Abstract:
The Nucleus Accumbens (NAc) is a critical brain region for the effects of psychostimulant drugs. Type-1 cannabinoid receptors (CB(1)), the main elements of the endocannabinoid system (ECS) in the brain, participate in these effects and modulate synaptic functions in the NAc. Besides their neuronal expression, CB(1) receptors are also present in astrocytes, where they contribute to the regulation of synaptic plasticity and behavior. However, the impact of astroglial CB(1) receptors on synaptic plasticity in the NAc and on psychostimulant-induced synaptic and behavioral effects is currently unknown. This study shows that the psychostimulant amphetamine impairs a form of astroglial CB(1) receptor-dependent synaptic plasticity in the NAc of male, but not female mice. Consistently, locomotor effects of amphetamine require astroglial CB(1) receptors in male, but not female mice. These results, by revealing unforeseen mechanisms underlying sex-dependent effects of amphetamine, pave the way to a better understanding of the diverse impact of psychostimulants in women and men.

Abstract:
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.

Abstract:
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 (CB(1)) receptors associated with mitochondrial membranes (mtCB(1)). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB(1) 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 mtCB(1) receptors in noradrenergic neurons to impair NOR consolidation, mtCB(1) 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.

Abstract:
This study investigated in male mice how age modulates the effects of acute 17beta-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 (CB(1)-R) in the aforementioned age-dependent effects of E2. Having confirmed that mRNA expression of CB(1)-R diminishes with age, we then observed that the deleterious effects of E2 on both memory and synaptic efficacy were both prevented by the CB(1)-R antagonist Rimonabant whilst being absent in CB(1)-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 CB(1)-R in mediating E2 deleterious effects in young adulthood. Aging-related reductions in CB(1)-R might thus underlie E2 paradoxical effects across age.

Abstract:
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-HT(1A) 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.

Abstract:
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.

Abstract:
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 Delta(9) -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.

Abstract:
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 Delta(9)-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.

Abstract:
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 15mug/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.

Abstract:
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.