Treadmill exercise rescues motor deficits in parkinsonian mice by modulating striatal D2-MSN activity: evidence from calcium imaging and chemogenetics

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Abstract
Objective: The aim of this study is to investigate whether treadmill exercise alleviates motor dysfunction in a mouse model of Parkinson’s disease (PD) by modulating the excitability of striatal medium spiny neurons expressing dopamine type 2 receptors (D2-MSNs). Methods: A unilateral 6-hydroxydopamine (6-OHDA) injection was performed in the right striatum of D2-Cre mice to establish a hemi-lesioned PD model, with sham-operated mice serving as controls. PD mice were subjected to treadmill exercise (18 m/min, 40 min/day, 5 days/week for 4 weeks). Motor function was evaluated using the open-field test, rotarod, and negative geotaxis test. The excitability of D2-MSNs was assessed via fiber-photometric calcium imaging (ΔF/F, AUC, and peak amplitude), Western blotting for c-Fos protein expression, and double immunofluorescence labeling of D2R and c-Fos. Furthermore, chemogenetic approaches (hM4Di-Gi for inhibition and hM3Dq-Gq for activation) were employed to validate the causal role of D2-MSN excitability in exercise-mediated motor recovery. Results: PD mice exhibited significant motor deficits, characterized by reduced locomotor activity, shortened latency to fall on the rotarod, and increased turning latency in the negative geotaxis test. Calcium imaging and c-Fos expression analyses revealed a marked hyperexcitability of striatal D2-MSNs in PD mice compared to controls ( p < 0.01). Treadmill exercise significantly attenuated this D2-MSN hyperexcitability and concurrently improved all motor performance metrics ( p < 0.01). Chemogenetic inhibition of D2-MSNs mimicked the beneficial effects of exercise in PD mice, whereas chemogenetic activation of these neurons abolished the exercise-induced motor improvements and reversed the reduction in neuronal excitability ( p < 0.01). Conclusion: Our findings demonstrate that striatal D2-MSN hyperexcitability is a critical pathological feature of motor dysfunction in PD mice. Treadmill exercise rescues motor deficits by suppressing this hyperexcitability. These results provide novel insights into the neurobiological mechanisms underlying the therapeutic benefits of physical exercise in Parkinson’s disease.

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