Unravelling the Neural Basis of Bimanual Coordination in Mouse Motor Cortex - PROJECT ABSTRACT In daily life, we use both hands to complete a wide variety of tasks as we navigate the world. Buttoning a shirt, preparing food, and driving a car rely on the ability to coordinate the movement of both hands freely and flexibly in pursuit of a goal. When people with motor disorders like Parkinson’s Disease (PD) lose their capacity to coordinate bimanual movement, these daily tasks become challenging with great detriment to their self-sufficiency and quality of life. Deficits in bimanual coordination—the structured, simultaneous movement of both hands—present early in the progression of PD and are resistant to classic modes of treatment. It is thought that a network of brain regions including the primary motor cortex and the supplementary motor area works together to coordinate the movement of both hands. Yet how populations of neurons in these brain areas organize their activity to achieve bimanual coordination and how these patterns degrade in PD remain unclear. To answer these questions, I will investigate the organization of activity patterns across neurons underlying the movement of both forelimbs in freely behaving healthy mice (Aim 1) and the MitoPark mouse model of PD-like pathology (Aim 2). The MitoPark model is a genetic model of PD that effectively captures the progressive onset of motor symptoms in PD through the selective disruption of mitochondrial function in dopaminergic neurons. To quantify whole-body motor coordination, I will use a combination of 3D tracking, wireless in vivo electrophysiology, and latent variable modeling. To encourage complex, naturalistic movement, I have designed a novel behavioral assay for bimanual coordination in which mice explore and climb in a transparent 3D environment that resembles their natural burrow structure. In Aim 1, I will track the 3D movement of healthy mice in daily sessions over the course of three weeks while wirelessly recording their neural activity in primary motor cortex (MOp) and secondary motor cortex (MOs). With canonical correlation analysis (CCA), a linear method for simultaneous dimensionality reduction, I will identify latent patterns of neural activity that covary with the movement of each forelimb. I hypothesize that these patterns occupy distinct subspaces of the population activity in MOp to enable precise, individuated forelimb control while occupying overlapping subspaces in MOs to facilitate coordinated movement. In Aim 2, I will use 3D tracking and wireless electrophysiology to capture the movement and neural activity of three cohorts of MitoPark mice at different stages of PD-like pathology. I hypothesize that, as deficits to bimanual coordination increase in severity with MitoPark progression, patterns of MOs activity underlying left and right limb movement will become more distinct—a neural population-level mechanism of motor dysfunction that could be targeted by future therapies relying on shifting neural dynamics toward a healthy state.
