Functional Integrity of the Aging Auditory Synapse

摘要：年龄相关性听力损失（ARHL）对生活质量有着重大影响， 超过70%的70岁以上的人。这是一个日益严重的问题， 社会经济影响。ARHL的原因很复杂，可能涉及两个方面 环境和遗传因素。与ARHL相关的症状，特别是 在嘈杂环境中辨别声音的能力最初丧失， 随着时间的推移，频率损失可以进一步发展到较低的频率，建议 与初始触发无关的常见漏洞。我们假设， ARHL的共同点是毛细胞传入纤维突触的初始损失。就像 噪音引起的听力损失，我们假设高阈值纤维的选择性损失。我们 将使用ARHL的多个遗传小鼠模型来测试这些假设。每个售价 使用包括听觉脑干反应的整个动物听觉测试进行监测 和畸变产物耳声发射来记录 每个型号的ARHL。具体目标2将评估突触维持和蛋白质 与突触前和突触后元件相关联，以进一步表征时间 与听力损失相关的窗口。Specific Aim 3将使用电生理学和 光学技术测量突触囊泡的释放和运输，监测钙离子浓度， 稳态和记录突触后特性突触电位以及电 特性.每一个目标都很好地与目标和技术相结合， 每个其他研究人员对这一建议，我们将共同确定一个全球性的 在这个框架中，解决这一重要的翻译问题。

Abstract: Age related hearing loss (ARHL) has a major impact on quality of life of more than 70% of those over the age of 70. It is a growing problem with significant socioeconomic ramifications. The cause of ARHL is complex and likely involves both environmental and genetic factors. Symptoms associated with ARHL, specifically, the initial loss of ability to discriminate sound in a noisy environment that progress to high frequency loss that can further progress to lower frequencies over time, suggest a common vulnerability that is independent of the initial trigger. We are postulating that common to ARHL is an initial loss of hair cell afferent fiber synapses. Much as with noise induced hearing loss, we hypothesize a selective loss of high threshold fibers. We will test these hypotheses using multiple genetic mouse models of ARHL. Each will be monitored using whole animal auditory testing including auditory brainstem responses and distortion product otoacoustic emissions to document the time course of onset of ARHL in each model. Specific Aim 2 will evaluate synaptic maintenance and proteins associated with pre and postsynaptic elements to further characterize the temporal windows associated with hearing loss. Specific Aim 3 will use electrophysiological and optical technologies to measure synaptic vesicle release and trafficking, monitor calcium homeostasis and record postsynaptic properties synaptic potentials as well as electrical properties. Each aim is well integrated with the goals and techniques available from each of the other investigators on this proposal and together we shall identify a global framework in which to address this important translational problem.