Ventromedial striatal GABAergic interneurons sex-dependently gate cost-benefit choices between food and exercise

Abstract 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.