Noise-Induced Synaptic Loss and Vestibular Dysfunction

摘要 前庭功能障碍是一个重要的公共卫生问题。Agrawal等人（2009年）报告说，35%的成年人 40岁以上的人有姿势不稳定的迹象。平衡功能障碍与以下可能性增加有关： 在美国，福尔斯是造成50%以上意外死亡的原因。虽然原因 前庭功能障碍是多种多样的，最近的研究表明，噪音引起的听力损失和 前庭功能障碍（Akin et al. 2012; Golz et al. 2001; Guest et al. 2011; Zuniga et al 2012）。的建议 噪声暴露也是前庭功能障碍的危险因素是有争议的，因为只有有限的 实验支持，特别是噪声暴露和前庭病理之间的因果关系。在 我们最近的研究（Stewart等人，2018），我们将大鼠暴露于6小时的120 dB SPL低频噪声（3- 以1500 Hz为中心的倍频程带），并发现前庭神经的神经活动减少， 通过前庭短潜伏期诱发电位（VsEP）进行评估。暴露于噪音的动物也表现出 具有花萼末梢的免疫染色传入纤维的数量减少，尤其是终止的仅花萼传入纤维 位于小囊纹状区的毛细胞上（Stewart et al. 2018）。最近的实验表明 噪声，根据其强度，可以导致VsEP反应的暂时或永久衰减 刺激物噪声诱导的VsEP急动阈值增加可能反映了一些肾盏的丧失和/或 在重新连接的肾盏内伴随着带状突触的丢失。这种损失可能是永久性的，也可能是 恢复与肾盏的重新连接有关。我们假设噪音干扰了周围前庭神经 突触和/或突触传递，暂时或永久性的，并导致功能性前庭损失。 确定前庭周围突触/信号传递失败的基础和参数 对破坏性噪声进行表征是发展未来预防措施的关键的第一步。 具体目标1将确定噪声参数，导致暂时与永久的变化， VsEP和前庭周围神经末梢及其在球囊中的突触。具体目标2将 扩展目标1的分析，以检查半规管嵴，并比较噪声引起的 在小囊中观察到的嵴。具体目标3将VsEP反应的变化与 噪声诱发的突触病理学与行为分析：一个梁交叉任务，一个耳石依赖行为 （黄斑眼反射，莫尔）和半规管依赖性行为（前庭眼反射，VOR）。

Abstract Vestibular dysfunction is a significant public health problem. Agrawal et al. (2009) reported that 35% of adults older than 40 had evidence of postural instability. Balance dysfunction is linked to an increased likelihood of falling and in the U.S., falls are responsible for more than 50% of accidental deaths. Although the causes of vestibular dysfunction are multiple, recent studies suggest a linkage between noise-induced hearing loss and vestibular dysfunction (Akin et al. 2012; Golz et al. 2001; Guest et al. 2011; Zuniga et al 2012). The suggestion that noise exposure is also a risk factor for vestibular dysfunction is controversial as there is only limited experimental support, especially for a causal relationship between noise exposure and vestibular pathology. In our recently study (Stewart et al. 2018), we exposed rats to 6 hours of 120dB SPL low frequency noise (3- octave band centered at 1500Hz) and found that neural activity in the vestibular nerve was reduced, as assessed by the vestibular short latency evoked potential (VsEP). Noise exposed animals also exhibited reduced numbers of immunostained afferents with calyx endings, especially calyx-only afferents that terminate on hair cells located in the striolar region of the sacculus (Stewart et al. 2018). More recent experiments show that noise, depending on its intensity, can cause either temporary or permanent attenuation of VsEP responses to jerk stimuli. Noise induced increases in VsEP jerk thresholds could reflect loss of some calyces and/or concomitant loss of ribbon synapses within reconnected calyces. This loss could be permanent or there could be recovery associated with reconnection of calyces. We hypothesize that noise disrupts peripheral vestibular synapses and/or synaptic transmission, transiently or permanently and causes functional vestibular loss. Determining the basis for synaptic/signal transmission failure in the vestibular periphery and the parameters that characterize damaging noise is a critical first step toward development of future preventative measures. Specific Aim 1 will determine the parameters of noise that causes temporary versus permanent changes to the VsEP, and to peripheral vestibular nerve terminals and their synapses in the sacculus. Specific Aim 2 will extend the analysis of Aim 1 to examine the semicircular canal cristae and compare noise induced changes in the cristae with those observed in the sacculus. Specific Aim 3 will correlate changes in VsEP responses and noise induced synaptic pathology with behavioral assays: a beam crossing task, an otolith dependent behavior (macular ocular reflex, MOR), and a semicircular canal dependent behavior (vestibuloocular reflex, VOR).