle treatments. Hippocampal mRNA expression of estrogen receptors by RT-PCR analyses revealed an age-related increase in each receptor mRNA expression. In keeping with the key role of the endocannabinoid system in memory processes and CA3 to dCA1 synaptic plasticity, we next examined the role of cannabinoid type 1 receptors (CB1-R) in the aforementioned age-dependent effects of E2. Having confirmed that mRNA expression of CB1-R diminishes with age, we then observed that the deleterious effects of E2 on both memory and synaptic efficacy were both prevented by the CB1-R antagonist Rimonabant whilst being absent in CB1-R knock out mice. This study (i) reveals age-dependent effects of acute E2 on temporal memory and CA3 to dCA1 synaptic efficacy and (ii) suggests a key role of CB1-R in mediating E2 deleterious effects in young adulthood. Aging-related reductions in CB1-R might thus underlie E2 paradoxical effects across age.

Insulin modulates emotional behavior through a serotonin-dependent mechanism.

Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.

Subcellular specificity of cannabinoid effects in striatonigral circuits.

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior.

Cannabis and exercise: Effects of Δ9-tetrahydrocannabinol on preference and motivation for wheel-running in mice.

Recent surveys have revealed close links between cannabis and exercise. Specifically, cannabis usage before and/or after exercise is an increasingly common habit primarily aimed at boosting exercise pleasure, motivation, and performance whilst facilitating post-exercise recovery. However, whether these beliefs reflect the true impact of cannabis on these aspects of exercise is unknown. This study has thus examined the effects of cannabis' main psychoactive ingredient, namely Δ9-tetrahydrocannabinol (THC), on (i) mouse wheel-running preference and performance and (ii) running motivation and seeking behaviour. Wheel-running preference and performance were investigated using a T-maze with free and locked wheels located at the extremity of either arm. Running motivation and seeking were assessed by a cued-running operant task wherein wheel-running was conditioned by nose poking. Moreover, because THC targets cannabinoid type 1 (CB1) receptors, i.e. receptors previously documented to control running motivation, this study also assessed the role of these receptors in running preference, performance, and craving-like behaviour. Whilst acute blockade or genetic deletion of CB1 receptors decreased running preference and performance in the T-maze, THC proved ineffective on either variable. The failure of THC to affect running variables in the T-maze extended to running motivation, as assessed by cued-running under a progressive ratio (PR) reinforcement schedule. This ineffectiveness of THC was not related to the treatment protocol because it successfully increased motivation for palatable food. Although craving-like behaviour, as indexed by a cue-induced reinstatement of running seeking, was found to depend on CB1 receptors, THC again proved ineffective. Neither running motivation nor running seeking were affected when CB1 receptors were further stimulated by increasing the levels of the endocannabinoid 2-arachidonoylglycerol. These results, which suggest that the drive for running is insensitive to the acute stimulation of CB1 receptors, raise the hypothesis that cannabis is devoid of effect on exercise motivation. Future investigation using chronic administration of THC, with and without other cannabis ingredients (e.g. cannabidiol), is however required before conclusions can be drawn.

Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons.

Physical exercise, which can be addictogenic on its own, is considered a therapeutic alternative for drug craving. Exercise might thus share with drugs the ability to strengthen excitatory synapses onto ventral tegmental area (VTA) dopaminergic neurones, as assessed by the ratio of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) to NMDA receptor (NMDAR)-mediated EPSCs. As did acute cocaine, amphetamine, or Δ9 -tetrahydrocannabinol (THC) pretreatments, an acute 1-h wheel-running session increased the AMPAR/NMDAR ratio in VTA dopaminergic neurones. To dissect the respective influences of wheel-running seeking and performance, mice went through an operant protocol wherein wheel-running was conditioned by nose poking under fixed ratio schedules of reinforcement. Conditioned wheel-running increased the AMPAR/NMDAR ratio to a higher extent than free wheel-running, doing so although running performance was lower in the former paradigm than in the latter. Thus, the cue-reward association, rather than reward consumption, played a major role in this increase. The AMPAR/NMDAR ratio returned to baseline levels in mice that had extinguished the cued-running motivated task, but it increased after a cue-induced reinstatement session. The amplitude of this increase correlated with the intensity of exercise craving, as assessed by individual nose poke scores. Finally, cue-induced reinstatement of running seeking proved insensitive to acute cocaine or THC pretreatments. Our study reveals for the first time that the drive for exercise bears synaptic influences on VTA dopaminergic neurones which are reminiscent of drug actions. Whether these influences play a role in the therapeutic effects of exercise in human drug craving remains to be established.

