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.

摘要 年龄相关性听力损失(ARHL)，也被称为老年性耳聋，是一种复杂的退行性疾病 以听力受损为特征的。这种情况是一个重大的公共卫生问题，影响到40%的 年龄在55岁至74岁之间的个人。ARHL归因于中枢和外周听觉系统的退行性变。 中枢性ARHL是指与年龄相关的中枢神经系统听觉部分的退行性变， 影响定位声音的时间和空间来源的能力，并损害语音理解 嘈杂的环境。然而，到目前为止，研究还没有完全阐明缺陷的细胞机制。 涉及到衰老过程中声音定位和语音理解的时间精度。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 衰老改变了中央突触的关键结构和分子参数。结果，末端鳞茎和花萼 所持有的突触的活性降低。目标2中的研究将确定年龄相关的结构 以及中枢神经轴突纤维的分子重塑。我们假设与年龄相关的髓鞘缺陷 沿听神经和盏轴突纤维的节间距离会降低传导速度(CV)。 并降低突触的活性。此外，ARHL的另一个最显著的变化是神经元的增加。 兴奋性。听神经轴周围输入的退化改变了兴奋和刺激的平衡 抑制贯穿整个听觉层级，包括耳蜗核(CN)、上橄榄复合体(SOC)、 和听觉皮质(ACTx)。它会导致神经元兴奋性改变和听觉功能障碍，包括耳鸣。 还有听觉过敏症。尽管已发现神经元兴奋性改变(“低兴奋性”或“高兴奋性”) 上行听觉系统中的脑站，人们对其在下行系统中的存在知之甚少。我们 假设ACTx中与年龄相关的神经元兴奋性改变的机制源于修饰的CN 以及SOC突触前和突触后的特性，以及神经元脱髓鞘。在目标3中，我们将确定 脑老化过程中锥体束投射通路的结构变化。我们假设 衰老导致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 衰老大脑中PT投射通路的感觉处理缺陷。我们假设这一点改变了 老年听觉系统中的兴奋性会系统地降低声音的频谱时间处理能力。这个 本项目的总体目标(P3)是为了了解年龄相关的中央动脉的结构和分子重构。 听觉突触和中枢神经轴突纤维，以及为衰老如何影响提供了新的见解 整个听觉系统的结构可塑性以及与下游脑区的连通性如何改变 在衰老过程中。