PROJECT SUMMARY/ABSTRACT: Myelin is essential for rapid and precise nerve signaling, and its loss in diseases like multiple sclerosis causes profound disability. Classically, myelin was considered to be inert—hardwired during development to maximize conduction velocity. However, over the last two decades, myelin has been revealed to be surprisingly dynamic in the adult brain and to possess broader roles in plasticity and metabolic support of neurons. We recently discovered that when mice learn a new motor task, the local pattern of myelin remodels in the motor cortex, specifically on neurons activated during learning. Remodeling occurs in two stages: existing sheaths shorten during learning, then new sheaths form after learning. The role of myelin remodeling in learning remains a major knowledge gap, largely due to our lack of tools to experimentally perturb sheath dynamics. In this application, we propose to investigate the cellular mechanisms that drive learning-induced sheath remodeling, then use this knowledge to test the extent to which remodeling is required for learning. Our central hypothesis is that oligodendrocyte calcium signaling is the key mechanistic link by which neural activity is sensed and translated into sheath dynamics—sheath elongation and/or shortening. The objectives of this proposal are: (1) Determine whether calcium signaling is require for myelin sheath shortening during learning. (2) Determine whether calcium signaling is required for new myelin sheath formation after learning. (3) Determine whether calcium signaling-dependent myelin remodeling regulates motor behavior. By combining our labs’ complementary expertise in longitudinal in vivo imaging of myelin dynamics during learning, myelin cell biology, and genetic tool building, our team is uniquely positioned to address these aims and make significant contributions to our understanding of the cell biological mechanisms that control myelin remodeling and its role in learning. Approaches used in this proposal will build a platform from which additional molecular mechanisms of myelin plasticity can be evaluated. These studies will thus provide important, novel insights into mechanisms underlying brain plasticity and may lead to therapies to promote the regeneration of lost myelin and recovery of function in diseases like multiple sclerosis and after stroke.