Motor cortical control of dopamine release dynamics during motor learning

Motor skill learning, which requires knowledge of body position and real-time feedback of performance, is essential for survival and quality of life. In addition to experiencing general motor deficits due to the loss of dopamine neurons, Parkinson’s patients also experience disruption in motor learning. Dopamine signaling from the substantia nigra pars compacta (SNc) to the dorsal striatum plays a crucial role in mediating motor learning as ablation of dopamine neurons in this pathway renders mice incapable of learning a motor skill task while minimally affecting general locomotion. SNc dopamine neurons that project to the DLS receive various excitatory and inhibitory inputs that can modulate its neuronal activity and its downstream dopamine release. Anatomical studies have shown that the motor cortex (M1/2) directly synapses onto DLS-projecting SNc dopamine neurons, however its functional role remains unknown. In Aim 1 and 2 of this proposal, I will test the hypothesis that M1/2 inputs onto DLS-projecting SNc dopamine neurons undergo synaptic plasticity during motor learning and is able to modulate dopamine release in vivo during motor learning. Although dopamine signaling is required for the acquisition of motor skills, the specific pattern and progression of the dopamine signal over the course of motor learning and how it leads to motor learning impairments remain unclear. In Aim 3, I will link dopamine release dynamics in the dorsolateral striatum (DLS), an area that’s been implicated motor learning and habitual behaviors, to specific kinematics and behavioral features across motor learning using an accelerating rotarod. Findings from these proposed studies will shed light on the neural mechanisms of motor cortical control of motor learning and will have broader implications in movement disorders like Parkinson’s Disease. Project Number: 1F32NS141898-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: ManHua Zhu | Institution: NORTHWESTERN UNIVERSITY, CHICAGO, IL | Award Amount: $75,052 | Activity Code: F32 | Study Section: NST-4 Study Section [NST-4] View on NIH RePORTER: https://reporter.nih.gov/project-details/11111594