Myelin loss disrupts neural synchrony directing skilled motor behavior in mouse primary motor cortex

Synchronization of neural activity is a fundamental component of information processing in the nervous system. Precise axonal conduction is required for correlated spiking activity between pairs of neurons at the millisecond timescale. Previous studies report that myelin loss results in deficient action potential propagation and a loss of population synchronization in the gamma band. Loss of myelination in demyelinating diseases like multiple sclerosis (MS) results in impaired motor function in patients with MS. However, a deeper understanding of how demyelination alters the timing, synchrony, and connectivity of motor microcircuits underlying behavioral impairments is needed. To determine the effect of demyelination on microcircuits required for skilled motor performance, high density Neuropixel recordings were performed in mice trained in a dexterous reaching task. Demyelination was induced via oral delivery of cuprizone, and concurrent in vivo two-photon imaging tracked myelin loss and repair in MOBP-EGFP transgenic mice. We found that varying degrees of demyelination concomitantly altered pairwise coordination of cortical neurons and behavioral performance. Furthermore, we found that demyelination caused layer-specific and cell-type specific hyperexcitability. Unexpectedly, we found that hyperexcitability was closely correlated with higher levels of remyelination and behavioral performance. Understanding how demyelination alters cortical microcircuits and neural synchrony to influence behavior will provide insights into the role of myelin in neural computation and strategies for recovery from myelin loss.