Wheel running increases impulsivity through midbrain dopamine signaling in mice

Introduction: Exercise is widely recognized for its benefits to physical and mental health, yet its effects on higher-order cognition, particularly impulsive decision-making, remain incompletely understood. While physical activity is often associated with improved executive function, emerging evidence suggests it may differentially influence distinct cognitive domains. Impulsive choice, often operationalized as a preference for smaller immediate rewards over larger delayed rewards, is a core feature of several neuropsychiatric disorders, including substance use and attention-deficit disorders. The delay-discounting task (DDT) provides a well-established framework to quantify such behavior. Here, we examined whether voluntary wheel running alters impulsive choice in adult male rodents and investigated the role of midbrain dopamine (DA) signaling in mediating these effects.

Methods: Animals were first trained in food self-administration (FR1), followed by initial choice training between a small (1 pellet) and large (3 pellets) reward without delay. During the DDT phase (30 sessions), each session comprised five blocks containing forced- and free-choice trials, with progressively increasing delays to the large reward within-session. Preference for the small reward indexed impulsivity. Based on stable performance at a 60-s delay, animals were classified as low- or high-impulsive. To assess the impact of exercise, subjects were exposed to 1 h/day of wheel running for 5 consecutive days, with wheels either unlocked (voluntary running) or locked (sedentary control) during testing. To study underlying mechanisms, optogenetic approaches were used to manipulate ventral tegmental area (VTA) DA neurons in transgenic DAT-cre mice. Non-contingent stimulation (25 Hz, 1–5 min) was delivered prior to testing, whereas contingent stimulation (25–50 Hz, 20 s) was delivered during lever presses associated with either large or small rewards.

Results: Voluntary wheel running unexpectedly increased impulsive choice, shifting preference toward the smaller immediate reward in both groups, with a more pronounced effect in low-impulsive animals. Non-contingent optogenetic activation of midbrain DA neurons in the ventral tegmental area (VTA) recapitulated this effect, selectively increasing impulsivity in low-impulsive subjects. In contrast, contingent stimulation of VTA DA neurons produced bidirectional effects depending on behavioral context: stimulation paired with large-reward choices reduced impulsivity in high-impulsive animals, whereas stimulation paired with small-reward choices increased impulsivity across both groups. These findings indicate that the timing and contingency of DA signaling critically shape decision-making processes.

Conclusions: Our results reveal a complex interaction between exercise, dopamine signaling, and impulsive choice. While voluntary physical activity and non-contingent DA activation promote impulsive decision-making, particularly in individuals with low baseline impulsivity, precisely timed, action-contingent DA signaling can either attenuate or exacerbate impulsive behavior depending on reward context. These findings highlight the importance of temporal dynamics in dopaminergic modulation of decision-making and suggest that exercise-induced changes in DA function may have context-dependent cognitive consequences. Future studies should investigate circuit-level mechanisms and assess whether these effects generalize across sexes, species, and different forms or durations of exercise.

Key words: Physical exercise, wheel-running, impulsive choice decision-making, dopamine

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