Emergence of Task-Related Motor Cortical Dysfunction in Mice with Progressive Parkinsonism

The primary motor cortex (M1) exhibits substantial changes in Parkinsons disease (PD). However, the temporal relationship between midbrain dopamine (DA) neurodegeneration, M1 circuit dysfunction, and motor symptoms remains poorly understood. Using the MitoPark mice, we investigated the time course of M1 cellular dysfunction during progressive DA loss. MitoPark mice developed gradually impaired skilled movements at a moderate motor stage of Parkinsonism. The motor deficits were associated with reduced cellular activity, impaired neuronal coactivation, and decreased proportion of responsive M1 pyramidal neurons. Moreover, the corticospinal (CSp), but not the intratelencephalic (IT), neurons showed a selective reduction in cellular activity during reaches. At the population level, M1 pyramidal neurons included heterogeneous functional clusters in relation to skilled movements and their stability in longitudinal encoding of movement degraded substantially in MitoPark mice. Together, these results delineate the emergence of M1 circuit pathophysiology at cellular and neural population levels during progressive Parkinsonism.