AFFERENT SYNAPTIC TRANSMISSION IN THE MAMMALIAN COCHLEA

哺乳动物耳蜗中的传入突触传递

• 批准号: 7931014
• 负责人: ELISABETH GLOWATZKI
• 金额: $ 17.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931014
• 关键词: Acoustic Nerve; Action Potentials; Affect; Animals; Basilar Membrane; Boxing; Brain; Calcium; Cell membrane; Cochlea; Cochlear Implants; Code; Data; Dependence; Elements; Fiber; Future; Generations; Goals; Hair Cells; Hearing; Human; In Vitro; Inherited; Inner Hair Cells; Knowledge; Labyrinth; Location; Measures; Mechanics; Membrane Potentials; Modeling; Monitor; Mus; Mutation; Nerve Fibers; OTOF gene; Pattern; Property; Rattus; Recovery; Rodent; Role; Shapes; Signal Transduction; Site; Synapses; Synaptic Transmission; Testing; Theoretical Studies; Tissues; Translating; Vesicle; Whole-Cell Recordings; auditory pathway; base; deafness; depression; design; extracellular; in vivo; neuronal cell body; postsynaptic; pressure; presynaptic; receptor; research study; response; ribbon synapse; sensor; sound; synaptic depression; synaptic function; transmission process

DESCRIPTION (provided by applicant): This proposal seeks to investigate mechanisms of synaptic transmission at the inner hair cell (IHC) afferent synapse in the mammalian cochlea. In the inner ear, sound signals are converted into hair cell receptor potentials, and subsequently are translated at the afferent synapse into firing rates in auditory nerve fibers. Coding of sound critically depends on the diverse firing properties of auditory nerve fibers. Important features of auditory nerve fibers are their spontaneous firing rates, their thresholds of activation and their `rate level functions', describing the changes in firing rates in response to different sound pressure levels. Three main `sites' in cochlear transmission have been suggested to determine auditory nerve fiber properties: 1) basilar membrane mechanics; 2) IHC receptor potential; 3) IHC afferent synaptic transmission. Convincing arguments have been made that auditory nerve fibers with distinct properties (low versus high spontaneous rates; high versus low thresholds of activation) innervate the same IHCs. However, all 10-20 afferent fibers contacting one IHC `sense' the same receptor potential and therefore it is likely that differences in afferent fiber properties must arise at single synapses. The aim of this study is to ask which properties of auditory nerve fibers arise at the IHC afferent synapse, and how pre- and/or postsynaptic components specifically determine these properties. Excised cochlear tissue from 2-4 week old rodents will be used to perform simultaneous whole cell recordings from IHCs and afferent fiber terminals directly where they contact the IHCs. The transfer function at the IHC afferent synapse will be measured directly by controlling the IHC membrane potential and monitoring postsynaptic activity in the afferent terminal. Extracellular recordings will be used to monitor the rate of action potentials at the afferent terminal. Key to this approach is that it allows recordings after hearing onset, when the diverse properties of auditory nerve fibers have developed. Afferent fiber spontaneous rates, thresholds and transfer functions will be determined and afferent fiber adaptation will be measured. Simultaneous recordings from pairs of afferent fibers will provide a direct test of whether fibers with different properties do innervate a single IHC. Hypotheses based on in vivo experiments that have suggested specific loci as the origin for specific auditory nerve fiber properties will be reevaluated. The specific pre-or postsynaptic mechanisms responsible for specific firing patterns will be further investigated. A better understanding of the mechanisms that underlie the generation of diverse auditory nerve fiber firing properties will provide the basis for an improvement in cochlear implant design. The studies outlined in this proposal seek to understand the mechanisms that underlie synaptic transmission at the first synapse in the auditory pathway, the synapse between hair cells and auditory nerve fibers. The conversion of the hair cell receptor potential into a firing rate in the auditory nerve fibers is an important step in coding the sound signal for transmission to the brain. Our results will support studies that aim to model how auditory nerve activity is generated. These approaches can provide a future basis for better cochlear implant design.

描述（由申请人提供）：本提案旨在研究哺乳动物耳蜗内毛细胞（IHC）传入突触的突触传递机制。在内耳中，声音信号被转换成毛细胞受体电位，随后在传入突触处被翻译成听觉神经纤维中的放电率。声音的编码主要依赖于听觉神经纤维的不同放电特性。听觉神经纤维的重要特征是它们的自发放电率、它们的激活阈值和它们的“速率水平函数”，描述了响应不同声压水平的放电率的变化。耳蜗传递中的三个主要“位点”被认为决定了听觉神经纤维的特性：1）基底膜力学; 2）IHC受体电位; 3）IHC传入突触传递。令人信服的论点是，具有不同特性（低与高自发率;高与低激活阈值）的听觉神经纤维支配相同的IHC。然而，所有10-20个传入纤维接触一个IHC“感觉”相同的受体电位，因此很可能传入纤维特性的差异必须出现在单个突触。本研究的目的是问哪些属性的听觉神经纤维出现在IHC传入突触，以及如何前和/或突触后组件具体确定这些属性。从2-4周龄啮齿动物中切除的耳蜗组织将用于从IHC和直接接触IHC的传入纤维末端进行同步全细胞记录。通过控制IHC膜电位和监测传入末端的突触后活动，直接测量IHC传入突触的传递函数。细胞外记录将用于监测传入末梢的动作电位速率。这种方法的关键是，它允许在听力开始后进行记录，此时听觉神经纤维的各种特性已经发展。将确定传入纤维自发率、阈值和传递函数，并测量传入纤维适应性。来自成对传入纤维的同时记录将提供具有不同性质的纤维是否支配单个IHC的直接测试。将重新评估基于体内实验的假设，这些实验表明特定位点是特定听觉神经纤维特性的起源。负责特定放电模式的特定突触前或突触后机制将进一步研究。更好地理解产生不同听觉神经纤维放电特性的机制将为改进人工耳蜗设计提供基础。本提案中概述的研究旨在了解听觉通路中第一个突触（毛细胞和听觉神经纤维之间的突触）的突触传递机制。在听觉神经纤维中，毛细胞受体电位转换成放电率是编码声音信号以传输到大脑的重要步骤。我们的研究结果将支持旨在模拟听觉神经活动如何产生的研究。这些方法可以为更好的人工耳蜗设计提供未来的基础。