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

Lewitus, V. J.; Russ, L. A.; Scott, C. B.; Kruszewski, O. M.; Shautidze, G.; Colon, Z. A.; Zhang, S. Q.; Walker, J. A.; Fernandez, A. B.; Croom, M. R.; Aleman, V. G.; Evans, R. C.

doi:10.64898/2026.04.24.720719

bioRxiv · 10.64898/2026.04.24.720719

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

Lewitus, V. J.·Russ, L. A.·Scott, C. B.·Kruszewski, O. M.·Shautidze, G.·Colon, Z. A.·Zhang, S. Q.·Walker, J. A.·Fernandez, A. B.·Croom, M. R.·Aleman, V. G.·Evans, R. C.

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Abstract

Exercise broadly affects the basal ganglia, brain structures involved in motor coordination. Exercise-induced changes in these regions can improve pathological conditions such as Parkinsons 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 exercises 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/720719v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@d0f755org.highwire.dtl.DTLVardef@11e2335org.highwire.dtl.DTLVardef@199a591org.highwire.dtl.DTLVardef@44e4d9_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIOne week of exercise enhances motor coordination in females but not males C_LIO_LIExercise increases SNc excitability and excitatory input onto the PPN in females C_LIO_LIExercise increases dorsomedial striatal cholinergic neurons activity in males C_LIO_LIBaseline sex differences in morphology of striatal cholinergic and SNc neurons C_LI

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Lewitus, V. J., Russ, L. A., Scott, C. B., Kruszewski, O. M., Shautidze, G., Colon, Z. A., Zhang, S. Q., Walker, J. A., Fernandez, A. B., Croom, M. R., Aleman, V. G., Evans, R. C.. 2026-04-24. Sex-specific effects of exercise on motor coordination and extended basal ganglia physiology.. https://doi.org/10.64898/2026.04.24.720719

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