Synaptic mechanisms underlying noise-induced and age-related hearing loss

噪音引起的和与年龄相关的听力损失的突触机制

• 批准号: 8677875
• 负责人: Ruili Xie
• 金额: $ 2.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677875
• 关键词: Acoustic Nerve; Affect; Age; Auditory system; Biological Neural Networks; Brain; Buffers; Calcium; Calcium Channel; Calmodulin; Cell physiology; Cells; Clinical Treatment; Data; Defect; Development; Egtazic Acid; Frequencies; Functional disorder; Future; Goals; Hair Cells; Hearing; Homeostasis; Inbred CBA Mice; Individual; Modification; Mus; Neuraxis; Neurophysiology - biologic function; Noise; Noise-Induced Hearing Loss; Outcome Study; Outcomes Research; Pathway interactions; Peripheral; Population; Pre-Clinical Model; Presbycusis; Presynaptic Terminals; Process; Property; Quality of life; Research; Research Project Grants; Ryanodine Receptors; Shapes; Signal Pathway; Signal Transduction Pathway; Slice; Source; Staging; Structure; Synapses; Synaptic Transmission; Testing; Trauma; aged; auditory nuclei; hearing impairment; postsynaptic; presynaptic; public health relevance; receptor; restoration; signal processing; sound; synaptic function; voltage

DESCRIPTION (provided by applicant): Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL) are two major hearing impairments, and affected individuals often show compromised ability in processing fine temporal structures of sound. While most studies of NIHL and AHL focus on the peripheral defects, much less is known about accompanying alterations in the central auditory system. This proposal will explore the changes of synaptic transmission and the underlying cellular mechanisms following NIHL and AHL at the endbulb of Held synapses. These synapses are the first synaptic connection of the central auditory system and are well known to be important in fine temporal processing. Preliminary data shows that synaptic transmission at mouse endbulbs of Held is compromised with NIHL and AHL, likely due to impaired calcium homeostasis in the endbulb terminals. The first aim of this proposal will test the hypothesis that elevation of calcium concentration at the presynaptic terminal underlines the aberrant synaptic release during sustained activity following NIHL. Synaptic transmission will be evaluated in both normal and NIHL mice utilizing manipulations that modify calcium buffering in the microdomain and nanodomains near the active zone. The source of the calcium elevation will be identified by assessing synaptic transmission while disrupting specific pathways including external calcium influx via voltage-gated calcium channels, Ca-calmodulin dependent calcium channel inactivation, and calcium induced calcium release from internal calcium stores via ryanodine receptors and IP3 receptors. The second aim of this proposal will explore the functional impact of the changes in synaptic transmission following NIHL by examining the firing properties of postsynaptic bushy cells. This aim will test the hypothesis that increase in asynchronous release in NIHL mice leads to decreased synaptic efficacy and compromised temporal precision. Particularly, the study will also explore manipulations that can acutely restore the normal firing properties of bushy cells in slice. The third aim of this proposal will tst the hypothesis that impaired synaptic transmission at the endbulbs during AHL share the same impaired calcium homeostasis mechanisms as observed in NIHL. As in Aims 1 and 2, Aim 3 will examine the synaptic transmission and test the signaling pathways in aged mice with AHL. The long-term goal of this study is to identify the common cellular mechanisms that underlie synaptic modifications of the central auditory system following NIHL and AHL, and to identify manipulations that can acutely rescue normal synaptic function in a preclinical model. Ultimately, these studies could suggest approaches for future clinical treatments of NIHL and AHL.

描述（由申请人提供）：噪声性听力损失（NIHL）和年龄相关性听力损失（AHL）是两种主要的听力障碍，受影响的个体在处理声音的精细时间结构方面通常表现出受损的能力。虽然大多数 NIHL 和 AHL 的研究都集中在外周缺陷上，但对中枢听觉系统伴随的改变知之甚少。该提案将探讨 NIHL 和 AHL 后 Held 突触末端突触传递的变化以及潜在的细胞机制。这些突触是中枢听觉系统的第一个突触连接，众所周知，它们在精细时间处理中非常重要。初步数据显示，小鼠 Held 终球的突触传递受到 NIHL 和 AHL 的影响，可能是由于终球末端钙稳态受损所致。该提案的第一个目标将检验以下假设：突触前末梢钙浓度的升高强调了 NIHL 后持续活动期间突触释放的异常。将利用改变活性区附近微域和纳米域中钙缓冲的操作来评估正常小鼠和 NIHL 小鼠的突触传递。钙升高的来源将通过评估突触传递来确定，同时破坏特定途径，包括通过电压门控钙通道的外部钙流入、钙调蛋白依赖性钙通道失活以及通过兰尼丁受体和IP3从内部钙库中钙诱导的钙释放受体。该提案的第二个目标是通过检查突触后浓密细胞的放电特性来探讨 NIHL 后突触传递变化的功能影响。这一目标将检验以下假设：NIHL 小鼠中异步释放的增加会导致突触功效降低和时间精度受损。特别是，该研究还将探索能够迅速恢复切片中浓密细胞正常放电特性的操作。该提案的第三个目标将验证以下假设：AHL 期间末球突触传递受损与 NIHL 中观察到的钙稳态机制受损相同。与目标 1 和 2 一样，目标 3 将检查患有 AHL 的老年小鼠的突触传递并测试信号通路。这项研究的长期目标是确定 NIHL 和 AHL 后中枢听觉系统突触改变的常见细胞机制，并确定可以在临床前模型中迅速挽救正常突触功能的操作。最终，这些研究可以为未来 NIHL 和 AHL 的临床治疗提供建议。