Role of Adaptive Myelination in Auditory Brain Plasticity

项目摘要/摘要 持续的听觉输入对于维持听觉大脑中的神经回路至关重要。在老化期间，减少 听觉输入会重组中枢听觉回路，损害听觉处理。听力损失与中枢神经系统 在阿尔茨海默病(AD)中经常观察到听力障碍，这表明听力损失 与阿尔茨海默病的认知衰退有关。值得注意的是，理解语音或检测声音的能力受损 位置与中枢听觉处理障碍密切相关，这种障碍出现在 阿尔茨海默病的临床诊断因此，了解减少的听觉输入如何影响听觉神经系统 对于开发治疗阿尔茨海默病神经功能障碍的策略至关重要。然而，病理生理学 听觉缺陷在阿尔茨海默病中的作用及其对早期发现阿尔茨海默病的价值仍有待阐明。更改后的 髓鞘形成是神经回路中断的一种常见的病理生理机制，并导致 中枢听觉处理和认知衰退。我们最近对正常成年小鼠的研究表明，声音 剥夺和浓缩动态地改变髓鞘形成，称为适应性髓鞘形成，它 有助于听觉脑干的可塑性。然而，听觉经验调节的程度 髓鞘的可塑性有助于AD的中枢听觉处理，以及适应性髓鞘如何影响AD- 听觉神经系统的相关神经病理改变尚不清楚。在此建议的管理中 作为父母NIH R01的补充，目标是解决听力损失如何影响适应性髓鞘形成，AD- 听觉脑的相关神经病理改变和症状前期的中枢听觉处理 公元后的阶段。我们假设听力损失会减少声音诱发的活动，损害适应性 髓鞘形成，并加剧神经病理特征，导致AD小鼠听觉处理障碍 症状前阶段。利用抗体聚集性AD小鼠模型，APP/PS1转基因小鼠， 我们将1)评估听觉体验如何改变AD小鼠的中枢听觉功能，2)研究如何 声音剥夺改变少突胶质细胞发育、少突胶质细胞成熟和髓鞘形成，以及3)测试 髓鞘丢失是否会影响听觉神经系统中与AD相关的神经病理变化。这项研究 将阐明听力损失和AD之间潜在的联系机制，以及听力损失如何 阿尔茨海默病患者的听觉处理和认知功能受损。这些机械论的研究可以显著地 增加对髓鞘改变引起的听觉处理受损的了解，并有助于 改善对阿尔茨海默病患者听觉和认知功能下降的治疗。

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.