Intrinsic Disruption of the M1 Cortical Network in a Mouse Model of Parkinson's Disease.

BACKGROUND Parkinson's disease (PD) disrupts motor performance by affecting the basal ganglia system. Yet, despite the critical position of the primary motor cortex in linking basal ganglia computations with motor performance, its contribution to motor disability in PD is largely unknown. The objective of this study was to characterize the role of the primary motor cortex in PD-related motor disability. METHODS Two-photon calcium imaging and optogenetic stimulation of primary motor cortex neurons was done during performance of a dexterous reach-to-grasp motor task in control and 6-hydroxydopamine-induced PD mice. RESULTS Experimental PD disrupted performance of the reach-to-grasp motor task and especially initiation of the task, which was partially restored by optogenetic activation of the primary motor cortex. Two-photon calcium imaging during task performance revealed experimental-PD affected the primary motor cortex in a cell-type-specific manner. It suppressed activation of output layer 5 pyramidal tract neurons, with greater effects on freeze versus nonfreeze trials. In contrast, it did not attenuate the initial movement-related activation response of layer 2/3 pyramidal neurons while diminishing the late inhibitory phase of their response. At the network level, experimental PD disrupted movement-related population dynamics of the layer 5 pyramidal tract network while almost not affecting the dynamics of the layer 2/3 neuronal population. It also disrupted short- and long-term robustness and stability of the pyramidal tract subnetwork, with reduced intertrial temporal accuracy and diminished reproducibility of motor parameter encoding and temporal recruitment of the output pyramidal tract neurons over repeated daily sessions. CONCLUSIONS Experimental PD disrupts both external driving and intrinsic properties of the primary motor cortex. Motor disability in experimental PD results primarily from the inability to generate robust and stable output motor sequences in the parkinsonian primary motor cortex output layer 5 pyramidal tract subnetwork. © 2021 International Parkinson and Movement Disorder Society.