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

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，而耳蜗神经纤维只有在毛细胞之后才会死亡 消失。最近在Kujawa和Liberman实验室进行的动物研究表明，在这两个实验室 噪音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联系，而这个耳蜗区 突触可以广泛存在(50%)，即使在没有阈值升高和没有毛发的耳朵中也是如此 细胞退化。突触丢失会使受影响的神经元沉默，而不是植入人工耳蜗， 然而，细胞体和中央投射的缓慢死亡提供了长期的治疗方法。 这是神经营养素相关疗法可能逆转损害的窗口。我们 假设存活内毛细胞的部分去传入在获得性疾病中普遍存在 感觉神经性听力损失是在嘈杂的环境中理解语言困难的主要原因 环境，无论毛细胞损伤的程度，如听力图所测量的。 利伯曼实验室最近的一项初步研究表明，同样的免疫染色 我们开发了量化小鼠、大鼠、豚鼠、恒河猴耳蜗突触的技术 和其他哺乳动物一样，可以应用于人类的尸检材料。对一家小型企业的分析 无明确耳科疾病的耳数显示有显著的耳蜗性突触 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 初步结果是尽可能广泛地量化耳蜗病的患病率。 使用新获得的人类颞叶，在广泛的听力损失病因中的传入 以及来自弥撒的骨头和档案部分。眼睛和耳朵收藏。具体来说，我们将， 对听力正常年龄段受试者的耳蜗神经传入和传出神经进行量化(目的 1)和表征感音神经性耳聋受试者的耳蜗性突触(目标2)， 病因包括噪音损害、氨基糖苷类抗生素和基于顺铂的 化疗。这些基础性研究的完成将揭示 原发性神经变性的问题跨越感音神经性耳聋的范围 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.