Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. This study demonstrates that optogenetic stimulation of the premotor cortex in awake, behaving mice increases the proliferation of neural progenitor cells and oligodendrocyte precursor cells (OPCs), leading to enhanced oligodendrogenesis and myelination in the deep layers of the premotor cortex and subcortical white matter. This activity-regulated myelination is associated with improved motor function of the corresponding limb. The findings suggest that oligodendrogenesis and myelination are necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement. The study shows that neuronal activity influences OPC function and selectively instructs myelination of an active neural circuit. Optogenetic stimulation of the premotor cortex in Thy1::ChR2 mice resulted in increased cell proliferation, with a significant increase in dividing Olig2-positive cells and EdU-marked OPCs. These findings indicate that neuronal activity promotes the differentiation of OPCs into mature oligodendrocytes and increases myelination, which is associated with improved motor function. The study also shows that neuronal activity-regulated oligodendrogenesis and myelination are necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement. The study further demonstrates that neuronal activity-regulated myelination is associated with an increase in myelin thickness, as evidenced by transmission electron microscopy (TEM) analysis. The g-ratio, which reflects the ratio of axon diameter to the total diameter of the axon and myelin sheath, was significantly decreased in optogenetically stimulated M2 and subcortical fibers compared to control mice, indicating increased myelin thickness. Additionally, the expression of myelin basic protein (MBP) was increased in the M2 and subcortical white matter of optogenetically stimulated mice, consistent with the TEM data. The study also shows that neuronal activity-regulated myelination is associated with improved motor function, as evidenced by CatWalk gait analysis. The study found that optogenetic stimulation of the premotor cortex resulted in improved swing speed of the left forelimb, with no change in other parameters of gait. The findings suggest that oligodendrogenesis and increased myelin thickness in response to neuronal excitation co-correlate with altered motor function 4 weeks later. The study further demonstrates that changes in myelin-forming cells account for the observed behavioral improvement. The findings suggest that oligodendrocyte differentiation and/or myelination are necessary for the motor behavioral improvement observed after neuronal activity in this model. The study also shows that the effects of neuronal activity on OPC proliferation, oligodendrogenesis, and myNeuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. This study demonstrates that optogenetic stimulation of the premotor cortex in awake, behaving mice increases the proliferation of neural progenitor cells and oligodendrocyte precursor cells (OPCs), leading to enhanced oligodendrogenesis and myelination in the deep layers of the premotor cortex and subcortical white matter. This activity-regulated myelination is associated with improved motor function of the corresponding limb. The findings suggest that oligodendrogenesis and myelination are necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement. The study shows that neuronal activity influences OPC function and selectively instructs myelination of an active neural circuit. Optogenetic stimulation of the premotor cortex in Thy1::ChR2 mice resulted in increased cell proliferation, with a significant increase in dividing Olig2-positive cells and EdU-marked OPCs. These findings indicate that neuronal activity promotes the differentiation of OPCs into mature oligodendrocytes and increases myelination, which is associated with improved motor function. The study also shows that neuronal activity-regulated oligodendrogenesis and myelination are necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement. The study further demonstrates that neuronal activity-regulated myelination is associated with an increase in myelin thickness, as evidenced by transmission electron microscopy (TEM) analysis. The g-ratio, which reflects the ratio of axon diameter to the total diameter of the axon and myelin sheath, was significantly decreased in optogenetically stimulated M2 and subcortical fibers compared to control mice, indicating increased myelin thickness. Additionally, the expression of myelin basic protein (MBP) was increased in the M2 and subcortical white matter of optogenetically stimulated mice, consistent with the TEM data. The study also shows that neuronal activity-regulated myelination is associated with improved motor function, as evidenced by CatWalk gait analysis. The study found that optogenetic stimulation of the premotor cortex resulted in improved swing speed of the left forelimb, with no change in other parameters of gait. The findings suggest that oligodendrogenesis and increased myelin thickness in response to neuronal excitation co-correlate with altered motor function 4 weeks later. The study further demonstrates that changes in myelin-forming cells account for the observed behavioral improvement. The findings suggest that oligodendrocyte differentiation and/or myelination are necessary for the motor behavioral improvement observed after neuronal activity in this model. The study also shows that the effects of neuronal activity on OPC proliferation, oligodendrogenesis, and my