Consequences of chronic noise exposure in nonhuman primates

摘要 噪声性听力损失（NIHL，包括临床可测量的听力阈值偏移）影响超过25 100万成年人中，主要原因是暴露于职业或其他响亮的环境噪音。 然而，许多暴露于噪声的个体报告在噪声环境中听力困难， 门槛明显提高。动物模型研究揭示了噪声诱导的潜在机制， 听力障碍（NIHD）及其伴随的心理物理和生理变化，包括 候选机制（来自啮齿动物模型的证据和来自猕猴模型的新支持） 临床上听力正常，在嘈杂的环境中有困难：耳蜗突触丧失。然而，动物模型 通常使用单次暴露协议来创建耳蜗病理，这与慢性噪声不同， 暴露导致人类的NIHL，这些人经历了较小的，重复的日常噪音剂量，导致NIHL。 来自我们的NIHL猕猴模型（具有与人类相似的噪声敏感性）的数据表明， 诱发NIHL和耳蜗突触丧失所需的暴露噪声水平远高于声音水平 通常是人类在工作或娱乐中经历的。尽管如此，猕猴的初步数据 表明，单次噪声暴露导致暂时性阈值偏移（TTS），导致耳蜗突触损失2- 暴露后10个月，但不是在暴露后10个月，和听觉处理缺陷。该项目将 将这些早期的观察扩展到更现实的慢性噪音暴露，类似于 工人我们建议进行心理物理、生理和组织学研究1）建立一个时间轴 长期暴露的猕猴持续性听觉处理缺陷和耳蜗病理学的发展 2）定义行为和电生理检测，以检测听力的变化， 永久性阈值偏移（PTS）。我们的假设是，慢性噪声暴露（每天8小时，5天 一周）引起一系列进展为PTS的非暂时性NIHD。具体来说，我们预测， 噪声暴露将导致心理物理变化（目标1）：最早的缺陷将在空间和时间 处理，其次是在噪声中处理信号的缺陷，其次是听力缺陷（PTS）。 生理变化（目标2）将与心理物理变化平行：最早的缺陷将出现在中耳肌肉中 反射（MEMR）和双耳和时间处理的措施，其次是失真产品的缺陷 耳声发射（DPOAE）振幅和掩蔽听性脑干反应（ABR），然后是缺陷 DPOAE和ABR阈值。这些缺陷将被耳蜗病理学所掩盖：早期，非暂时性 耳蜗突触丢失，然后是外毛细胞丢失，然后是外毛细胞和内毛细胞的组合丢失 (Aim 3）。这些研究的结果将揭示早期听觉损伤的敏感标记与现实的噪音 暴露和耳蜗病理学的顺序。研究结果将用于开发可靠的，临床上 可行的NIHL早期指标，并提高听力损失预防计划的结果。

ABSTRACT Noise-induced hearing loss (NIHL, including clinically measurable audiometric threshold shifts) affects over 25 million adults, with the primary cause being exposure to occupational or other loud environmental sound. However, many noise-exposed individuals report difficulty hearing in noisy environments without clinically significant threshold increases. Animal model studies have revealed potential mechanisms of noise induced hearing difficulties (NIHD) and their accompanying psychophysical and physiological changes, including a candidate mechanism (with evidence from rodent models and emerging support from the macaque model) for clinically normal hearing with difficulty in noisy environments: cochlear synapse loss. However, animal models typically use single exposure protocols to create cochlear pathology, which are unlike the chronic noise exposures leading to NIHL in humans, who experience smaller, repeated daily noise doses that result in NIHL. Data from our macaque model of NIHL (having noise susceptibility similar to humans) suggests that the single exposure noise levels needed to induce NIHL and cochlear synapse loss are much higher than sound levels typically experienced by humans occupationally or recreationally. Nonetheless, preliminary data in macaques show that single noise exposures that cause temporary threshold shifts (TTS) result in cochlear synapse loss 2- months post exposure but not at 10-months post-exposure, and auditory processing deficits. This project will expand these early observations to more realistic chronic noise exposures similar to those experienced by workers. We propose psychophysical, physiological, and histological studies 1) to establish a timeline for the development of sustained auditory processing deficits and cochlear pathology in macaques chronically exposed to noise, and 2) to define behavioral and electrophysiological assays that detect changes in hearing that develop prior to permanent threshold shifts (PTS). Our hypothesis is that chronic noise exposures (8 hours a day, 5 days a week) cause a sequence of non-transient NIHD that progress to PTS. Specifically, we predict that chronic noise exposures will cause psychophysical changes (Aim 1): the earliest deficits will be in spatial and temporal processing, followed by deficits in processing signals in noise, followed by audiometric deficits (PTS). Physiological changes (Aim 2) will parallel psychophysical changes: earliest deficits will be in middle ear muscle reflex (MEMR) and measures of binaural and temporal processing, followed by deficits in distortion product otoacoustic emission (DPOAE) amplitudes and masked auditory brainstem responses (ABR), followed by deficits in DPOAEs and ABR thresholds. These deficits will be paralleled by cochlear pathology: early, non-transient cochlear synapse loss, followed by outer hair cell loss, followed by a combination of outer and inner hair cell loss (Aim 3). The results of these studies will reveal sensitive markers of early auditory damage with realistic noise exposures, and the sequence of cochlear pathology. Study results will be used to develop reliable, clinically viable early indicators of NIHL and enhance hearing loss prevention program outcomes.