Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activity-dependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here, we report that while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases OPC differentiation, oligodendrocyte generation, and myelin sheath remodeling in the forelimb motor cortex. Immediately followingdemyelination, neurons exhibit hyperexcitability, learning is impaired, and behavioral intervention provides no benefit to remyelination. However, partial remyelination restores neuronal and behavioral function allowing learning to enhance oligodendrogenesis, remyelination of denuded axons, and the ability of surviving oligodendrocytes to generate new myelinsheaths. Previously considered controversial, we show that sheath generation by mature oligodendrocytes is not only possible but also increases myelin pattern preservation following demyelination, presenting a new target for therapeutic interventions. Together, our findings demonstrate that precisely-timed motor learning improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.