Medial olivocochlear protection from environmental noise exposure

描述(申请人提供)：人类对声音暴露表现出广泛的脆弱性。这些个体差异使得制定准确的听力保护指南变得困难，这些指南对工业化社会有效和现实。天然橄榄耳(OC)传出反馈机制的强度可能是个体一生积累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将把听力损失的模式与实验室小鼠的OC功能联系起来。OC功能的强度将通过根据生理标准从正常品系中选择受试者，研究OC系统受损的近交系菌株，以及在基因工程小鼠中干扰OC信号来控制。有强有力的证据表明，OC神经元保护耳朵免受声音暴露的影响。这种保护效果的生态意义受到了质疑，因为它只在极端的声音水平上得到了证明。OC神经元也可能保护耳朵免受长期适度声音暴露的累积影响。年龄较小的受试者和中等音量的受试者将检验这一假设。将通过失真产物耳声发射和听性脑干反应来评估耳蜗的完整性。听力损失的年表将在由年龄、OC强度和累积声音暴露定义的小鼠组中纵向描述。根据人类的沟通障碍，提高的生理阈值预计代表着功能衰退的终点，这种衰退更早开始是在噪音中听力障碍。目标2将通过跟踪每组在噪声中信号行为任务的知觉变化来证实这一预测。其目的是在生理阈值漂移开始之前，证明在背景噪声中的行为缺陷。这些不同形式的听力损失之间的解剖学联系很难分离出来，因为实验动物和人类一样，在听力损失的比率和模式上表现出很大的个体差异。AIMS 1和AIMS 2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的同时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。据预测，听觉功能的长期维持需要传入神经元和功能性传出神经的存活。相关性：这项工作的结果将有助于更好地理解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.