Project Summary/ Abstract: Early auditory experience is crucial for establishing and remodeling neural circuits in the auditory brain. A loss of peripheral sound input in congenital and early-onset deafness structurally and functionally alters central auditory circuits, even after peripheral sound sensitivity is restored with hearing aids. To prevent and reverse central auditory dysfunctions following peripheral hearing deficits, it is important to understand how plasticity in the auditory brain creates new connections between restored sound input and central auditory processing centers. Our previous studies showed that myelin was an important feature in resolving auditory signals with extreme temporal precision for central auditory processing. Sound input itself is critical for myelin development and maintenance along auditory brainstem circuitry throughout life. However, the extent to which auditory experience-regulated myelin development and plasticity contribute to central auditory processing, and how adaptive myelination occurs in the auditory brainstem, are unclear. The goal of this proposal is to determine the cellular mechanisms whereby auditory experiences regulate auditory brain plasticity and central processing via adaptive myelination. Our recent studies pioneered a new concept in understanding communication between neurons and myelin-forming cells, oligodendrocytes (OLs) by defining OL excitability in the auditory brainstem. A new subpopulation of OLs expresses glutamate receptors, voltage-gated Na+ (Nav), and Ca2+ channels, which underlie OL depolarization, Na+ current-mediated spiking and Ca2+ dynamics. Thus, these OLs are ideally poised to communicate with electrically active neurons and reward with increased myelination. Based on these data, we hypothesize that increased sound-evoked activity enhances electrical and chemical communication between this novel class of excitable OLs and neurons to regulate OL development and drives adaptive myelination for fine-tuning temporal fidelity of auditory impulses. To test this hypothesis, we will utilize sound modification (stimulation or deprivation), in vivo and ex vivo electrophysiology (auditory brainstem responses and patch-clamp recordings), intracellular Ca2+ imaging, and anatomical analysis techniques. We will determine how sound stimulation modulates neuron-OL communication and OL excitability (Aim 1), how OL excitability enhances adaptive myelination (Aim 2), and how loss of Nav1.2-mediated OL excitability impacts adaptive myelination and auditory brainstem circuitry (Aim 3). The proposed study will provide novel mechanistic insights into how peripheral auditory signals contribute to adaptive myelination and neural plasticity via neuron- oligodendroglia communication in the auditory brain. Elucidating the mechanisms of sound-driven adaptive myelination is essential for understanding auditory brain plasticity during development and for developing an effective therapeutic strategy ...