The cannabinoid receptor 1 mediates exercise-induced improvements of motor skill learning and performance in parkinsonian mouse

The endocannabinoid system (eCBs) modulates corticostriatal circuits through cannabinoid receptor 1 (CB1R). These circuits are crucial for encoding goal-directed and habitual learning behaviors and are implicated in the occurrence and progression of Parkinson's disease (PD). While exercise has been shown to enhance motor performance and reverse learning deficits in PD patients, the underlying molecular mechanisms remain unclear. We hypothesized that a treadmill training program could rescue changes in striatal plasticity and ameliorate early motor and cognitive deficits in mice subjected to an intrastriatal 6-hydroxydopamine injection. Our findings demonstrated that exercise training would improve motor performance and learning abilities in PD mice. Moreover, both immunofluorescence and reverse transcription polymerase chain reaction results suggested that corticostriatal activation decreased CB1R expression in the dorsomedial striatum of PD mice but increased expression in the substantia nigra pars reticulata following treadmill exercise. These results suggest that dysregulated CB1R expression is associated with the pathogenesis of Parkinsonism, highlighting the vital role of the CB1R in corticostriatal pathway functionality enhanced by exercise. Our results suggest the potential benefits of treadmill exercise in alleviating Parkinsonism, providing valuable insights into future potential treating strategies.