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: 10222644
• 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/10222644
• 关键词: Acoustic Nerve; Adult; Affect; Age; Aging; Aminoglycoside Antibiotics; Animal Model; Animals; Archives; Autopsy; Axon; Birth; Brain; Cavia; Cell Count; Cell Death; Cells; Cessation of life; Cisplatin; Clinical Trials; Cochlea; 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; Hearing Tests; Histologic; Histopathology; Human; Hyperacusis; Impairment; Inner Hair Cells; Laboratories; Labyrinth; Life; 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; Rhesus; 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; cisplatin induced hearing loss; cochlear synaptopathy; functional loss; ganglion cell; hearing impairment; hearing range; hidden hearing loss; nerve damage; nerve supply; neurotrophic factor; normal aging; normal hearing; 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 在获得性感音神经性听力损失中，人们一直认为毛细胞是主要的 目标，是最先退化的，并且耳蜗神经纤维仅在毛细胞之后死亡 消失。 Kujawa 和 Liberman 实验室最近的动物研究表明， 噪音引起的和与年龄相关的听力损失，最脆弱的因素实际上是 毛细胞和耳蜗神经元之间的突触连接，并且该耳蜗 即使在没有阈值升高且没有毛发的耳朵中，突触病也可能广泛存在（> 50%） 细胞变性。在没有人工耳蜗的情况下，突触丧失会使受影响的神经元沉默， 然而，细胞体和中心投射的缓慢死亡提供了长期的治疗 神经营养素相关疗法可能逆转损伤的窗口期。我们 假设幸存的内毛细胞的部分传入神经阻滞在获得性毛细胞中普遍存在 感音神经性听力损失，是在嘈杂的环境中理解言语困难的主要原因 无论毛细胞损伤程度如何（通过听力图测量）。 利伯曼实验室最近的一项初步研究表明，相同的免疫染色 我们开发的技术用于量化小鼠、大鼠、豚鼠、恒河猴的耳蜗突触病 和其他哺乳动物可应用于人类尸检材料。一个小分析 没有明显耳科疾病的耳朵数量显示出显着的耳蜗突触病变 耳朵老化，尽管毛细胞没有明显损失。在这里，我们建议在这些基础上 初步结果，尽可能广泛地量化耳蜗脱发的患病率 使用新获得的人类颞叶在各种听力损失病因中进行传入 骨头以及马萨诸塞州眼睛和耳朵收藏的档案部分。具体来说，我们将， 量化年龄分级的“正常听力”受试者的耳蜗传入和传出神经支配（Aim 1) 并表征感音神经性听力损失受试者的耳蜗突触病特征（目标 2）， 病因包括噪音损伤、氨基糖苷类抗生素和顺铂类抗生素 化疗。完成这些基础研究将揭示这种现象的广泛程度 原发性神经变性问题涉及感音神经性听力损失的各个方面 人类的耳朵。