ALTERED DOPAMINE DYNAMICS UNDERLIE MOTOR SLOWNESS AND REDUCED MOTIVATION IN OBESITY

The global rise in the prevalence of obesity is a pressing public health challenge. Regular physical activity is a cost-effective strategy to support weight management and improve metabolic health. However, many individuals with obesity struggle to adhere to exercise programs. Dopamine signaling from ventral tegmental area (VTA) neurons to the striatum is essential for movement vigor and reinforcement learning. We propose that impaired striatal dopamine signaling reduces engagement in exercise, limiting obesity treatment efficacy. To test our hypothesis, we investigated obesity-related changes in learning and motivated behavior in humans and mice. We assessed learning using a two-arm bandit task. We also measured effort-based motivation in mice using a progressive ratio assay. To link behavioral changes to neurobiological adaptations, we monitored tonic and phasic striatal dopamine signaling using fiber photometry in control and obese mice. These measures were complemented by analysis of dopamine-related gene expression in the striatum and VTA. In the bandit task, obese mice, but not humans, displayed reduced accuracy, consistent with impaired learning. However, both mice and humans with obesity displayed increased retrieval time in the task, a sign of motor slowness. In addition, obese mice exhibited reduced motivation in the progressive ratio task. Fiber photometry revealed reduced tonic and enhanced phasic dopamine signaling, highlighting an altered tonic-phasic balance of dopamine transmission in obesity. Across species and behavioral domains, these results link obesity-related changes in dopamine dynamics to impaired learning, reduced motor vigor, and motivational deficits, providing a mechanistic framework for reduced engagement in physical activity.