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  • Book
    David Arnold Purger.
    Digital2015
    Myelin sheaths, specialized segments of oligodendrocyte plasma membranes in the central nervous system, facilitate fast, saltatory conduction of action potentials down axons. Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells. Changes to the fine structure of myelin in a neural circuit are expected to affect conduction velocity of action potentials. Recent evidence from humans and animal models suggests that myelination may be sensitive to experiences during development and adulthood, and that varying levels of neuronal activity may underlie these experience-dependent changes in myelin and myelin-forming cells, perhaps selectively instructing myelination of an active neural circuit. In this thesis, I present work using optogenetic stimulation of premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural and oligodendrocyte precursor cells, promotes oligodendrogenesis and increases myelination within the deep layers of the premotor cortex and subcortical white matter. Neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement. A deeper understanding of adaptive myelination may provide insights into diseases involving damage and dysregulation of myelin and myelin-forming cells.