Sex-specific effects of exercise on motor coordination and extended basal ganglia physiology

Exercise broadly affects the basal ganglia, brain structures involved in motor coordination. Exercise-induced changes in these regions can improve pathological conditions such as Parkinson's disease and substance use disorders. Importantly, biological sex is a significant factor in the effects of exercise and in the presentation of these basal ganglia-related conditions. Here, we find surprising sex differences in exercise's influence over motor coordination and neural activity across three extended basal ganglia structures: dorsomedial striatum cholinergic interneurons (CINs), substantia nigra pars compacta (SNc) dopaminergic neurons, and caudal pedunculopontine nucleus (PPN) cholinergic neurons. Using voluntary wheel running, accelerating rotarod, ex vivo electrophysiology, and morphological reconstructions, we found that exercise enhances motor coordination, increases SNc excitability, and strengthens excitatory input onto the PPN selectively in female mice. By contrast, exercise increases spontaneous firing rate and reduces dendritic complexity selectively in male CINs. These data reveal sex-specific exercise effects correlated across behavioral and cellular levels.