Medial olivocochlear protection from environmental noise exposure

描述（由申请人提供）：人类对声音暴露表现出广泛的脆弱性。这些个体差异使得很难为工业化社会制定有效和现实的听力保护准确指南。自然橄榄耳蜗（OC）传出反馈机制的强度可能是个体一生中累积的噪声性听力损失易感性的主要决定因素。为了验证这一假设，目标1将听力损失的模式与实验室小鼠的OC功能联系起来。OC功能的强度将通过基于生理标准从正常品系中选择受试者、研究具有受损OC系统的近交系以及破坏基因工程小鼠中的OC信号传导来操纵。有强有力的证据表明，OC神经元保护耳朵免受声音暴露。保护作用的生态意义受到质疑，因为它只在极端的声音水平下得到证明。OC神经元也可以保护耳朵免受长期适度声音暴露的累积效应。在安静与中等音量下的老年受试者将测试这一假设。将用畸变产物耳声发射和听性脑干反应评价耳蜗完整性。将在小鼠组内纵向表征听力损失的时间顺序，所述小鼠组通过年龄、OC强度和累积声音暴露来定义。基于人类交流障碍，预期升高的生理阈值代表功能下降的终点，该功能下降较早开始为噪声中的听力缺陷。目标2将通过跟踪每组中的感知变化来证实这一预测。其目的是证明在生理阈值偏移开始之前在背景噪声中的行为缺陷。这些不同形式的听力损失的解剖学相关性一直难以分离，因为实验动物，如人类，在损伤的速率和模式方面表现出很大的个体差异。在目标1和2的实验中获得的生理和行为表型为研究听力损失的解剖学基础和内耳中的并发代偿机制提供了理想的背景。目的3将使用定量免疫荧光和电子显微镜分析来描述已知加工缺陷小鼠的传入和传出突触复合体。听觉功能的长期维持需要传入神经元和功能性传出神经支配的存活。相关性：这项工作的结果将有助于更好地了解OC系统的保护作用，并可能导致更好的人类听力损失预防策略。

DESCRIPTION (provided by applicant): Humans exhibit a wide range of vulnerability to sound exposure. These individual differences make it difficult to develop accurate guidelines for hearing conservation that are effective and realistic for an industrialized society. The strength of natural olivocochlear (OC) efferent feedback mechanisms may be a primary determinant of individual susceptibility to noise-induced hearing loss accumulated over a lifetime. To test this hypothesis, Aim 1 will relate patterns of hearing loss to the OC function of laboratory mice. The strength of OC function will be manipulated by selecting subjects from normal strains based on physiological criteria, investigating inbred strains with compromised OC systems, and disrupting OC signaling in genetically engineered mice. There is strong evidence that OC neurons protect the ear from sound exposure. The ecological significance of the protective effect has been questioned because it has been demonstrated only at extreme sound levels. OC neurons may also protect the ear from the accrued effects of long-term moderate sound exposure. Aging subjects in quiet versus moderate sound levels will test this hypothesis. Cochlear integrity will be evaluated with distortion product otoacoustic emissions and auditory brainstem responses. The chronology of hearing loss will be characterized longitudinally within groups of mice that are defined by age, OC strength, and cumulative sound exposure. Based on human communication impairments, elevated physiological thresholds are expected to represent the endpoint of a functional decline that begins earlier as deficits in listening in noise. Aim 2 will confirm this prediction by tracking the perceptual changes in each group with a signal-in-noise behavioral task. The objective is to demonstrate behavioral deficits in background noise before the onset of physiological threshold shifts. The anatomical correlates of these diverse forms of hearing loss have been difficult to isolate because experimental animals, like humans, show large individual differences in the rate and pattern of impairment. The physiological and behavioral phenotypes achieved in the experiments of Aims 1 and 2 provide an ideal context for investigating the anatomical basis of hearing loss and concurrent compensatory mechanisms in the inner ear. Aim 3 will use quantitative immunofluorescence and electron microscopic analyses to describe the afferent and efferent synaptic complexes of mice with known processing deficits. Long-term maintenance of auditory function is predicted to require the survival of afferent neurons and functional efferent innervation. Relevance: Results from this work will lead to a better understanding of the protective effects of the OC system, and may lead to better hearing loss prevention strategies in humans.