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)报告称，35%的成年人 40岁以上的患者有姿势不稳定的证据。平衡功能障碍与罹患 坠落和在美国坠落是造成50%以上的意外死亡的原因。尽管造成这种情况的原因 前庭功能障碍是多方面的，最近的研究表明噪音导致的听力损失和 前庭功能障碍(Akin等人2012年；Golz等人。2001年；Guest等人。2011年；Zuniga等人2012年)。这个建议 噪声暴露也是前庭功能障碍的一个危险因素是有争议的，因为只有有限的 噪声暴露与外周前庭病变之间因果关系的实验支持 行为症状(例如，平衡不良)。在我们最近发表的研究中(Stewart等人2018)，我们曝光了 大鼠以6小时120dBSPL低频噪声(以1500赫兹为中心的3倍频程频段)为中心，发现神经 根据前庭短潜伏期诱发电位的评估，前庭神经的活动减少。 (VsEP)。噪声暴露的动物也表现出免疫染色的带有花萼的传入神经元数量减少。 终末，尤指终止于位于球囊纹状体区域的毛细胞的仅有花萼的传入纤维 (Stewart等人)2018年)。最近的实验表明，根据其强度的不同，噪音可以引起 刺激刺激时VsEP反应的暂时性或永久性阈值漂移。永久性噪声诱发的VsEP 阈值漂移可能反映了花瓣的丢失和/或伴随的花瓣内带状突触的丢失。这 丢失可能是永久性的，也可能是与重新连接肾盏或恢复 突触。我们假设噪音扰乱了外周前庭突触和/或突触传递， 暂时性的或永久性的，并导致功能性前庭丧失。 确定前庭周围突触/信号传递失败的基础和参数 这一破坏性噪音的特征是制定未来预防措施的关键第一步。 具体目标1将确定导致临时与永久性变化的噪声参数 球囊和椭圆形内的VsEP和前庭外周神经末梢及其突触 斑点。特殊目标2将扩大目标1的分析范围，以检查半规管和 将噪声引起的眉骨变化与耳石器官中观察到的变化进行比较。具体目标3将 VsEP反应和噪声诱导的突触病理变化与行为分析的相关性：A BEAM 交叉作业、耳石依赖行为(黄斑眼反射，MOR)和半规管依赖 行为(前庭眼球反射，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 for causal relationships between noise exposure and peripheral vestibular pathology and behavioral symptoms (e.g., poor balance). In our recently published 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 threshold shifts of VsEP responses to jerk stimuli. Permanent noise induced VsEP threshold shifts could reflect loss of calyces and/or concomitant loss of ribbon synapses within calyces. This loss might be permanent or there could be recovery associated with reconnection of calyces or recovery of synapses. 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 saccular and utricular maculae. 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 otolith organs. 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).