How myelin regulates vestibular circuit function and balance behaviors - SUMMARY/ABSTRACT Loss of myelin, as seen in conditions like multiple sclerosis, frequently leads to balance issues. These dis- ruptions in balance are attributed to the compromised function of neural circuits associated with the vestibu- lar system. Despite the clinical significance of this problem, our understanding of how myelin loss affects the functioning of these circuits remains limited. Consequently, there is a pressing need to elucidate the mecha- nisms underlying the impact of myelin, its loss and restoration on circuit function. To address these questions, I propose using zebrafish larvae as a model. They allow for in vivo observation of myelinated axons and func- tional/behavioral testing. My preliminary data using a pharmacological hypomyelination model showed specific changes in pitch sensitivity linked to a particular circuit, the vestibulospinal circuit. My aim is to understand the role of myelin in behavior and circuit function, as well as the deficits caused by myelin loss and potential rescue through remyelination. In the K99 phase, I will (1) investigate changes in vestibulospinal circuit neuron responses to body tilts after hypomyelination, (2) analyze postural and functional deficits after targeted demyelination, and (3) develop a novel tool for circuit-specific myelin manipulations. These experiments will define the impact of demyelination on vestibular processing and postural instability. Successful completion will provide functional characterization of vestibular circuits and validate a selective myelin disruption tool. In the R00 phase, I will (1) explore mech- anisms of neuronal and behavioral recovery after remyelination and (2) create conditional myelin inhibitors to model circuit-specific incomplete remyelination. Achieving these goals will shed light on circuit-specific effects of remyelination after loss. My long-term goal is to run an independent laboratory using larval zebrafish to (1) understand the mechanisms by which loss of myelin disrupts neural circuit function and behavior and (2) understand how remyelination rescues behavioral and functional deficits. To achieve this, my lab will leverage the behavioral technologies I have used in the first stage of my post-doctoral training, the functional imaging I will master in the K99 training phase, and my previous training as a molecular and cellular glia -biologist. The proposed studies target an un- met need: understanding the role of myelin in a circuit specific manner. This work is broadly significant as it ad- vances our understanding of the relationship of myelin, circuit function and behavior with implications for novel treatment approaches for demyelinating diseases.
