Aging and Dysfunction in the Peripheral Vestibular System

项目摘要 随着年龄的增长，前庭功能障碍变得更加普遍，据估计，超过80%的人 80岁的老人经历了功能障碍5。此外，美国约有800万成年人患有 由于外周前庭系统受损导致的平衡障碍，但有效的平衡治疗 功能障碍几乎不存在。前庭管和耳石器官内的前庭毛细胞转化 毛束运动转化为感受器电位，感觉信息通过动作电位传递到大脑 前庭传入神经前庭神经上皮中央区传入神经的反应不同 前庭刺激比外周区传入神经更敏感。有三种类型的前庭传入： 传入神经支配一个或多个I型毛细胞，终扣树突支配II型毛细胞， 传入纤维接触两种类型的毛细胞。仅花萼传入仅存在于中央区，并且具有不规则的 放电模式，而二形传入存在于这两个区域，并有规则的放电模式。我们将研究 使用新制剂观察沙土鼠前庭器官中与年龄相关的带萼传入功能障碍 在主要研究者的实验室中开发的。我们将使用电生理，发束 刺激，免疫组织化学和行为方法来解决与年龄相关的变化， 老化前庭上皮在目标1中，我们将确定前庭毛细胞的功能变化， 机械转导和/或基底外侧电流随年龄而发生。目标2将测试突触 花萼末端的退化将表现为I型毛细胞从其 前庭诱发反应和行为的相关的肾盏和缺陷。在目标3中，我们直接 研究I型毛细胞/萼突触的变化，通过记录自发活动和对 毛束刺激在成熟和老年花萼传入。我们的调查小组有着独特的优势 开展拟议的研究。这项工作的结果将提供关于衰老过程如何的新信息。 影响外周前庭信号，并可能为前庭神经治疗靶向的发展提供信息 传入神经，以恢复正常前庭功能。

Project Summary Vestibular dysfunction becomes more prevalent with age and it is estmated that more than 80% of people over 80 years old experience dysfunction5. Furthermore, approximately 8 million adults in the US suffer from balance impairment due to damage to the peripheral vestibular system, but effective treatments for balance dysfunction are virtually non-existent. Vestibular hair cells within vestibular canal and otolith organs convert hair bundle motion into receptor potentials and sensory information is relayed to the brain by action potentials in vestibular afferent nerves. Afferents in central zones of vestibular neuroepithelia exhibit different responses to vestibular stimuli than afferents in peripheral zones. There are three types of vestibular afferents: calyx-only afferents innervate one or more type I hair cells, bouton dendrites innervate type II hair cells and dimorphic afferents contact both hair cell types. Calyx-only afferents are present only in central zones and have irregular firing patterns, whereas dimorphic afferents exist in both zones and have regular firing patterns. We will study age-related dysfunction in calyx-bearing afferents in gerbil vestibular organs using novel preparations developed in the laboratories of the principal investigators. We will use electrophysiological, hair bundle stimulation, immunohistochemical and behavioral approaches to address age-related changes in mature and aged vestibular epithelia. In Aim 1 we will determine if functional changes in vestibular hair cell mechanotransduction and/or basolateral currents occur with age. Aim 2 will test the hypotheses that synaptic degeneration of calyx terminals will manifest as morphological uncoupling of type I hair cells from their associated calyces and deficits in vestibular evoked responses and behaviors. In Aim 3 we will directly investigate changes at the type I hair cell/calyx synapse by recording spontaneous activity and responses to hair bundle stimulation in mature and aged calyx afferents. Our investigative team is uniquely positioned to carry out the proposed studies. Results from this work will provide new information on how the aging process impacts peripheral vestibular signals and may inform development of vestibular neurotherapeutics targeting afferent nerves in order to restore normal vestibular function.