The Effect of Noise Exposure on the Vestibular System

 描述(由申请人提供)： 军队中的观察表明，暴露在与战场相关的噪音中会导致平衡障碍，其特征是姿势不稳、头晕和眩晕；然而，其潜在的机制尚不清楚。造成这种认识差距的一个原因可能是以前的大多数评估都集中在水平半规管功能的评估上。然而，最近的动物和人类研究提供了证据表明，噪音过度刺激对“球囊”的影响要比其他任何前庭感觉感受器大得多(Akdogan等人，2009；Akin等人，2012)。颈部和眼前庭诱发肌源性电位结合视频头部脉冲测试的新发展，现在允许对所有五个前庭感觉器官(三个半规管和两个耳石末端器官-椭圆形和球囊)进行全面评估，以区分每个器官的功能完整性。这种新颖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，足以导致听力损失的噪音也可以导致球囊功能障碍，通常对其他前庭末梢器官没有影响。这将在患有噪声性听力损失的退伍军人和大鼠身上进行测试，动物研究能够定义和控制噪音暴露条件。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)与噪声引起的功能障碍(在人类和动物研究中发现)相关联的能力，以及确定可能指向治疗方法的潜在分子机制的能力。锰增强磁共振成像(MEMRI)是一种强大的成像手段，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，并确定周围损伤后活动的变化(Pautler，2004,2006；Holt等人，2010；Cacace等人，2014)。我们假设球囊诱发的中央前庭活动将在噪声过度刺激后发生变化。具体目标1：在人类和动物中，验证这样一种假设，即引起听力敏感性永久性阈值漂移的噪声也会导致球囊前庭功能障碍，而椭圆囊和半规管的影响较小。具体目标2A：验证这样一种假设，即导致耳蜗外毛细胞中度丧失的噪声也会导致前庭毛细胞和肾盏前庭神经连接的丧失，这种丧失主要在球囊中发现，在椭圆形或半规管中影响较小。目的2B：验证噪声过度刺激导致耳蜗感觉神经上皮自由基形成增加的假说也会导致球囊的类似增加。具体目标3：验证这样一种假设，即导致耳蜗外毛细胞适度丧失的噪声也会导致与球囊相关的中央前庭通路内神经元活动的变化。

 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.