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 持续的听觉输入对于维持听觉脑中的神经回路至关重要。老化期间， 听觉输入可以重组中枢听觉回路并损害听觉处理。听力损失和中枢神经系统 听觉功能障碍是阿尔茨海默病（AD）中常见的疾病，这表明听力损失是 与AD的认知能力下降相关。特别是，理解语言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，这种疾病出现在 AD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中的作用及其对早期发现AD的价值仍有待充分阐明。改变 髓鞘形成是神经回路中断的常见病理生理机制，并导致神经回路的缺陷。 中枢听觉处理和认知能力下降。我们最近对正常成年老鼠的研究表明， 剥夺和富集动态地改变髓鞘形成，称为适应性髓鞘形成， 有助于听觉脑干的可塑性。然而，听觉经验调节的程度 髓鞘可塑性有助于AD的中枢听觉处理，以及适应性髓鞘形成如何影响AD- 听觉神经系统的相关神经病理学变化尚不清楚。在这份行政建议中， 补充父母NIH R01，目标是解决听力损失如何影响适应性髓鞘形成，AD- 相关的神经病理学变化的听觉大脑，和中央听觉处理在症状前 AD的阶段。我们假设听力损失会降低声音诱发的活动， 髓鞘形成，并加剧神经病理学特征，导致AD小鼠的听觉处理缺陷， 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）评估听觉经验如何改变AD小鼠的中枢听觉功能，2）研究听觉经验如何改变AD小鼠的中枢听觉功能， 声音剥夺改变了少突胶质细胞的发生、成熟和髓鞘形成; 3）测试 髓鞘缺失是否影响听觉神经系统中AD相关的神经病理学变化。研究 将阐明听力损失和AD之间联系的潜在机制，以及听力损失是如何 损害AD中的听觉处理和认知功能。这些机制研究可以显著地 增加对髓鞘改变引起的听觉处理受损的理解，并有助于 改善AD患者听觉感知和认知功能下降的治疗。