Synaptopathy, Neural Pathophysiology and Suprathreshold Processing in Gerbils with Normal or Elevated Thresholds

项目1摘要-摘要 在人类听力损失的常见原因中，如衰老和噪音暴露，永久性阈值损失是 与永久性耳蜗损伤相关，通常是毛细胞损伤或损失。最近，动物模型的研究 揭示了这些和其他后天感觉神经性疾病原因的更常见后果。 听力损失这项工作表明，内毛细胞（IHC）和耳蜗神经元之间的突触是 最脆弱的是，在毛细胞丧失之前，它们的丧失就中断了感觉与神经的交流。 在听力损失出现在阈值听力图上之前很久。受影响的沉默 神经元的结果是一个可能的贡献者各种听觉知觉异常，包括语音中， 噪声困难，耳鸣和听觉过敏，可能会发生或没有阈值灵敏度损失。 随着这些发现被转化为人类听力损失的研究，动物模型将继续提供 一个强有力的方法来测试假设，表征结构和功能的后果仔细- 滴定操作，并评估评估对基础组织病理学的敏感性。 在这里，人类常见的感音神经性听力损失病因的动物模型;暴露于噪声， 氨基糖苷类抗生素和含铂化疗药物，将被创建。模特们将 解决了混合（感觉+神经）病理学，这可能会出现在许多人和人类 在其他项目中评估的颞骨。将应用人体试验组合（目标2）及其 通过直接测量潜在的耳蜗组织病理学来评估诊断能力（目的1）。结构- 功能相关性将进一步探讨使用详细的电生理分析，可能是精简 用于未来的临床应用（目标3）。工作将在沙鼠中进行，沙鼠是一种具有良好低频听力的物种， 可以被训练来执行听觉任务。通过将这些复杂的听力任务的表现与 电生理学在相同的主题和明确的测量潜在的突触病， 耳蜗神经病变对知觉下降的贡献可以被定量评估， 直接与人类受试者中获得的结果进行比较。 对突触机制在常见形式中受损程度的更好理解， 人类感音神经性听力损失将对识别药物或其他治疗方法的努力产生广泛的影响 有可能针对这些机制进行预防或救援。实际上，这些知识将告知 临床诊断，监测新的治疗方法的疗效或监测有风险的个体， 因为药物和噪音而听力受损这也可能有助于解释听觉表现的差异 在具有相同听力配置的个体中，即使对于那些具有正常阈值的个体。

Project 1 Summary – Abstract In common causes of human hearing loss like aging and noise exposure, permanent threshold losses are associated with permanent cochlear injury, often hair cell damage or loss. Recently, work in animal models has revealed what may be a more common consequence of these and other causes of acquired sensorineural hearing loss. This work has shown that synapses between inner hair cells (IHCs) and cochlear neurons are most vulnerable, with their loss interrupting sensory-to-neural communication long before loss of the hair cells themselves, and long before sensitivity losses appear on the threshold audiogram. The silencing of affected neurons that results is a likely contributor to a variety of auditory perceptual abnormalities, including speech-in- noise difficulties, tinnitus and hyperacusis that can occur with or without threshold sensitivity loss. As these findings are translated to the study of human hearing loss, animal models will continue to provide a powerful approach to test hypotheses, to characterize structural and functional consequences of carefully- titrated manipulations and to evaluate the sensitivity of the assessments to the underlying histopathology. Here, animal models of sensorineural hearing loss etiologies common in humans; exposure to noise, to aminoglycoside antibiotics and to platinum-containing chemotherapeutics, will be created. The models will address the mixed (sensory + neural) pathology that will likely be present in many of the humans and human temporal bones evaluated in the other Projects. The human test battery will be applied (Aim 2) and its diagnostic power assessed by directly measuring the underlying cochlear histopathology (Aim 1). Structure- function correlations will be probed further using detailed electrophysiologic assays that might be streamlined for future clinical use (Aim 3). Work will be performed in gerbil, a species with good low frequency hearing and can be trained to perform auditory tasks. By correlating performance on these complex listening tasks with electrophysiology in the same subjects and with explicit measurement of the underlying synaptopathy, the contribution of cochlear neuropathy to the perceptual declines can be quantitatively evaluated and results can be directly compared to those obtained in human subjects. An improved understanding of the extent to which synaptic mechanisms are damaged in common forms of human sensorineural hearing loss will have broad implications for efforts to identify drugs or other treatments with the potential to target these mechanisms for prevention or rescue. Practically, this knowledge will inform clinical diagnostics, the monitoring of new treatments for efficacy or the monitoring of individuals at risk of hearing compromise from drug and noise exposure. It also may help explain auditory performance differences among individuals with the same audiometric configurations, even for those with normal thresholds.