PROJECT SUMMARY In the central nervous system, individual oligodendrocytes produce variable amounts of myelin on different axons. The underlying mechanisms governing how specific amounts of myelin are made on certain axons remains a fundamental question in cellular neurobiology. Recent work has provided evidence that neural activity promotes myelin sheath growth in spinal circuits, yet the signaling mechanisms that function within oligodendrocytes to transduce activity-evoked signaling from axons into selective myelin membrane growth remain unknown. The PI3K-Akt-mTOR signaling pathway is a prime candidate to mediate these events, as it both promotes myelin sheath growth and can be activated in response to neural activity. Using a combination of genetic manipulations and in vivo live-cell imaging of zebrafish larvae, this project seeks to build on this knowledge to further elucidate the intracellular signaling events within oligodendrocytes that drive myelin sheath growth. The proposed work has two parts: Aim 1 will identify a novel regulator of myelin sheath growth and Aims 2 and 3 will test if this mediates mTOR and neural activity-regulated myelin sheath growth. Together, this work will define a signaling axis within oligodendrocytes that mediates myelin sheath growth in response to neural activity.