Role of Adaptive Myelination in Auditory Brain Plasticity

适应性髓鞘形成在听觉脑可塑性中的作用

• 批准号: 10713730
• 负责人: Jun Hee Kim
• 金额: $ 39.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713730
• 关键词: APP-PS1; Acceleration; Acoustics; Address; Administrative Supplement; Adult; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Auditory; Auditory Brainstem Responses; Auditory Perception; Auditory Perceptual Disorders; Auditory Threshold; Auditory system; Axon; Brain; Brain Stem; Cell Lineage; Central Auditory Diseases; Central Auditory Processing Disorder; Central Nervous System; Chemicals; Communication; Development; Early Diagnosis; Electron Microscopy; Environment; Equilibrium; Goals; Hearing; Hearing Aids; Hearing problem; High-Frequency Hearing Loss; Impaired cognition; Impairment; Link; Location; Memory; Memory impairment; Modeling; Molecular; Mus; Myelin; Nerve Degeneration; Nervous System; Neurobehavioral Manifestations; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Oligodendroglia; Parents; Patients; Peripheral; Play; Population; Prevention strategy; Preventive; Process; Proliferating; Reading; Reflex action; Rehabilitation therapy; Reporter; Role; Speech; Testing; Therapeutic; Thick; Transgenic Mice; United States National Institutes of Health; age related; auditory deprivation; auditory pathway; auditory processing; axonal degeneration; brain circuitry; brain dysfunction; clinical diagnosis; cognitive function; disability; experience; functional plasticity; hearing impairment; impaired capacity; improved; mouse model; myelin degeneration; myelination; neural; neural circuit; neuromechanism; neuropathology; neurophysiology; oligodendrocyte lineage; oligodendrocyte progenitor; prevent; remediation; response; sensory input; sound; stem cells; transmission process

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.

项目概要/摘要 连续的听觉输入对于维持听觉大脑中的神经回路至关重要。老化过程中，减少 听觉输入可以重组中枢听觉回路并损害听觉处理。听力损失和中枢性 阿尔茨海默病 (AD) 中经常观察到听觉功能障碍，这表明听力损失与 与 AD 认知能力下降有关。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，中枢听觉处理障碍早在几年前就出现了。 AD的临床诊断。因此，了解听觉输入减少如何影响听觉神经系统 对于制定 AD 神经功能障碍的治疗策略至关重要。然而，病理生理学 听觉缺陷在 AD 中的作用及其对 AD 早期检测的价值仍有待充分阐明。改变 髓鞘形成是神经回路破坏的常见病理生理机制，并导致神经回路缺陷 中枢听觉处理和认知能力下降。我们最近对正常成年小鼠的研究表明，声音 剥夺和丰富动态地改变髓鞘形成，称为适应性髓鞘形成， 有助于听觉脑干可塑性。然而，听觉体验调节的程度 髓磷脂可塑性有助于 AD 的中枢听觉处理，以及适应性髓鞘形成如何影响 AD- 听觉神经系统相关的神经病理学变化尚不清楚。在本拟议的行政 作为家长 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学变化以及症状前的中枢听觉处理 AD阶段。我们假设听力损失会降低声音诱发的活动，损害适应性 髓鞘形成，并加剧神经病理学特征，导致 AD 小鼠听觉处理缺陷 症状前阶段。利用 Ab 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) 检查如何 声音剥夺会改变少突胶质细胞发生、少突胶质细胞成熟和髓鞘形成，以及 3) 测试 髓磷脂缺失是否会影响听觉神经系统中与 AD 相关的神经病理变化。研究 将阐明听力损失和 AD 之间联系的潜在机制，以及听力损失如何 损害 AD 的听觉处理和认知功能。这些机制研究可以显着 增加对髓磷脂改变引起的听觉处理受损的了解，并有助于 改善 AD 听觉感知和认知功能下降的治疗方法。