Role of Adaptive Myelination in Auditory Brain Plasticity

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Project summary/Abstract Continuous auditory input is crucial for maintaining neural circuitry in the auditory brain. During aging, reduced auditory input can reorganize central auditory circuits and impair auditory processing. Hearing loss and central auditory dysfunction are freqently observed in Alzheimer's disease (AD), suggesting that hearing loss is associated with cognitive decline in AD. Notably, impaired capacity to understand speech or detect sound location is closely related to central auditory processing disorders, which appear several years before the clinical diagnosis of AD. Thus, understanding how reduced auditory input impacts the auditory nervous system is essential for developing therapeutic strategies for neural dysfunction in AD. However, the pathophysiologic role of the auditory deficits in AD and their value for early detection of AD remain to be fully elucidated. Altered myelination is a common pathophysiologic mechanism for neural circuit disruption, and causes deficits in central auditory processing and cognitive decline. Our recent studies in normal adult mice suggest that sound deprivation and enrichment dynamically change myelination, referred as adaptive myelination, which contributes to auditory brainstem plasticity. However, the extent to which auditory experience-regulated myelin plasticity contributes to central auditory processing in AD, and how adaptive myelination impacts AD- related neuropathologic changes in the auditory nervous system, are unclear. In this proposed Administrative Supplement to a parent NIH R01, the goal is to address how hearing loss impacts adaptive myelination, AD- related neuropathologic changes in the auditory brain, and central auditory processing at the pre-symptomatic stage of AD. We hypothesize that hearing loss decreases sound-evoked activity, impairs adaptive myelination, and exacerbates neuropathologic features, leading to auditory processing deficits in AD mice at the pre-symptomatic stage. Utilizing an Ab-aggregative AD mouse model, the APP/PS1 transgenic mouse, we will 1) evaluate how auditory experience alters central auditory functions in AD mice, 2) examine how sound deprivation alters oligodendrogenesis, oligodendrocyte maturation, and myelination, and 3) test whether myelin loss impacts AD-related neuropathologic changes in the auditory nervous system. The study will elucidate potential mechanisms underlying the link between hearing loss and AD, and how hearing loss impairs auditory processing and cognitive functions in AD. These mechanistic studies could significantly increase understanding of damaged auditory processing caused by myelin alterations, and contribute to improving treatments for the decline in auditory perception and cognitive function in AD.