Francis Chaouloff

Healthy energy balance relies on an equilibrated trade-off between the respective drives for food and exercise. However, the motivation circuitry underlying the choice between these two rewards remains unknown. Here, we developed a neuroeconomic model wherein mice living in operant chambers needed to choose between standard food and wheel running under increasing effort demands. Reward seeking resistance to increasing costs was then quantified using feeding and exercise essential values (EVs). Through conditional genetics and viral approaches, we show that cannabinoid type-1 receptors (CB ₁ Rs) located on GABAergic neurons gate in necessary and sufficient manners exercise EV, exercise preference over feeding and exercise duration per rewarded sequence. Further, we report that these GABAergic neurons are located in the ventromedial striatum in males, but not females. CB ₁ R deletion from medium spiny neurons did not impact exercise motivation, revealing an unforeseen role for ventromedial striatal GABAergic interneurons in effort-based decision-making between food and exercise.

The Nucleus Accumbens (NAc) is a critical brain region for the effects of psychostimulant drugs. Type‐1 cannabinoid receptors (CB₁), 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, CB₁ receptors are also present in astrocytes, where they contribute to the regulation of synaptic plasticity and behavior. However, the impact of astroglial CB₁ 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 CB₁ receptor‐dependent synaptic plasticity in the NAc of male, but not female mice. Consistently, locomotor effects of amphetamine require astroglial CB₁ 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.

It is recognized worldwide that physical exertion provides health benefits. This positive effect is linked to the improvement of numerous functions, including cardiovascular, immunological, metabolic, osteoarticular, and brain functions. The identification of the mechanisms through which physical exercise exerts these health-protective effects is considered essential as it paves the way for future fundamental and therapeutic knowledge (Powell & Paffenbarger, 1985). Among health benefits provided by exercise, those related to central functions have been well documented. In particular, the observations of positive consequences of acute and chronic exercise on emotional behaviors in humans, including through anti-stress properties (Salmon, 2001), have led clinicians to use exercise as a therapeutic tool against several psychopathologies, especially mild depression and anxiety (Martinsen & Morgan, 1997; Raglin, 1997; Salmon, 2001; Ströhle, 2009). Thus, exercise alone, or in combination with subeffective antidepressant/anxiolytic medications, is reported to trigger mood and emotional improvements similar to those elicited by classical antidepressants and anxiolytics (Martinsen & Morgan, 1997; Raglin, 1997).

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.

SUMMARY: The idea that the effects of drugs largely depend on subcellular target location is emerging as a novel predictive factor of their beneficial or adverse outcomes. G protein-coupled type-1 cannabinoid receptors (CB ₁ ) are regulators of several brain functions as well as the main targets of cannabinoid-based medicines. Besides their classical location at plasma membranes, CB ₁ receptors are present at different locations within cells, including in association to mitochondrial membranes (mtCB ₁ ). Here we report the generation and characterization of a mutant mouse line, which lack mtCB ₁ receptors.

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.