Ion Channels and Excitability in the Peripheral Vestibular System

周围前庭系统的离子通道和兴奋性

• 批准号: 10361492
• 负责人: Katherine Janet Rennie
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361492
• 关键词: 3-Dimensional; Action Potentials; Adult; Afferent Neurons; Artificial Implants; Axon; Biophysics; Brain; Cells; Characteristics; Code; Crista ampullaris; Custom; Data; Dendrites; Development; Electric Stimulation; Electrophysiology (science); Epithelial; Equilibrium; Exhibits; Face; Fiber; Frequencies; Functional disorder; Future; Generations; Geometry; Gerbils; Goals; Hair; Hair Cells; Implant; Individual; Ion Channel; Kinetics; Label; Laboratories; Mediating; Membrane Potentials; Modeling; Motion; Nature; Nerve Fibers; Organ; Patients; Pattern; Peripheral; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Physiologic pulse; Physiological; Population; Potassium Channel; Preparation; Process; Property; Prosthesis; Protocols documentation; Regulation; Rodent; Role; Sensory; Shapes; Signal Transduction; Slice; Stimulus; Synapses; System; Testing; Tetrodotoxin; Tissues; Type I Hair Cell; Type II Hair Cell; Utricle structure; Variant; Vestibular Hair Cells; Work; afferent nerve; analog; cell type; combat; cyclic-nucleotide gated ion channels; density; dimorphism; effective therapy; electrical property; equilibration disorder; extracellular; implant design; insight; mathematical model; novel; novel therapeutics; otoconia; patch clamp; postnatal; receptor; regional difference; relating to nervous system; response; therapeutic target; tool; vestibular prosthesis; voltage; voltage clamp

Project Summary Approximately 8 million adults in the US suffer from balance impairment due to damage to the peripheral vestibular system, but effective treatments for balance dysfunction are lacking. Vestibular hair cells within vestibular canal and otolith organs convert motion into receptor potentials and sensory information is relayed to the brain by action potentials (APs) in vestibular afferent nerves. Afferents in central zones (CZ) of vestibular neuroepithelia exhibit different responses to vestibular stimuli than afferents in peripheral zones (PZ). The nature of the neural code conveying vestibular information in distinct afferent types is poorly understood. There are 3 types of vestibular afferents: calyx-only afferents innervate one or more type I hair cells, bouton dendrites innervate type II hair cells and dimorphic afferents contact both hair cell types. Our goal is to elucidate distinct AP firing mechanisms in afferents with calyx terminals to better understand vestibular coding. Calyx-only afferents are present solely in CZ and have irregular firing patterns, whereas dimorphic afferents exist in both CZ and PZ and have regular firing patterns. To achieve our goal we will refine novel preparations of vestibular cristae and utricles, developed by our laboratory, as tools to study calyx-bearing afferents in CZ and PZ of gerbil neuroepithelia. Electrophysiological, hair bundle stimulation, immunohistochemical and pharmacological approaches will allow characterization of ion channels in afferent fibers in developing and mature epithelia. In Aim 1 we will determine the contributions of K+ channels and hyperpolarization-activated cyclic nucleotide- gated channels to AP firing in CZ and PZ afferents. Aim 2 will test the hypotheses that Nav1.6 channels with transient and resurgent characterisitics contribute uniquely to AP firing in mature PZ dimorphs. In Aim 3 we will incorporate ion channel data from Aims 1 and 2 into a novel, custom-written three dimensional mathematical model of the calyx to provide insight into our zonally-driven experimental findings. To determine how channel localization directly impacts AP firing, identified channel types will be strategically placed on the inner and outer faces of the calyx terminal and associated axon and channel density varied. Our results will clarify how sensory information is conveyed and how zonal encoding is generated within segregated vestibular afferents. Our data will inform development of vestibular neurotherapeutics targeting specific groups of ion channels in afferent nerves. Existing vestibular prosthetic implants attempt to restore normal vestibular function by direct electrical stimulation of vestibular afferents. A clearer understanding of AP generation and propagation within vestibular afferent sub-types is needed to inform appropriate electrical stimulation parameters. Results from this work could provide important new information on vestibular afferent coding and inform development of pharmaceutical and electrical strategies to combat vestibular dysfunction.

项目概要 美国约有 800 万成年人因周围神经系统受损而患有平衡障碍 前庭系统，但缺乏平衡功能障碍的有效治疗方法。前庭毛细胞内 前庭管和耳石器官将运动转化为受体电位，并将感觉信息传递给 大脑通过前庭传入神经的动作电位（AP）。前庭中央区 (CZ) 的传入 神经上皮对前庭刺激的反应与外周区（PZ）传入细胞的反应不同。这 人们对以不同传入类型传递前庭信息的神经编码的性质知之甚少。那里 前庭传入神经有 3 种类型： 仅花萼传入神经支配一个或多个 I 型毛细胞、布顿树突 支配 II 型毛细胞，二态传入神经接触两种毛细胞类型。我们的目标是阐明不同的 具有萼末端的传入神经中的 AP 发射机制，以更好地理解前庭编码。仅花萼 传入神经仅存在于 CZ 中，并且具有不规则的放电模式，而二态传入神经则存在于 CZ 中 CZ 和 PZ 具有规则的射击模式。为了实现我们的目标，我们将完善前庭的新颖准备工作 嵴和椭圆囊，由我们实验室开发，作为研究 CZ 和 PZ 中萼轴承传入的工具 沙鼠神经上皮。电生理学、发束刺激、免疫组织化学和药理学 这些方法将能够表征发育中和成熟上皮细胞传入纤维中的离子通道。在 目标 1 我们将确定 K+ 通道和超极化激活的环核苷酸的贡献 CZ 和 PZ 传入中 AP 发射的门控通道。目标 2 将测试 Nav1.6 通道的假设 瞬态和复活特征对成熟 PZ 二形体中的 AP 放电有独特的贡献。在目标 3 中，我们将 将目标 1 和 2 中的离子通道数据合并到新颖的、定制的三维数学模型中 花萼模型，以深入了解我们的区域驱动的实验结果。确定如何通道 定位直接影响AP发射，确定的通道类型将战略性地放置在内部和外部 萼末端的面以及相关的轴突和通道密度各不相同。我们的结果将阐明感官如何 信息的传递以及区域编码是如何在分离的前庭传入神经中生成的。我们的数据 将为针对传入神经中特定离子通道组的前庭神经治疗药物的开发提供信息 神经。现有的前庭假体植入物试图通过直接电恢复正常的前庭功能 刺激前庭传入神经。更清楚地了解前庭内 AP 的生成和传播 需要传入子类型来告知适当的电刺激参数。这项工作的结果 可以提供有关前庭传入编码的重要新信息，并为前庭传入编码的发展提供信息 对抗前庭功能障碍的药物和电策略。