Dopaminergic Degeneration Differentially Modulates Primary Motor Cortex Activity and Motor Behavior in Hemiparkinsonian Rats.

Background/Goal: Parkinson's disease (PD) disrupts dopaminergic transmission, leading to motor deficits and altered activity in the primary motor cortex (M1). While M1 modulation is critical for motor control, its response to dopaminergic degeneration and treatment remains unclear. This study aimed to characterize M1 neuronal activity and motor behavior in hemiparkinsonian rats using in vivo calcium imaging across naïve, lesioned, and levodopa-treated states. METHODS: Thirteen Sprague Dawley rats were injected with GCaMP6f in the M1 and implanted with a GRIN lens and guide cannula targeting the medial forebrain bundle. Calcium imaging and motor behavior were assessed longitudinally using a single pellet reaching test (SPRT) before and after unilateral 6-hydroxydopamine (6-OHDA) lesioning and subsequent levodopa/carbidopa treatment. Dopaminergic lesion severity was quantified via tyrosine hydroxylase immunohistochemistry. Calcium event frequency and influx were analyzed with CNMF-E and statistical modeling. RESULTS: Levodopa treatment improved fine motor performance as shown by a significant reduction in grasp errors (mean difference: -8.91, 95% CI: -16.66 to -1.16, p = 0.031) and increased reaching duration (mean difference: 4.13, 95% CI: 0.94 to 7.32, p = 0.019) compared to the lesioned state. M1 calcium activity showed modulation dependent on lesion severity: low-lesion rats exhibited reduced event frequency (mean difference: 0.04 Hz, 95% CI: 0.001 to 0.08, p = 0.045) and increased influx post-lesion (mean difference: -0.20 z·s, 95% CI: -0.38 to -0.02, p = 0.038), while high-lesion rats showed increased influx only after levodopa treatment (mean difference: -0.34 z·s, 95% CI: -0.52 to -0.16, p = 0.003). Correlation analyses revealed that calcium influx, but not frequency, was negatively correlated with lesion severity during levodopa treatment (Spearman r = -0.857, p = 0.024). CONCLUSION: M1 neuronal activity appears to be differentially modulated by dopaminergic degeneration and levodopa treatment in a lesion-dependent manner. These preliminary findings suggest dynamic cortical responses in PD and support the utility of calcium imaging for monitoring circuit-level changes in disease and therapy. Further research with larger cohorts and complementary methodologies will be necessary to validate and extend these observations.