The ergogenic impact of the glucocorticoid prednisolone does not translate into increased running motivation in mice.

Glucocorticoids, such as prednisolone, are considered sport doping agents owing to their ergogenic properties. These are accounted for by peripheral mechanisms associated with energetic and anti-inflammatory processes. However, because glucocorticoids target brain tissues, it is likely that these ergogenic impacts are associated with central effects. One of these might be reward motivation, which relies on glucocorticoid receptor-expressing mesocorticolimbic dopaminergic neurons. In keeping with this possibility, this study has explored in mice whether repeated prednisolone administration (5 or 15 µg/ml of drinking water for 10 days) affected intrinsic motivation for running, a strong reinforcer in rodents. Running motivation was assessed by means of a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses under fixed (FR), and then progressive (PR), ratio reinforcement schedules. Sub-chronic ingestion of prednisolone decreased the running distance covered during each rewarded sequence under FR schedules. This finding did not extend to wheel-running performances in mice provided free (i.e. unconditioned) wheel-running opportunities. Running motivation, as estimated under a PR reinforcement schedule, was found to be decreased (lowest concentration) or to remain unaffected (highest concentration) by prednisolone concentration. Lastly, an inter-individual analysis of the respective effects of prednisolone on muscular endurance (as assessed in the wire grid-hanging test) and on running motivation indicated that the former was not predictive of the latter. This observation suggests that prednisolone ergogenic impacts might occur without any concomitant increase in intrinsic exercise motivation.

Beyond the Activity-Based Anorexia Model: Reinforcing Values of Exercise and Feeding Examined in Stressed Adolescent Male and Female Mice.

Anorexia nervosa (AN), mostly observed in female adolescents, is the most fatal mental illness. Its core is a motivational imbalance between exercise and feeding in favor of the former. The most privileged animal model of AN is the "activity-based anorexia" (ABA) model wherein partly starved rodents housed with running wheels exercise at the expense of feeding. However, the ABA model bears face and construct validity limits, including its inability to specifically assess running motivation and feeding motivation. As infant/adolescent trauma is a precipitating factor in AN, this study first analyzed post-weaning isolation rearing (PWIR) impacts on body weights and wheel-running performances in female mice exposed to an ABA protocol. Next, we studied through operant conditioning protocols i) whether food restriction affects in a sex-dependent manner running motivation before ii) investigating how PWIR and sex affect running and feeding drives under ad libitum fed conditions and food restriction. Besides amplifying ABA-elicited body weight reductions, PWIR stimulated wheel-running activities in anticipation of feeding in female mice, suggesting increased running motivation. To confirm this hypothesis, we used a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses. It was first observed that food restriction increased running motivation in male, but not female, mice. When fed grouped and PWIR mice were tested for their running and palatable feeding drives, all mice, excepted PWIR males, displayed increased nose poke responses for running over feeding. This was true when rewards were proposed alone or within a concurrent test. The increased preference for running over feeding in fed females did not extend to running performances (time, distance) during each rewarded sequence, confirming that motivation for, and performance during, running are independent entities. With food restriction, mice displayed a sex-independent increase in their preference for feeding over running in both group-housed and PWIR conditions. This study shows that the ABA model does not specifically capture running and feeding drives, i.e. components known to be affected in AN.

The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors.

The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.

An Operant Conditioning Task to Assess the Choice between Wheel Running and Palatable Food in Mice.

Wheel running, especially in the homecage, has been widely used to study the neurobiology of exercise because animal tends to use it voluntarily. However, as for each reward, its consumption (in the present case, running performance) does not specifically provide information on its incentive value, i.e., the extent to which animals are motivated to run independently from their consumption of that reward. This is a major drawback, especially when focusing on the neurobiology governing the pathological imbalances between exercise and e.g., feeding (obesity, anorexia nervosa). Yet, few studies have shown that operant conditioning wherein wheel-running is used as a reinforcer that can be "consumed" after nose-poking or lever-pressing allows to distinguish motivation from consumption. Thus, nose-poking or lever-pressing under a progressive ratio schedule of reinforcement in animals trained under fixed ratio reinforcement schedules provides, through the so-called breakpoint, an index of running motivation. As compared to wheel-running, numerous studies have used food as a reinforcer, which helped to uncover the neurobiology of feeding. However, to our knowledge, there is no paradigm allowing the assessment of the choice between running and feeding when presented in concurrence, with the possibility to measure a priori the motivation for each reward. Herein, we describe a protocol that first permits to measure the drive for each of these two rewards before it allows to measure the preference for one over the other in a reward choice setting. This paradigm could help to better characterize the neurobiology underlying pathological imbalances between physical activity and feeding, which is the core feature of eating disorders.

