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; 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 在衰老和噪声暴露等人类听力损失的常见原因中，永久阈值损失为 与永久耳蜗损伤有关，通常是毛细胞损伤或损失。最近，动物模型的工作 揭示了这些获取的感觉神经性的这些和其他原因可能是更普遍的结果 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 本身，在灵敏度损失出现在阈值听力图上之前。被影响的沉默 结果的神经元可能是导致各种听觉感知异常的原因，包括语音 噪声难度，耳鸣和超源，在有或没有阈值敏感性丧失的情况下可能发生。 由于这些发现转化为对人类听力损失的研究，动物模型将继续提供 一种强大的检验假设的方法，以仔细的结构和功能后果来表征 滴定的操作并评估评估对基础组织病理学的敏感性。 在这里，人类常见的感官听力损失病因的动物模型；暴露于噪音， 将创建氨基糖苷抗生素和含铂化学治疗剂的抗生素。这些模型会 解决许多人和人类可能存在的混合（感觉 +神经）病理 在其他项目中评估了临时骨骼。将使用人体测试电池（AIM 2）及其 通过直接测量潜在的耳蜗组织病理学评估的诊断能力（AIM 1）。结构- 功能相关将使用可能会简化的详细电生理测定进一步探测 用于将来的临床用途（AIM 3）。工作将在Gerbil进行，该物种具有良好的低频听力和 可以培训以执行听觉任务。通过将这些复杂聆听任务的性能与 相同受试者的电生理学，并明确测量了基础突触病， 人工耳蜗神经病对感知下降的贡献可以进行定量评估，结果可以 直接将其与人类受试者获得的那些进行比较。 对合成机制的共同形式损害的程度有了改进的理解 人类的感官听力损失将对识别药物或其他治疗的努力具有广泛的影响 有可能针对预防或救援的这些机制。实际上，这些知识将告知 临床诊断，监测效率的新治疗方法或对有风险的个人监测 毒品和噪声暴露的听力妥协。这也可能有助于解释听觉性能差异 在具有相同听力构型的个体中，即使对于那些具有正常阈值的人也是如此。