Myelin Supports Cortical Circuit Function Underlying Skilled Movement.

Primary motor cortex (M1) is among the most heavily myelinated cortical regions and generates tightly coordinated neuronal activity patterns that drive skilled movement. Activity-dependent myelination is required for motor skill acquisition, and myelin loss in demyelinating diseases such as multiple sclerosis leads to motor impairment. Yet how myelination influences neuronal activity underlying skilled behavior remains unclear. By combining in vivo imaging of oligodendrocytes with high density Neuropixels recordings during dexterous reaching, we demonstrate that cuprizone-induced demyelination impairs movement efficiency, and alters cell-type-specific neuronal activity and synchrony in a manner that predicts motor output. Using a computational model constrained by these data, we identify inhibitory axonal propagation failures as a mechanistic link between myelin loss and altered circuit function. Partial remyelination normalizes cortical network-level metrics and reach consistency but leaves smooth movement impaired, revealing a selective vulnerability in inhibitory circuits. These findings close a critical gap between cellular models of demyelination and clinical motor impairment by demonstrating how myelin supports cortical circuit dynamics driving skilled behavior.