Cochlear Synaptopathy: Prevalence, Diagnosis and Functional Consequences

耳蜗突触病：患病率、诊断和功能性后果

• 批准号: 10222641
• 负责人: Sharon G Kujawa
• 金额: $ 236.19万
• 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/10222641
• 关键词: Acoustic Nerve; Address; Affect; Afferent Neurons; Aging; Aminoglycoside Antibiotics; Animal Model; Animal Testing; Animals; Auditory; Autopsy; Biological Markers; Brain; Brain Stem; Cell Death; Cell Therapy; Cells; Cisplatin; Clinical Trials Design; Cochlea; Complement; Consensus; Coupled; Diagnosis; Diagnostic; Diffuse; Disease; Drug Exposure; Ear; Elderly; Electrophysiology (science); Elements; Environment; Etiology; Exposure to; Frequencies; Functional disorder; Generations; Gerbils; Hair Cells; Hearing; Hearing Tests; Histopathology; Human; Hyperacusis; Immersion; Impairment; Inner Hair Cells; Intervention; Labyrinth; Measures; Midbrain structure; Modeling; Mus; Music; Nerve; Nerve Degeneration; Neurites; Neurons; Noise; Outer Hair Cells; Patients; Pattern; Performance; Peripheral; Physiological; Pilot Projects; Population; Presbycusis; Prevalence; Psychophysics; Public Health; Reporting; Research; Risk; Sampling; Sensorineural Hearing Loss; Sensory; Signal Transduction; Speech; Structure; Synapses; Temporal bone structure; Testing; Therapeutic; Tinnitus; Training; Work; base; cell injury; cellular development; chemotherapy; clinically relevant; cochlear synaptopathy; diagnostic biomarker; drug testing; hearing impairment; hidden hearing loss; human subject; improved; insight; nerve damage; neurotrophic factor; normal aging; normal hearing; ototoxicity; ototoxin; public health relevance; relating to nervous system; sound; speech in noise; spiral ganglion; success; synaptogenesis; therapy design; university student; young adult

Overall Project Summary New insights from animal studies of noise-induced and age-related hearing loss suggest that the most vulnerable elements in the inner ear are the synaptic connections between hair cells and sensory neurons. This primary neural degeneration, also called cochlear synaptopathy, does not elevate thresholds. Thus, it can be widespread in ears with intact hair cell populations and normal audiograms, where it has been called “hidden” hearing loss. It likely contributes to difficulties understanding speech in a noisy environment and may be an instigating factor in the generation of tinnitus and hyperacusis. Cochlear synaptopathy may also be widespread in acquired sensorineural hearing loss of other etiologies and degrees of hair cell damage. Thus, it may be a major contributor to the well-known differences in auditory performance among people with identical audiometric patterns of “overt” hearing loss. Our Research Center aims to take these paradigm-shifting ideas from animal models to human subjects. Based on the synthesis of many research threads from the study of overt and hidden hearing loss, we have devised a set of physiological, electrophysiological and psychophysical tests of hearing and cochlear function that we believe are most powerful in the diagnosis and understanding of cochlear synaptopathy in human subjects. In Project 1, we apply this test battery to gerbils exposed to noise or ototoxic drugs and test their diagnostic power by directly measuring the underlying cochlear histopathology in cases of overt or hidden hearing loss. In Project 2, we use immunostaining to directly assess the prevalence of cochlear synaptopathy in human temporal bones from subjects with overt or hidden hearing loss with a range of etiologies. In Project 3, we study hidden hearing loss in college students by applying the test battery to subjects with normal audiograms but a broad range of reported and measured sound exposures. In Project 4, we assess older adults with overt hearing loss by applying the tests to a subject pool with carefully matched down-sloping audiograms and by characterizing training-based improvements in speech-in-noise performance as reflected at different peripheral, brainstem, midbrain and cortical levels. Our preliminary studies of young adults show clear signs of hidden hearing loss in a group with repeated exposure to high-level music, suggesting the importance of this phenomenon to the public health. The success of neurotrophin-based approaches to the treatment of cochlear synaptopathy in animal models suggests that therapies may be on the horizon. Thus, the need for better understanding of the prevalence, diagnosis and functional consequences of cochlear synaptopathy is clear.

项目总体概要 对噪音引起的和与年龄相关的听力损失的动物研究的新见解表明， 内耳中最脆弱的部分是毛细胞和感觉细胞之间的突触连接 神经元。这种原发性神经变性，也称为耳蜗突触病，不会升高 阈值。因此，它可以广泛存在于具有完整毛细胞群和正常听力图的耳朵中， 这被称为“隐性”听力损失。它可能会导致理解言语的困难 在嘈杂的环境中，可能是产生耳鸣和听力过敏的诱发因素。 耳蜗突触病也可能广泛存在于其他获得性感音神经性听力损失中 毛细胞损伤的病因和程度。因此，它可能是众所周知的主要贡献者 具有相同“外显”听力听力模式的人之间的听觉表现差异 损失。 我们的研究中心旨在将这些范式转变的想法从动物模型转移到人类身上 科目。基于显性和隐性听力研究中许多研究线索的综合 损失，我们设计了一套听力的生理、电生理和心理物理测试 我们认为耳蜗功能对于耳蜗的诊断和理解最为有力 人类受试者的突触病。在项目 1 中，我们将此测试电池应用于暴露于噪音或环境中的沙鼠。 耳毒性药物并通过直接测量底层耳蜗来测试其诊断能力 明显或隐性听力损失的组织病理学。在项目2中，我们使用免疫染色直接 评估患有明显或严重疾病的受试者的人类颞骨中耳蜗突触病的患病率 具有多种病因的隐性听力损失。在项目3中，我们研究大学中的隐性听力损失 学生通过将测试电池应用于听力图正常但报告范围广泛的受试者 并测量了声音暴露。在项目 4 中，我们通过以下方式评估患有明显听力损失的老年人 将测试应用于具有仔细匹配的向下倾斜听力图的主题库，并通过 描述基于训练的噪声中语音性能的改进，反映在不同的环境中 外周、脑干、中脑和皮质水平。 我们对年轻人的初步研究表明，患有隐性听力损失的人群存在明显的隐性听力损失迹象。 反复接触高水平音乐，表明这种现象对公众的重要性 健康。基于神经营养蛋白的方法治疗耳蜗突触病的成功 动物模型表明治疗方法可能即将出现。因此，需要更好地理解 耳蜗突触病的患病率、诊断和功能后果是明确的。