Chemical Proteomics Maps Brain Region Specific Activity of Endocannabinoid Hydrolases.

The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate endocannabinoid-mediated activation of the cannabinoid CB1 receptor. Monitoring the activities of these endocannabinoid hydrolases in different brain regions is, therefore, key to gaining insight into spatiotemporal control of CB1 receptor-mediated physiology. We have employed a comparative chemical proteomics approach to quantitatively map the activity profile of endocannabinoid hydrolases in various mouse brain regions at the same time. To this end, we used two different activity-based probes: fluorophosphonate-biotin (FP-biotin), which quantifies FAAH, ABHD6, and MAG-lipase activity, and MB108, which detects DAGL-α, ABHD4, ABHD6, and ABHD12. In total, 32 serine hydrolases were evaluated in the frontal cortex, hippocampus, striatum, and cerebellum. Comparison of endocannabinoid hydrolase activity in the four brain regions revealed that FAAH activity was highest in the hippocampus, and MAGL activity was most pronounced in the frontal cortex, whereas DAGL-α was most active in the cerebellum. Comparison of the activity profiles with a global proteomics data set revealed pronounced differences. This could indicate that post-translational modification of the endocannabinoid hydrolases is important to regulate their activity. Next, the effect of genetic deletion of the CB1 receptor was studied. No difference in the enzymatic activity was found in the cerebellum, striatum, frontal cortex, and hippocampus of CB1 receptor knockout animals compared to wild type mice. Our results are in line with previous reports and indicate that the CB1 receptor exerts no regulatory control over the basal production and degradation of endocannabinoids and that genetic deletion of the CB1 receptor does not induce compensatory mechanisms in endocannabinoid hydrolase activity.

Running per se stimulates the dendritic arbor of newborn dentate granule cells in mouse hippocampus in a duration-dependent manner.

Laboratory rodents provided chronic unlimited access to running wheels display increased neurogenesis in the hippocampal dentate gyrus. In addition, recent studies indicate that such an access to wheels stimulates dendritic arborization in newly formed neurons. However, (i) the presence of the running wheel in the housing environment might also bear intrinsic influences on the number and shape of new neurons and (ii) the dendritic arborization of new neurons might be insensitive to moderate daily running activity (i.e., several hours). In keeping with these uncertainties, we have examined neurogenesis and dendritic arborization in newly formed granular cells in adult C57Bl/6N male mice housed for 3 weeks under standard conditions, with a locked wheel, with a running wheel set free 3 h/day, or with a running wheel set permanently free. The results indicate that the presence of a blocked wheel in the home cage increased cell proliferation, but not the number of new neurons while running increased in a duration-dependent manner the number of newborn neurons, as assessed by DCX labeling. Morphological analyses of the dendritic tree of newborn neurons, as identified by BrdU-DCX co-staining, revealed that although the presence of the wheel stimulated their dendritic architecture, the amplitude of this effect was lower than that elicited by running activity, and was found to be running duration-dependent.

To stress or not to stress: a question of models.

Stress research is a rapidly evolving field that encompasses numerous disciplines ranging from neuroscience to metabolism. With many new researchers migrating into the field, navigating the hows and whys of specific research questions can sometimes be enigmatic given the availability of so many models in the stress field. Additionally, as with every field, there are many seemingly minor experimental details that can have dramatic influences on data interpretation, although many of these are unknown to those not familiar with the field. The aim of this overview is to provide some suggestions and points to guide researchers moving into the stress field and highlight relevant methodological points that they should consider when choosing a model for stress and deciding how to structure a study. We briefly provide a primer on the basics of endpoint measurements in the stress field, factors to consider when choosing a model for acute stress, the difference between repeated and chronic stress, and importantly, influencing variables that modulate endpoints of analysis in stress work.

Opposite control of frontocortical 2-arachidonoylglycerol turnover rate by cannabinoid type-1 receptors located on glutamatergic neurons and on astrocytes.

