Orexin neurons mediate temptation-resistant voluntary exercise

Abstract Despite the well-known health benefits of physical activity, many people underexercise; what drives the prioritization of exercise over alternative options is unclear. We developed a task that enabled us to study how mice freely and rapidly alternate between wheel running and other voluntary activities, such as eating palatable food. When multiple alternatives were available, mice chose to spend a substantial amount of time wheel running without any extrinsic reward and maintained this behavior even when palatable food was added as an option. Causal manipulations and correlative analyses of appetitive and consummatory processes revealed this preference for wheel running to be instantiated by hypothalamic hypocretin/orexin neurons (HONs). The effect of HON manipulations on wheel running and eating was strongly context-dependent, being the largest in the scenario where both options were available. Overall, these data suggest that HON activity enables an eat–run arbitration that results in choosing exercise over food.