Synaptic Processing in the Vestibular System

前庭系统中的突触处理

• 批准号: 10357902
• 负责人: Ruth Anne Eatock
• 金额: $ 62.35万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-16 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357902
• 关键词: Action Potentials; Affect; Afferent Neurons; Anatomy; Area; Automobile Driving; Awareness; Axon; Biophysics; Brain; Cells; Chemicals; Chick; Complement; Computer Models; Consensus; Data; Development; Distal; Electrophysiology (science); Epithelial; Equilibrium; Excitatory Postsynaptic Potentials; Exocytosis; Fiber; Gap Junctions; Generations; Genetic; Genetic Models; Glutamate Receptor; Glutamates; Goals; HCN1 gene; Hair; Hair Cells; Head; Incidence; Individual; Investigation; Ion Channel; Ion Channel Gating; Ions; Kinetics; Labyrinth; Location; Maps; Methods; Modeling; Molecular; Morphology; Motion; Mus; Nerve Fibers; Neurites; Neurons; Pattern; Pharmacology; Phase; Physiological; Physiology; Population; Positioning Attribute; Postsynaptic Membrane; Posture; Preparation; Presynaptic Terminals; Property; Pump; Rattus; Receptor Cell; Recording of previous events; Reflex action; Regenerative research; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Saccule structure; Sensory; Sensory Receptors; Shapes; Signal Transduction; Sodium Channel; Source; Speed; Stains; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; System; Testing; Tetrapoda; To specify; Transgenic Animals; Turtles; Type I Epithelial Receptor Cell; Type I Hair Cell; Type II Hair Cell; Update; Utricle structure; Variant; Vertigo; Vesicle; Vestibular Hair Cells; Vestibular Nerve; Vestibular ganglion; Vestibular loss; Vision; Voltage-Gated Potassium Channel; Whole-Cell Recordings; afferent nerve; base; cell type; design; developmental genetics; experimental study; gaze; morphometry; neuronal patterning; patch clamp; postsynaptic; programs; quantum; response; ribbon synapse; transmission process; vesicular release; vestibular reflex; voltage

Project Summary/Abstract The vestibular inner ear supplies information about head motion and position to the brain, driving powerful reflexes that stabilize gaze and posture during head motions, and contributing to our sense of heading and orientation as we move through the world. Although we are not normally aware of these functions, their loss severely affects mobility by destabilizes vision and causes vertigo. Loss of vestibular function often originates in damage to hair cells and their synapses with the afferent vestibular nerve fibers that project to the brain. These hair cells, synapses, and afferent fibers have striking properties that are only partly understood. The longterm goal of this program of research is to build a comprehensive understanding of how vestibular information is generated and encoded in the inner ear. The current proposal focuses on the synaptic transfer of head motion signals from hair cells to primary vestibular neurons (Aim 1) and the subsequent initiation of action potentials (spikes) (Aim 2) in the mouse utricle, a model preparation for genetic, developmental and physiological studies. Principal methods are whole-cell patch clamping of hair cells and afferent neurons; immunolocalization of voltage-gated ion channels, pumps and synaptic markers; and computational modeling of the hair cells, synapses and afferent nerve fibers, incorporating current information on ion channels, pumps, and morphology. Vestibular afferent neurons make conventional bouton synaptic terminals on type II hair cells and unique calyceal contacts on type I hair cells. At both boutons and calyces, hair cells release vesicles of glutamate (“quantal” synaptic transmission) into the synaptic cleft, activating glutamate receptor-channels in the postsynaptic membrane to produce excitatory postsynaptic potentials and initiate spikes. At calyceal contacts, an additional “non-quantal” transmission mechanism depends not on vesicular release or gap junctions, but rather on flow of ions from the hair cell through ion channels into the synaptic cleft and into the calyx through different ion channels. Postsynaptic responses to controlled stimulation of individual hair bundles show that quantal and non-quantal transmission modes can occur at the same calyceal synapse and that the non-quantal mode provides a fast signal that may be important for high-speed vestibular reflexes. Proposed experiments and modeling will investigate the impact of key hair cell ion channels on non-quantal transmission and delineate how quantal and non-quantal transmission are integrated in individual calyces and afferent nerve fibers. Other experiments will test how specific voltage-gated potassium and sodium channels in calyces and boutons shape the postsynaptic voltage response and spikes in the axonal initial segment. Immunolocalization has revealed remarkable concentrations of ion channels in microdomains of the calyx ending and nearby spike initiation zone. Experiments focus on channels with the potential to shape salient differences in response dynamics and spike timing between afferents of different connectivity (hair cell inputs) and different zones of the sensory epithelium.

项目概要/摘要 前庭内耳向大脑提供有关头部运动和位置的信息，驱动强大的 在头部运动过程中稳定凝视和姿势的反射，有助于我们的方向感和方向感 当我们穿越世界时的方向。尽管我们通常不知道这些功能，但它们的丢失 视力不稳定并导致眩晕，严重影响行动能力。前庭功能丧失通常源于 毛细胞及其突触与投射到大脑的传入前庭神经纤维受到损害。 这些毛细胞、突触和传入纤维具有令人震惊的特性，但人们对这些特性的了解还只是部分。这 该研究计划的长期目标是全面了解前庭如何 信息在内耳中生成和编码。目前的提案侧重于突触转移 从毛细胞到初级前庭神经元的头部运动信号（目标 1）以及随后的启动 小鼠椭圆囊中的动作电位（尖峰）（目标 2），遗传、发育和发育的模型准备 生理学研究。主要方法是毛细胞和传入神经元的全细胞膜片钳； 电压门控离子通道、泵和突触标记的免疫定位；和计算建模 毛细胞、突触和传入神经纤维，结合离子通道、泵的当前信息， 和形态。 前庭传入神经元在 II 型毛细胞上形成传统的 bouton 突触末端，并且独特 I 型毛细胞上的肾盏接触。在纽扣和花萼处，毛细胞释放谷氨酸囊泡 （“量子”突触传递）进入突触间隙，激活神经元中的谷氨酸受体通道 突触后膜产生兴奋性突触后电位并启动尖峰。在肾盏接触处， 额外的“非量子”传输机制不依赖于囊泡释放或间隙连接，而是 相反，离子从毛细胞通过离子通道进入突触间隙并通过 不同的离子通道。对单个发束受控刺激的突触后反应表明 量子和非量子传输模式可以发生在同一个肾盏突触处，并且非量子传输模式可以发生在同一个肾盏突触处。 模式提供快速信号，这对于高速前庭反射可能很重要。提议的实验 建模将研究关键毛细胞离子通道对非量子传输和 描述量子和非量子传输如何在个体肾盏和传入神经中整合 纤维。其他实验将测试肾盏中特定的电压门控钾和钠通道如何 纽扣塑造突触后电压响应和轴突初始段的尖峰。免疫定位 揭示了花萼末端和附近尖峰的微域中离子通道的显着浓度 起始区。实验重点关注有可能形成显着响应差异的通道 不同连接（毛细胞输入）和不同区域的传入神经之间的动态和尖峰时序 感觉上皮。