PROJECT SUMMARY The long-term goal of this research program is to understand how specific axons of the developing central nervous system (CNS) are ensheathed with specific amounts of myelin, a specialized, proteolipid-rich membrane produced by oligodendroglia. During development, subpopulations of neural progenitors produce oligodendrocyte precursor cells (OPCs), which migrate and divide to populate the CNS. Subsequently, some OPCs differentiate as myelinating oligodendrocytes whereas other OPCs persist through adulthood. Importantly, myelin is plastic and can be modified by brain activity. Recent evidence indicates that changes in OPC proliferation, oligodendrocyte differentiation, myelin sheath characteristics and axon selection for myelination contribute to myelin plasticity. However, the molecular mechanisms that regulate myelination, particularly in response to neuronal activity, are poorly understood. The investigations that comprise this research program focus on three broad areas of developmental myelination. First, using single cell RNA-seq data we generated, we will investigate how neural progenitors are specified as OPCs. Second, will axo-glial interactions and mRNA localization promote myelin sheath growth. Third, we will investigate how microglia, the resident innate immune cells of the CNS, modify myelin coverage on axons in response to neuronal activity. We use zebrafish as a model system, which enables us to combine time-lapse imaging with genetic and pharmacological manipulations to observe and test cell behaviors and myelination in an intact, living animal. The results of this research program have the potential to provide important new insights to the developmental basis of learning, memory and psychiatric disease and to provide a foundation for designing therapeutic strategies to promote myelination of brains damaged by disease or injury.