This study examined the respective influences of cannabinoid type-1 (CB1) receptors expressed either in forebrain GABAergic neurons, in cortical glutamatergic neurons, or in astrocytes on the turnover rates of the endocannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), and the non-cannabinoid N-acylethanolamides, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), in mouse forebrain regions. To this end, conditional mutant mice lacking CB1 receptors from either of these cell types were pre-treated systemically with JZL195, a dual inhibitor of fatty acid amide hydrolase, the enzyme degrading AEA, PEA, and OEA, and of monoacylglycerol lipase, the main 2-AG-degrading enzyme. The analyses of frontocortical, hippocampal, and striatal AEA, 2-AG, PEA, and OEA concentrations revealed that their respective baseline concentrations were not influenced by the mouse genotype. On the other hand, the accumulation of frontocortical and/or hippocampal 2-AG levels in JZL195-pre-treated mice was dependent on the mouse genotype. Thus, JZL195-induced 2-AG accumulation rates were diminished in the frontal cortex of mice lacking CB1 receptors in glutamatergic neurons while their respective values were increased in the frontal cortex and hippocampus of mice lacking these receptors in astrocytes. These genotypic differences occurred with parallel and proportionate changes in the fractional rate constants for degradation of 2-AG, thus providing a mechanism whereby the baseline levels of 2-AG remained constant between genotypes. Besides suggesting a cell-type-specific control of frontocortical and/or hippocampal 2-AG synthesis and degradation rates by CB1 receptors, this study highlights the interest of assessing endocannabinoid turnover rates when questioning the status of the endocannabinoid system.

Duration- and environment-dependent effects of repeated voluntary exercise on anxiety and cued fear in mice.

Several studies have indicated that animal models of exercise, such as voluntary wheel running, might be endowed with anxiolytic properties. Using the light/dark test of unconditioned anxiety, we have reported that one confounding factor in the estimation of wheel running impacts on anxiety might be the housing condition of the sedentary controls. The present mouse study analyzed whether the aforementioned observation in the light/dark test (i) could be repeated in the elevated plus-maze and social interaction tests of unconditioned anxiety, (ii) extended to conditioned anxiety, as assessed during cued fear recall tests, and (iii) required unlimited daily access to the running wheel. Housing with a locked wheel or with a free wheel that allowed limited or unlimited running activity triggered anxiolysis in the light/dark test, but not in the elevated plus-maze test, compared to standard housing. In the social interaction test, the duration, but not the number, of social contacts was increased in mice provided unlimited (but not limited) access to a wheel, compared to standard housing or housing with a locked wheel. Lastly, freezing responses to a cue during fear recall tests indicated that the reduction in freezing observed in mice provided limited or unlimited access to the wheels was fully accounted for by housing with a wheel. Besides confirming that the housing condition of the sedentary controls might bias the estimation of the effects of wheel running on anxiety, this study further shows that this estimation is dependent on the test used to assess anxiety.

Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor.

Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expose investigators to risks of false positive and/or false negative results. As an example, the functional presence of cannabinoid type 1 (CB1) receptors on brain mitochondrial membranes (mtCB1) was recently reported and rapidly challenged, claiming that the original observation was likely due to artifact results. Here, we addressed this issue by directly comparing the procedures used in the two studies. Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria. These data further underline the importance of adapted experimental procedures to study brain mitochondrial functions.

Stress switches cannabinoid type-1 (CB1) receptor-dependent plasticity from LTD to LTP in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) exerts a coordinated modulation of the psychoneuroendocrine responses to stress. However, how acute stress impacts on BNST in vivo plasticity is a crucial question that still remains unanswered. Here, neurons from the anterior portion of the BNST (aBNST) were recorded in vivo during and after stimulation of their medial prefrontal cortical (mPFC) afferents. In C57BL/6N mice, a 1 h restraint stress induced a switch from long-term depression (LTD) to long-term potentiation (LTP) in the aBNST after a 10 Hz mPFC stimulation. This switch was independent from glucocorticoid receptor stimulation. Because the endocannabinoid system regulates aBNST activity, we next examined the role of cannabinoid type-1 receptors (CB1-Rs) in these changes. Mutant mice lacking CB1-Rs (CB1(-/-) mice) displayed a marked deficit in the ability to develop plasticity under control and stress conditions, compared with their wild-type littermates (CB1(+/+) mice). This difference was not accounted for by genetic differences in stress sensitivity, as revealed by Fos immunohistochemistry analyses. Local blockade of CB1-Rs in the aBNST and the use of mutant mice bearing a selective deletion of CB1-Rs in cortical glutamatergic neurons indicated that stress-elicited LTP involved CB1-Rs located on aBNST excitatory terminals. These results show that acute stress reverts LTD into LTP in the aBNST and that the endocannabinoid system plays a key role therein.