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. Outstanding questions such as, what are the consequences of demyelination on neural physiology in the intact CNS, how demyelinating injuries affect the acquisition of new skills, and can therapies that can enhance remyelination can restore neural and behavioral function remain unknown. Recently, we have developed new approaches to visualize myelin, oligodendrocytes, and their precursors in the intact mouse brain, as well as longitudinal approaches to record and monitor neural activity in behaving animals. We have also identified novel behavioral interventions that enhance myelin repair. In this application, we propose to capitalize on the dynamics revealed by these techniques to discern the effects of myelin loss and repair on local circuit activity and motor behavior. The objectives of this proposal are: 1) evaluate how myelin loss affects neuronal circuit function and 2) to elucidate the effectiveness of remyelination therapies on restoring neural function and behavior. This proposal will demonstrate the effects of demyelination on cortical neuronal and circuit function in vivo. These studies will validate an in vivo mouse model platform to test efficacy of new therapeutic candidates for MS, and provide clinically relevant data regarding the efficacy of therapies that stimulate endogenous remyelination in MS on restoring neural and behavioral function.