Neuronal Activity Promotes Oligodendrogliogenesis and Myelination in the Mammalian Brain (S42.004)

OBJECTIVE: In the present study, we investigate the role of neuronal activity in directing the proliferation, differentiation, and myelination of oligodendroglial lineage cells in the mammalian motor cortex. BACKGROUND: Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPC). While previous work supports the concept that electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit, direct in vivo evidence has been lacking to date. DESIGN/METHODS: We use optogenetic stimulation of motor cortex in awake, behaving mice at frequencies identical to the physiological firing rates of cortical layer V Betz cells to evoke a behavioral response. Using immunohistochemistry, quantitative confocal microscopy and transmission electron microscopy, we analyze the dynamics of neural and oligodendrocyte precursor cells, their daughter oligodendrocytes, and the resulting changes in deep cortical myelination. RESULTS: We demonstrate that neuronal electrical activity elicits a brisk mitogenic response of neural progenitor and oligodendrocyte precursor cells, promotes oligodendrogliogenesis and increases myelination within the deep layers of the motor cortex and local subcortical white matter. We further show that this neuronal activity-regulated oligodendrogliogenesis and myelination produces lasting behavioral consequences, with improved motor function of the corresponding limb. New mature oligodendrocyte production is necessary for the observed motor function improvement, as epigenetic blockade of oligodendrocyte precursor differentiation prevents the activity-regulated behavioral improvement without affecting baseline behavior. CONCLUSIONS: These results provide the first in vivo evidence of neuronal activity-regulated myelin development and remodeling, supporting experience-based myelin adaptation as a form of neural plasticity in the mammalian brain and highlighting potential strategies for regeneration. Disclosure: Dr. Purger has nothing to disclose. Dr. Gibson has nothing to disclose. Dr. Mount has nothing to disclose. Dr. Goldstein has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Inema has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Bieri has nothing to disclose. Dr. Zuchero has nothing to disclose. Dr. Barres has nothing to disclose. Dr. Woo has nothing to disclose. Dr. Vogel has nothing to disclose. Dr. Monje has nothing to disclose.