The Effect of Noise Exposure on the Vestibular System

 描述（由申请人提供）： 在军事上的观察表明，暴露于战场相关的噪音会导致平衡障碍，其特征是姿势不稳定、头晕和眩晕;然而，其潜在机制还不清楚。这种知识差距的一个原因可能是大多数以前的评估集中在水平半规管功能的评价。然而，最近的动物和人类研究提供了噪声过度刺激影响“球囊”（最接近耳蜗的前庭终末器官）的证据，其程度比任何其他前庭感觉受体大得多（Akdogan等人，2009年; Akin等人，2012年）。颈部和眼部前庭诱发肌源性电位结合视频头部脉冲测试的使用的新发展，现在允许所有五个前庭感觉器官（三个半规管和两个耳石末端器官-椭圆囊和球囊）进行评估，以全面的方式，允许每个功能的完整性进行区分。这种新的测试电池允许在噪声暴露后以快速和非侵入性的方式进行评估。拟议研究的基本假设是，足以引起听力损失的噪声也可以引起球囊功能障碍，通常对其他前庭终末器官没有影响。这将在患有噪声性听力损失的退伍军人和大鼠中进行测试，动物研究能够定义和控制噪声暴露条件。使用平行的人类和动物研究提供了将特定的细胞损伤（来自动物研究）与噪声诱导的功能障碍（在人类和动物研究中发现）相关联的能力，以及鉴定可能指向治疗的潜在分子机制的能力。锰增强磁共振成像（MEMRI）是一种强大的成像模式，用于绘制和评估中枢神经系统通路在损伤后是否保持完整，并确定外周损伤后活动的变化（Pautler，2004，2006; Holt等人，2010; Cacace等人，2014）。我们假设，球囊引起的中枢前庭活动将改变后，噪声过度刺激。具体目标1：测试这一假设，即噪声导致听力敏感性的永久性阈值偏移，也会导致球囊前庭功能障碍，对人类和动物的椭圆囊和半规管影响较小。具体目标2A：测试以下假设：导致耳蜗外毛细胞中度损失的噪声也会导致前庭毛细胞和前庭神经连接的损失，这种损失主要发生在球囊中，对椭圆囊或半规管的影响较小。目标2B：测试噪声过度刺激导致耳蜗感觉神经上皮中自由基形成增加将导致球囊中类似增加的假设。具体目标3：测试噪声引起耳蜗外毛细胞中度损失也会引起球囊相关中央前庭通路内神经元活动变化的假设。

 DESCRIPTION (provided by applicant): Observations in the military have shown that exposure to battlefield-related noise can cause balance disorders characterized by postural instability, dizziness, and vertigo; however, underlying mechanisms are not well understood. One reason for this knowledge gap may be that most previous assessments have been focused on evaluation of horizontal semicircular canal function. Recent animal and human studies, however, provide evidence that noise overstimulation impacts the "sacculus;" the vestibular end-organ closest to cochlea, to a much greater extent than any of the other vestibular sensory receptors (Akdogan et al., 2009; Akin et al., 2012). New developments in the use of cervical and ocular vestibular evoked myogenic potentials combined with video head impulse testing, now allow all five vestibular sensory organs (three semicircular canals and two otolith end organs - utricle and saccule) to be assessed in a comprehensive manner that allows the functional integrity of each to be differentiated. This novel test battery allows assessment in a rapid and non-invasive manner following noise exposure. The underlying hypothesis of the proposed studies is that a noise sufficient to induce hearing loss can also induce dysfunction in the sacculus, often without effects on other vestibular end-organs. This will be tested in Veterans with noise-induced hearing loss and in the rat, with the animal studies able to define and control the noise exposure conditions. The use of parallel human and animal studies provides the ability to correlate specific cellular damage (from animal studies) with the noise-induced dysfunction (found in both the human and animal investigations) as well as to identify underlying molecular mechanisms that could point to therapeutics for treatment. Manganese enhanced magnetic resonance imaging (MEMRI) is a powerful imaging modality used to map and assess whether a central nervous system pathway remains intact following insult and to determine changes in activity following peripheral damage (Pautler, 2004, 2006; Holt et al., 2010; Cacace et al., 2014). We hypothesize that sacculus evoked central vestibular activity will change following noise overstimulation. Specific Aim 1: Test the hypothesis that noise that causes permanent threshold shifts in hearing sensitivity will also cause vestibular dysfunction in the sacculus with less effet in the utricle and semicircular canals in humans and in animals. Specific Aim 2A: Test the hypothesis that noise that causes moderate loss of cochlear outer hair cells will also cause loss of vestibular hair cells and calyceal vestibular nerve connections and this loss will primarily be found in the sacculus with less effect in the utricle or semicircular canals. Aim 2B: Test the hypothesis that noise overstimulation that causes increased free radical formation in cochlear sensorineural epithelium will cause a similar increase in the sacculus. Specific Aim 3: Test the hypothesis that noise that causes moderate loss of cochlear outer hair cells will also cause changes in neuronal activity within the sacculus-associated central vestibular pathways.