A Direct Primary Motor Cortex-Globus Pallidus Internus Circuit Regulates Both Motor and Non-Motor Symptoms in Parkinson's Disease.

The cortico-basal ganglia (BG) circuit is vital for motor control and Parkinson's disease (PD) symptoms. The Globus Pallidus Internus (GPi) is a principal BG output nucleus and a key target for Deep Brain Stimulation (DBS) in PD treatment. However, the structure and function of the cortico-GPi circuit have not been completely addressed. In the present studies, data demonstrate a direct Primary Motor Cortex (M1)-GPi pathway, bypassing the classical direct, indirect, and hyperdirect pathways. This direct M1-GPi pathway plays an essential role in motor regulation under normal conditions. Importantly, in PD, post-synaptic inhibition of this pathway alleviates motor deficits. Post-synaptic activation of the M1-GPi pathway ameliorates depression symptoms associated with PD but exacerbates the PD motor symptoms. Interventions targeting the pre-synaptic M1-GPi pathway do not significantly affect motor regulation or PD symptoms. It suggests that the M1-GPi pathway may play a crucial role in motor regulation, PD motor symptoms and non-motor symptoms. Aberrant activities of the post-synaptic M1-GPi pathway potentially contributing to PD deficits. And the mechanism of GPi-DBS in PD therapy may involve post-synaptic regulation of M1-GPi pathway activities, rather than the retrograde modulation of pre-synaptic M1-GPi pathways.