Alterations and mechanisms of auditory information processing in the aging auditory pathway

摘要 老年性听力损失（ARHL）是一种复杂的退行性疾病 以听力受损为特点。这种情况是一个重大的公共卫生问题，影响40%的 年龄在55至74岁之间。ARHL是由于中枢和外周听觉系统的退化。 中枢ARHL是指中枢神经系统听觉部分的年龄相关性变性， 影响定位声音的时间和空间来源的能力，并损害言语理解， 嘈杂的环境。然而，迄今为止的研究还没有完全阐明缺陷背后的细胞机制 声音定位和语言理解的时间精度。在目标1中，我们将确定 中枢听觉突触的年龄依赖性结构和分子重塑。我们假设 衰老改变了中枢突触的关键结构和分子参数。结果，内鳞茎和花萼 的Held突触表现出活动减少。目标2中的研究将确定年龄依赖性结构 以及中枢神经轴突纤维的分子重塑。我们假设年龄相关的髓鞘缺陷 听神经和听萼轴索纤维的节间距离沿着增加，传导速度（CV）降低 并降低突触活动。此外，ARHL的另一个最显著的变化是神经元凋亡的增加。 兴奋性听觉神经轴外围输入的退化改变了兴奋和兴奋的平衡， 整个听觉层级的抑制，包括耳蜗核（CN），上级橄榄复合体（SOC）， 听觉皮层（ACtx）它会导致神经元兴奋性改变和听觉功能障碍，包括耳鸣 和听觉过敏尽管在几个神经元中发现了改变的神经元兴奋性（“低”或“高”兴奋性）， 虽然大脑位于听觉系统的上行层次，但它在下行系统中的存在却不太为人所知。我们 假设ACtx中年龄相关神经元兴奋性改变的机制源于修饰的CN 和SOC的突触前和突触后性质，以及神经元脱髓鞘。在目标3中，我们将确定 老年脑锥体束（PT）投射通路的结构变化。我们假设 衰老引起PT投射神经元下游靶点的结构可塑性。目标4中的研究将确定 老年大脑PT投射通路的感觉处理缺陷。我们假设 老年听觉系统中的兴奋性系统地降低了声音的频谱时间处理。的 本项目（P3）的总体目标是了解中枢神经系统的年龄依赖性结构和分子重塑， 听觉突触和中枢神经轴突纤维，以及提供新的见解如何老化的影响， 整个听觉系统的结构可塑性以及与下游大脑区域的连接如何改变 在衰老。

Abstract Age-related hearing loss (ARHL), also referred to as presbycusis, is a complex degenerative disease characterized by hearing impairment. The condition is a significant public health problem, affecting 40% of individuals aged between 55 and 74. ARHL is attributed to central and peripheral auditory system degeneration. Central ARHL refers to age-associated degeneration in the auditory portion of the central nervous system, which affects the ability to localize the temporal and spatial origins of sounds and impairs speech understanding in noisy environments. However, studies so far have not fully elucidated the cellular mechanisms underlying deficits to temporal precision of sound localization and speech understanding in aging. In Aim 1, we will determine the age-dependent structural and molecular remodeling of central auditory synapses. We hypothesize that aging alters key structural and molecular parameters at the central synapses. As a result, the endbulb and calyx of Held synapses exhibit decreased activity. Studies in Aim 2 will determine the age-dependent structural and molecular remodeling of central nerve axonal fibers. We hypothesize that age-related deficits in myelin and internode distance along the auditory nerve and calyx axonal fibers will decrease conduction velocity (CV) and degrade synaptic activity. In addition, another most notable change in ARHL is an increase in neuronal excitability. The degradation of input at the auditory neural axis periphery shifts the balance of excitation and inhibition throughout the auditory hierarchy, including the cochlear nucleus (CN), superior olivary complex (SOC), and auditory cortex (ACtx). It leads to altered neuronal excitability and auditory dysfunctions, including tinnitus and hyperacusis. Although altered neuronal excitability (“hypo-” or “hyper”-excitability) has been found in several brain stations in the ascending auditory hierarchy, its presence in descending systems is less understood. We hypothesize that the mechanism of altered age-related neuronal excitability in the ACtx stems from modified CN and SOC pre- and post-synaptic properties, as well as neuronal demyelination. In Aim 3, we will identify structural changes in pyramidal tract (PT) projection pathways in the aging brain. We hypothesize that aging incurs structural plasticity in PT projection neurons' downstream targets. Studies in Aim 4 will determine sensory processing deficits in PT projection pathways in the aging brain. We hypothesize that altered excitability in the aged auditory system systematically degrades the spectrotemporal processing of sound. The overall goal in this project (P3) is to understand the age-dependent structural and molecular remodeling of central auditory synapses and central nerve axonal fibers, as well as providing novel insights into how aging influences structural plasticity throughout the auditory system and how connectivity with downstream brain areas are altered in aging.