Synaptopathy and Suprathreshold Processing in Human Temporal Bone Cases with Normal or Elevated Thresholds

阈值正常或升高的人类颞骨病例中的突触病和阈上处理

• 批准号: 9362740
• 负责人: M. Charles Liberman
• 金额: $ 39.35万
• 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/9362740
• 关键词: Acoustic Nerve; Adult; Affect; Age; Aging; Aminoglycoside Antibiotics; Animal Model; Animals; Archives; Audiometry; Autopsy; Axon; Birth; Brain; Cavia; Cell Count; Cell Death; Cells; Cessation of life; Cisplatin; Clinical Trials; Cochlear Implants; Cochlear Nerve; Collection; Complex; Confocal Microscopy; Data; Dendrites; Diagnosis; Disease; Ear; Elements; Environment; Etiology; Eye; Fiber; Foundations; Future; Gold; Guidelines; Hair Cells; Hearing; Histologic; Histopathology; Human; Hyperacusis; Impairment; Inner Hair Cells; Laboratories; Labyrinth; Life; Macaca mulatta; Mammals; Measures; Mus; Nerve; Nerve Degeneration; Nerve Fibers; Neurites; Neurons; Noise; Outer Hair Cells; Patients; Performance; Peripheral; Pharmaceutical Preparations; Pilot Projects; Pre-Clinical Model; Presbycusis; Prevalence; Public Health; Publishing; Quantitative Evaluations; Rattus; Sampling; Sensorineural Hearing Loss; Sensory; Speech; Speech Discrimination; Structure; Subjects Selections; Synapses; Techniques; Temporal bone structure; Testing; Therapeutic; Therapeutic Intervention; Time; Tinnitus; Work; aged; aminoglycoside-induced ototoxicity; base; cell injury; chemotherapy; functional loss; ganglion cell; hearing impairment; nerve supply; neurotrophic factor; neurotropin; normal aging; ototoxicity; public health relevance; spiral ganglion; synaptogenesis

Project 2 Summary - Abstract In acquired sensorineural hearing loss, the dogma has been that hair cells, as primary targets, are the first to degenerate, and that cochlear nerve fibers die only after the hair cells disappear. Recent animal work in the Kujawa and Liberman laboratories has shown, in both noise-induced and age-related hearing loss, that the most vulnerable elements are actually the synaptic connections between hair cells and cochlear neurons, and that this cochlear synaptopathy can be widespread (> 50%) even in ears with no threshold elevation and no hair cell degeneration. Synaptic loss silences the affected neurons, absent a cochlear implant, however the slow death of the cell bodies and central projections offers a long therapeutic window in which neurotrophin-related therapies could potentially reverse the damage. We hypothesize that partial de-afferentation of surviving inner hair cells is widespread in acquired sensorineural hearing loss and is a major cause of difficulties understanding speech in a noisy environment, regardless of the degree of hair cell damage, as measured by the audiogram. A recent pilot study from the Liberman lab showed that the same immunostaining techniques we developed to quantify cochlear synaptopathy in mouse, rat, guinea pig, rhesus and other mammals can be applied to human post-mortem material. An analysis of a small number of ears without explicit otologic disease revealed significant cochlear synaptopathy in aged ears, despite no significant loss of hair cells. Here we propose to build on these preliminary results to quantify, as broadly as possible, the prevalence of cochlear de- afferentation in a wide range of hearing loss etiologies, using newly acquired human temporal bones as well as archival sections from the Mass. Eye and Ear collection. Specifically we will, quantify cochlear afferent and efferent innervation in age-graded “normal-hearing” subjects (Aim 1) and characterize cochlear synaptopathy in subjects with sensorineural hearing loss (Aim 2), with etiologies including noise damage, aminoglycoside antibiotics, and cisplatin-based chemotherapy. Completion of these foundational studies will reveal how widespread the problem of primary neural degeneration is across the spectrum of sensorineural hearing loss in human ears.

项目2摘要 - 摘要 在获得的感官听力损失中，教条一直是毛细胞，作为主要的 靶标，是第一个退化的靶标，该人工耳蜗神经纤维仅在毛细胞后死亡 消失。在Kujawa和Liberman Laboratories的最新动物工作已经表明 噪声引起的和年龄有关的听力损失，最脆弱的元素实际上是 毛细胞和耳蜗神经元之间的突触连接，并且该耳蜗 突触病也可以是宽度（> 50％），即使在没有阈值高程且没有头发的耳朵中 细胞变性。突触损失使受影响的神经元沉默，没有人工耳蜗， 但是，细胞体和中央项目的缓慢死亡提供了长期疗法 神经营养相关疗法的窗口可能会扭转损害。我们 假设生存内毛细胞的部分消除率在获得 感官听力损失，是难以理解噪音中语音的主要原因 环境，无论毛细胞损伤程度如何，通过听力图测量。 自由实验室的最新试点研究表明，相同的免疫染色 我们开发的技术来量化小鼠，大鼠，豚鼠，恒河神中的耳蜗突触性疾病 其他哺乳动物可以应用于人类后材料。对小的分析 没有明确的耳科疾病的耳朵数量显示出明显的人工耳蜗病 老化的耳朵，目的地没有明显的毛细胞损失。在这里，我们建议以这些为基础 初步结果，以尽可能广泛地量化人工耳蜗的普遍性 使用新近获得的人类临时性的范围内的听力损失病因范围 骨骼以及大众眼和耳朵收集的档案部分。具体而言，我们将 量化年龄级别的“正常听力”受试者的人工耳蜗传入和有效的神经支配（AIM 1）并表征具有感觉性听力损失受试者中的耳蜗突触病（AIM 2）， 具有病因，包括噪声损伤，氨基糖苷抗生素和基于顺铂的抗生素 化学疗法。这些基础研究的完成将揭示如何普遍 一级神经变性问题跨越了感官听力损失的范围 人耳。