Postsynaptic Activity of Type II Cochlear Afferents

II 型耳蜗传入神经的突触后活动

• 批准号: 7911353
• 负责人: Catherine Jeanne Chalenski Weisz
• 金额: $ 3.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911353
• 关键词: Acoustics; Action Potentials; Afferent Neurons; Agonist; Auditory; Cochlea; Data; Dendrites; Fiber; Frequencies; Hearing; Literature; Measures; Modeling; Morphology; Neuraxis; Neurons; Outer Hair Cells; Pathway interactions; Perception; Population; Process; Purines; Research Proposals; Role; Second Messenger Systems; Sensory; Stimulus; Substance P; Synapses; Techniques; Testing; Time; Tracer; auditory stimulus; base; cell injury; electrical property; postsynaptic; public health relevance; purine; receptor; response; seal; second messenger; sound; spiral ganglion; tool

DESCRIPTION (provided by applicant): The cochlea contains two types of primary afferent neurons, the Type I and Type II spiral ganglion neurons. 95% of the spiral ganglion population consists of the Type I neurons, which encode acoustic stimuli. The remaining 5% of the spiral ganglion population, the Type II neurons, ramify extensively among outer hair cells (OHCs). Little is known about their electrical properties as only a few recordings have been performed from the neurons. This lack of functional information precludes hypotheses as to the role of the Type II afferents in perception of auditory stimuli. We have developed a technique that allows gigaohm-seal intracellular recordings in Type II afferent dendrites near their synaptic inputs. Use of a neuronal tracer allows identification of the neurons based upon comparison to the known dendritic morphology well described in the literature. We propose to demonstrate that synaptic inputs to the Type II afferents from OHCs are functional, and to describe the strength of these inputs to Type II neurons. Comparison of the activation induced by synaptic inputs to the threshold for fiber activation as determined within the aims of this proposal will allow estimation of the level of stimulation of OHCs that may be necessary to induce supra-threshold activation of the Type II afferent. Electrophysiological parameters of the Type II dendrite will be incorporated into a cable model of the neuron. This can be used to determine the likelihood that stimuli will produce enough activation of the dendritic field to generate action potentials that may then be transmitted centrally to be incorporated into our perception of auditory stimuli. Purines stimulate the Type II afferents, both directly and by eliciting synaptic input from OHCs (preliminary data). While ATP serves many purposes, it can also be released from damaged cells and may be involved in signaling of cell damage in response to loud sounds. Other compounds implicated in cellular damage will be tested for their ability to activate Type II dendrites to further probe this hypothesis. Further, we will begin to describe processes by which the neurons are sensitized. Activation of UTP, an agonist at metabotropic P2Y receptors, stimulates Type II dendrites. Therefore, we will use pharmacological tools to manipulate second messenger pathways that may be downstream of P2Y activation in order to determine their role in Type II dendrite excitability. We will also test other compounds that may similarly initiate these second messenger cascades, such as Substance P, for their actions on activation and sensitization of Type II afferent dendrites. Prior to preliminary data presented for this proposal, nearly nothing was known regarding the activity in response to stimuli of one of the only two classes of primary auditory neurons. Therefore, analysis of the functions of Type II afferent neurons is crucial to a broader understanding of perception of sound. PUBLIC HEALTH RELEVANCE: The cochlea contains two types of neurons that transmit sensory information to the central nervous system, the Type I neurons which carry the acoustic information of sound timing, intensity and frequency, and the poorly understood Type II neurons about which little is known. This research proposal aims to develop techniques to measure electrical activity within the Type II neurons, which may enable a determination of their functional roles. An understanding of responses of both classes of auditory neurons is necessary for a complete understanding of perception of sound.

描述（由申请人提供）：耳蜗包含两种类型的初级传入神经元，即I型和II型螺旋神经节神经元。95%的螺旋神经节群由编码声刺激的I型神经元组成。螺旋神经节的其余5%的人口，II型神经元，广泛分歧之间的外毛细胞（OHC）。关于它们的电特性知之甚少，因为只有少数记录来自神经元。这种功能信息的缺乏排除了假设的作用，第二类传入的听觉刺激的感知。我们已经开发出一种技术，允许千兆欧姆密封的细胞内记录在II型传入树突附近的突触输入。神经元示踪剂的使用允许基于与文献中充分描述的已知树突形态的比较来鉴定神经元。我们建议证明，突触输入的第二型传入OHC的功能，并描述这些输入的强度II型神经元。将突触输入诱导的激活与本提案目标内确定的纤维激活阈值进行比较，将允许估计OHC刺激水平，这可能是诱导II型传入的阈上激活所必需的。将II型树突的电生理参数并入神经元的电缆模型中。这可以用来确定刺激将产生足够的树突场激活以产生动作电位的可能性，这些动作电位然后可以被集中传输以并入我们对听觉刺激的感知中。嘌呤刺激II型传入神经，既直接刺激，也通过诱发OHC的突触输入（初步数据）。虽然ATP有许多用途，但它也可以从受损细胞中释放出来，并可能参与细胞损伤的信号传导。将测试与细胞损伤有关的其他化合物激活II型树突的能力，以进一步探讨这一假设。此外，我们将开始描述神经元被敏化的过程。UTP是一种代谢型P2Y受体的激动剂，其激活可刺激II型树突。因此，我们将使用药理学工具来操纵可能是P2Y激活下游的第二信使途径，以确定它们在II型树突兴奋性中的作用。我们还将测试其他化合物，可能类似地启动这些第二信使级联反应，如P物质，其对II型传入树突的激活和敏化作用。在为这个提议提供初步数据之前，几乎没有人知道只有两类初级听觉神经元之一对刺激的反应。因此，分析II型传入神经元的功能对于更广泛地理解声音感知至关重要。 公共卫生相关性：耳蜗包含两种类型的神经元，它们将感觉信息传递到中枢神经系统，I型神经元携带声音定时，强度和频率的声学信息，而对II型神经元知之甚少。这项研究计划旨在开发测量II型神经元内电活动的技术，这可能有助于确定它们的功能作用。理解这两类听觉神经元的反应对于完全理解声音的感知是必要的。