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，永久性的阈值损失是 与永久性耳蜗性损伤有关，通常是毛细胞损伤或丢失。最近，动物模型的研究已经取得了进展 揭示了获得性感觉神经的这些和其他原因可能更常见的后果是什么 听力损失。这项研究表明，内毛细胞(IHC)和耳蜗神经元之间的突触是 最脆弱的，因为它们的丢失在毛细胞丢失之前很久就中断了感觉到神经的交流 而且在阈值听力图上出现敏感度损失之前很久。受影响的人的沉默 由此产生的神经元可能是各种听觉知觉异常的贡献者，包括言语中的- 噪声困难、耳鸣和听力亢进，可在阈值敏感度丧失的情况下或不在阈值敏感度丧失的情况下发生。 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 一种强有力的方法来检验假说，来表征仔细- 并评估这些评估对潜在的组织病理学的敏感性。 在这里，人类常见的感觉神经性听力损失病因的动物模型；暴露在噪音中，到 氨基糖苷类抗生素和含铂化疗药物将被创造出来。模特们将会 解决可能会出现在许多人类和人类身上的混合(感觉神经)病理 在其他项目中对颞骨进行了评估。人体测试电池将被应用(目标2)，其 通过直接测量潜在的耳蜗组织病理学来评估诊断能力(目标1)。结构- 将使用可能简化的详细电生理分析来进一步探讨功能相关性 以供将来临床使用(目标3)。这项工作将在沙鼠身上进行，沙鼠是一种具有良好低频听力和 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 在相同受试者的电生理学和对潜在突触的明确测量下， 耳蜗神经病变对知觉下降的贡献可以定量评估，结果可以 直接与人类受试者获得的结果进行比较。 更好地了解常见形式的突触机制受损的程度 人类感音神经性听力损失将对识别药物或其他治疗方法产生广泛的影响。 有可能针对这些机制进行预防或救援。实际上，这一知识将告诉我们 临床诊断学，监测新的治疗方法的疗效或监测有风险的个人 因接触毒品和噪音而导致听力受损。这也可能有助于解释听觉表现的差异。 在听力测试配置相同的个体中，即使是那些阈值正常的个体也是如此。

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.