Lam, M.; Dehtiarov, O.; Geraghty, A. C.; Yalcin, B.; Duan, L.; Iyer, M.; Schuster, K. H.; Monje, M.; Hughes, E. G.; Zuchero, J. B.

Myelin remodeling is emerging as a dynamic facet of plasticity in the adult brain. Learning and sensory experience induce remodeling of existing myelin sheaths through incompletely understood mechanisms, leaving its causal contribution to adaptive behaviors unclear. Here, we identify activity-dependent exocytosis in mature oligodendrocytes as a key driver of myelin remodeling. Live-cell imaging reveals that neuronal activity stimulates oligodendrocyte exocytosis. Exocytosis in mature oligodendrocytes drives myelin sheath elongation on optogenetically stimulated axons in adult mice. Disrupting exocytosis in pre-existing myelin, but not newly formed myelin, impairs motor skill acquisition, suggesting that remodeling of pre-existing myelin sheaths is required for learning. These results uncover a cellular mechanism that couples neuronal activity to myelin membrane remodeling and provide a molecular handle to interrogate the function of myelin plasticity across different circuits, behaviors, and neurological disorders.