This study investigates the role of neuronal activity in promoting oligodendrogenesis and myelination in the mammalian brain. Using optogenetic stimulation of the premotor cortex in awake, behaving mice, the authors demonstrate that neuronal activity elicits a mitogenic response in neural progenitor cells and oligodendrocyte precursor cells (OPCs), leading to increased oligodendrogenesis and myelination within the deep layers of the premotor cortex and subcortical white matter. This neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. The study further shows that epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the observed behavioral improvement, indicating that these processes are necessary for the functional enhancement. The findings highlight the plastic nature of myelin in the mammalian brain and suggest that experience can modulate neural circuit function through direct effects on myelin-forming cells.This study investigates the role of neuronal activity in promoting oligodendrogenesis and myelination in the mammalian brain. Using optogenetic stimulation of the premotor cortex in awake, behaving mice, the authors demonstrate that neuronal activity elicits a mitogenic response in neural progenitor cells and oligodendrocyte precursor cells (OPCs), leading to increased oligodendrogenesis and myelination within the deep layers of the premotor cortex and subcortical white matter. This neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. The study further shows that epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the observed behavioral improvement, indicating that these processes are necessary for the functional enhancement. The findings highlight the plastic nature of myelin in the mammalian brain and suggest that experience can modulate neural circuit function through direct effects on myelin-forming cells.