PROJECT SUMMARY The long-term goal of this project is to understand how oligodendrocytes, which are glial cells of the central nervous system, ensheath specific axons with specialized, proteolipid-rich myelin membrane. To myelinate axons, oligodendrocytes extend numerous membrane processes than spirally wrap axons. However, not all axons are myelinated, and myelinated axons can be covered with different amounts of myelin. Based on observations that brain activity can modify myelin, we hypothesize that signals from axons are communicated to oligodendrocyte processes to direct axon ensheathment and myelination. Using zebrafish as a model system, this project combines in vivo live cell imaging with genetic, optogenetic and pharmacological manipulations to investigate mechanisms that guide formation of myelin on specific axons during development. Specific Aim 1 will test the hypothesis that canonical synaptic proteins mediated axon-oligodendrocyte interactions to regulate myelin sheath formation and growth. Specific Aim 2 will use in vivo imaging of mTOR signaling activity combined with genetic, optogenetic and pharmacological approaches to test the hypothesis that intrasheath mTOR signaling mediates axonal signals to control translation. Completion of these aims will substantially extend our understanding of the cellular and molecular mechanisms by which oligodendrocytes ensheath axons with specific amounts of myelin during development and reveal how neuronal activity might modify axonal myelination. The results of this project have the potential for important new insights to learning, memory and psychiatric disease and to provide a foundation for designing therapeutic strategies to promote myelination of brains damaged by disease or injury.