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

阈值正常或升高的沙鼠的突触病、神经病理生理学和阈上处理

• 批准号: 9362739
• 负责人: Sharon G Kujawa
• 金额: $ 56.04万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-02 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362739
• 关键词: Address; Affect; Aging; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Audiometry; Auditory; Behavioral; Binaural; Biological Assay; Brain; Brain Stem; Caliber; Cisplatin; Clinical; Communication; Complex; Diagnosis; Diagnostic; Discrimination; Dose; Ear; Electrocochleographies; Electrophysiology (science); Elements; Etiology; Exposure to; External auditory canal; Fiber; Frequencies; Functional disorder; Future; Gentamicins; Gerbils; Hair Cells; Hearing; Hearing problem; High-Frequency Hearing Loss; Histologic; Histopathology; Human; Hyperacusis; Impairment; Inbred Mouse; Individual; Injury; Inner Hair Cells; Interruption; Knowledge; Labyrinth; Lead; Loudness; Masks; Measurement; Measures; Medial; Methods; Modeling; Monitor; Nature; Nerve; Nerve Fibers; Neurons; Neuropathy; Neurophysiology - biologic function; Noise; Outcome; Pathology; Pattern; Performance; Peripheral; Pharmaceutical Preparations; Platinum; Population; Prevalence; Prevention; Process; Psychophysics; Public Health; Reflex action; Risk; Sensorineural Hearing Loss; Sensory; Sensory Hair; Series; Severities; Speech; Structure; Synapses; Techniques; Temporal bone structure; Test Result; Testing; Text; Tinnitus; Training; Translating; Treatment Efficacy; Work; age related; awake; base; cell injury; clinical application; clinical diagnostics; density; design; ear muscle; exposed human population; functional decline; hearing impairment; human subject; improved; insight; middle ear; neuron loss; otoacoustic emission; ototoxicity; pressure; public health relevance; relating to nervous system; response; sound

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.

项目 1 摘要 – 摘要 在人类听力损失的常见原因中，例如衰老和噪音暴露，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丢失。最近，动物模型方面的工作 揭示了这些和其他获得性感觉神经性原因的可能更常见的后果 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，早在毛细胞丧失之前，它们的丧失就中断了感觉与神经的交流 早在阈值听力图上出现灵敏度损失之前。受影响者的沉默 所产生的神经元可能是导致各种听觉感知异常的原因，包括语音 噪声困难、耳鸣和听觉过敏可能会在有或没有阈值灵敏度损失的情况下发生。 随着这些发现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设，表征仔细的结构和功能后果 滴定操作并评估评估对潜在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；暴露于噪音、 将创建氨基糖苷类抗生素和含铂化疗药物。这些模型将 解决可能存在于许多人类和人类中的混合（感觉+神经）病理学 在其他项目中评估了颞骨。将应用人体测试电池（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（目标 1）。结构- 将使用可能简化的详细电生理测定进一步探讨功能相关性 供未来临床使用（目标 3）。工作将在沙鼠身上进行，沙鼠是一种具有良好低频听力和 可以接受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 在同一受试者中进行电生理学检查并明确测量潜在的突触病， 耳蜗神经病变对知觉下降的影响可以定量评估，结果可以 直接与在人类受试者中获得的结果进行比较。 更好地了解突触机制在常见形式中受损的程度 人类感音神经性听力损失将对药物或其他治疗方法的识别产生广泛影响 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、新疗法疗效监测或有风险的个体监测 药物和噪音暴露导致听力受损。它还可能有助于解释听觉表现差异 具有相同听力配置的个体之间，甚至对于具有正常阈值的个体而言。