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

项目2摘要-摘要 在后天性感音神经性听力损失中， 目标，是第一个退化，耳蜗神经纤维死亡后，只有毛细胞 消失最近在Kujawa和Liberman实验室的动物研究表明， 噪声引起的和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， 即使在没有阈值升高和没有毛发的耳朵中，突触病也可以广泛存在（> 50 细胞退化如果没有人工耳蜗，突触缺失会使受影响的神经元沉默， 然而，细胞体和中央突起的缓慢死亡提供了长期的治疗效果， 神经营养因子相关疗法可能逆转损伤的窗口。我们 假设存活的内毛细胞的部分去传入在获得性神经损伤中广泛存在， 感音神经性听力损失是在嘈杂环境中难以理解言语的主要原因。 无论毛细胞损伤的程度如何，都可以通过听力图测量。 利伯曼实验室最近的一项初步研究表明， 我们开发的技术可以量化小鼠、大鼠、豚鼠、恒河猴的耳蜗突触病 和其它哺乳动物的方法也可应用于人类死后材料。一个小的分析 无明显耳科疾病的耳数显示明显的耳蜗突触病， 老年耳朵，尽管没有明显的毛细胞损失。在这里，我们建议在这些基础上， 初步结果，以量化，尽可能广泛地，耳蜗去的患病率， 在广泛的听力损失病因的传入，使用新获得的人类颞 骨头和弥撒的档案部分眼睛和耳朵收藏具体来说， 在年龄分级的“听力正常”受试者中量化耳蜗传入和传出神经支配（目的 1)并描述感音神经性听力损失受试者的耳蜗突触病（目标2）， 病因包括噪声损伤、氨基糖苷类抗生素和顺铂类抗生素 化疗这些基础研究的完成将揭示 原发性神经变性的问题是在整个感音神经性听力损失的范围内， 人类的耳朵

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.