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

衰老听觉通路中听觉信息处理的改变和机制

• 批准号: 10496287
• 负责人: Maria Eulalia Rubio
• 金额: $ 41.23万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10496287
• 关键词: Acoustic Nerve; Affect; Age; Aging; Area; Auditory; Auditory area; Auditory system; Axon; Biological Markers; Brain; Brain Stem; CBA/CaJ Mouse; Central Nervous System; Cochlea; Cochlear nucleus; Code; Complex; Data; Degenerative Disorder; Demyelinations; Diameter; Environment; Equilibrium; Exhibits; Fiber; Fluorescent Antibody Technique; Glutamate Receptor; Goals; Hearing problem; Hyperacusis; Impairment; Individual; Joints; Molecular; Monitor; Motor Activity; Myelin; Nerve; Nerve Fibers; Neurons; Optics; Organelles; Outcome; Pathway interactions; Peripheral; Physiological; Physiology; Presbycusis; Presynaptic Terminals; Process; Property; Public Health; Pupil; Pyramidal Tracts; Research Personnel; Sensory; Signal Transduction; Site; Sound Localization; Speech; Structure; Sum; Synapses; Synaptic Transmission; System; Testing; Tinnitus; age related; aged; aging auditory system; aging brain; arm; auditory pathway; auditory stimulus; experimental study; hearing impairment; information processing; innovation; insight; myelination; neural; neuronal excitability; novel; postsynaptic; presynaptic; sound; stem; transmission process

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.

抽象的 与年龄相关的听力损失（ARHL），也称为长期疾病，是一种复杂性疾病 以听力障碍为特征。这种情况是一个重大的公共卫生问题，影响了40％ 年龄在55至74岁之间的个体归因于中央和周围听觉系统的变性。 中央ARHL指的是中枢神经系统的听觉部分与年龄相关的变性，该变性 影响声音的临时和空间起源的能力，并损害语音理解 嘈杂的环境。但是，到目前为止的研究尚未完全阐明缺乏层面的细胞机制 在衰老中的声音定位和语音理解的暂时精确度。在AIM 1中，我们将确定 中央听觉突触的年龄依赖性结构和分子重塑。我们假设这一点 老化会改变中央突触处的关键结构和分子参数。结果，末端和花萼 持有的突触表现出删除活性。 AIM 2中的研究将确定与年龄有关的结构 和中枢神经轴突纤维的分子重塑。我们假设髓鞘中与年龄有关的缺陷 沿听觉神经和花萼轴突纤维的节点距离将降低传导速度（CV） 和降解突触活动。此外，ARHL的另一个最显着的变化是神经元的增加 兴奋性。在听觉神经轴外围的输入降解会改变兴奋的平衡和 整个听觉层次结构的抑制作用，包括耳蜗核（CN），上橄榄络合物（SOC）， 和听觉皮层（ACTX）。它导致神经元的兴奋性和听觉功能障碍，包括耳鸣 尽管在几种 在上升的听觉层次结构中，其在下降系统中的存在的理解较低。我们 假设ACTX中与年龄相关的神经元更令人兴奋的机制源于修饰的CN 以及SOC前后突触的特性以及神经元脱髓鞘。在AIM 3中，我们将确定 衰老大脑中锥体道（PT）投影途径的结构变化。我们假设这一点 衰老会在PT投影神经元下游靶标中产生结构可塑性。 AIM 4的研究将决定 衰老大脑的PT投影途径中的感觉处理防御。我们假设发生了变化 老年听觉系统的兴奋性会系统地降解声音的光谱处理。 该项目的总体目标（P3）是了解中央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，并提供有关衰老如何影响的新见解 整个听觉系统中的结构可塑性以及与下游大脑区域的连通性如何改变 在衰老中。