The role of myelination in cortical circuit function and motor behavior

Project Summary Nearly 1 million people in the United States alone are affected by Multiple Sclerosis (MS). MS is an inflammatory, demyelinating disease of the central nervous system (CNS). While MS is classically regarded as a disease of the white matter, the number of white matter lesions does not correlate with physical disability or cognitive impairment. Recent evidence indicates that gray matter areas have significant myelin loss and increased cortical lesion load is associated with increased cortical atrophy and cognitive decline. Functional imaging of patients with MS reveals increased hyperexcitability within primary motor cortex and throughout the motor network. Moreover, functional recovery in MS patients is associated with normalization of aberrant cortical activity, suggesting a relationship between motor network hyperexcitability and impaired motor behavior. However, our understanding of how myelin loss influences the activity of single neurons, or neural circuits, within grey matter is extremely limited. Our overarching goal is to understand how demyelination results in motor dysfunction. Previously, we used longitudinal characterization of single neuron firing patterns in motor cortex following demyelination to demonstrate early neuronal hyperexcitability that recovers during remyelination. Moreover, we found that enhancing neuronal activity through skilled motor learning after demyelination enhances oligodendrocyte regeneration. However, additional work is needed to determine the dynamic nature of electrophysiological changes across myelin loss and repair to elucidate the neural foundations for behavioral dysfunction. This proposal aims to dive deeper into the cell and circuit mechanisms involved in the relationship between myelin loss and behavioral deficits. By combining three-photon in vivo imaging, high-density electrophysiology, and computational approaches, we will probe the impact of myelin loss across spatial and temporal scales in the motor system, and gain a foundational understanding of the impact of myelin loss on behavior.