Elucidating the signaling pathways that underlie calcium-dependent myelin remodeling

PROJECT SUMMARY/ABSTRACT Myelin is crucial for efficient neural communication and proper circuit function. Recent evidence shows that myelin is not static but capable of remodeling throughout life, influencing learning, memory, and behavioral adaptation. Calcium signaling is a well-established driver of myelin formation during development, yet the mechanisms underlying activity-dependent calcium signaling in mature myelin and its role in myelin remodeling remain poorly understood. The mechanisms linking neuronal activity to calcium dynamics in myelin sheaths and their structural changes during learning are unexplored. This project will test the hypothesis that learning-induced neuronal activity drives intracellular calcium release through inositol triphosphate receptors (IP3Rs) in myelin, triggering structural remodeling. Aim 1 will use in vivo 2-photon imaging in awake, behaving mice to determine how neuronal activity induces calcium signals in pre-existing myelin and whether these signals predict remodeling. Aim 2 will combine genetic and pharmacological tools to test whether IP3R-mediated calcium release is essential for myelin retraction and motor learning. Results from these studies will elucidate the molecular pathways that mediate activity-dependent myelin remodeling, providing critical insights into how myelin plasticity contributes to neural circuit function. This work has significant implications for understanding the pathophysiology of myelin-related diseases, such as multiple sclerosis, and could uncover novel therapeutic targets for enhancing CNS plasticity and repair.