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.

项目摘要 在美国，大约有800万成年人因外周受损而患有平衡障碍 前庭系统，但缺乏有效的平衡障碍的治疗方法。前庭毛细胞内 前庭管和耳石器官将运动转化为感受器电位，感觉信息被传递到 前庭传入神经的动作电位(AP)对大脑的影响。前庭中央区(CZ)的传入 神经上皮细胞对前庭刺激的反应与周围区(PZ)的传入细胞不同。这个 在不同的传入类型中传递前庭信息的神经编码的性质还知之甚少。那里 前庭传入有3种类型：仅有花萼传入支配一个或多个I型毛细胞，周围有树突 支配II型毛细胞和双形态传入接触这两种毛细胞。我们的目标是阐明不同 为更好地理解前庭编码，具有花冠终末的传入神经元的AP放电机制。仅限花萼 传入仅存在于CZ，并具有不规则的放电模式，而两种类型的传入都存在 Cz和Pz，并有规律的放电模式。为了达到我们的目标，我们将改进前庭的新制剂 本实验室研制的冠状突起和胞果，可作为研究丘脑腹侧带和腹侧带的花萼传入纤维的工具。 沙土鼠神经上皮细胞。电生理、毛束刺激、免疫组织化学和药理学 方法将允许在发育和成熟的上皮细胞中表征传入纤维中的离子通道。在……里面 目的1我们将确定K+通道和超极化激活的环核苷酸的贡献。 在CZ和PZ传入中通向AP的门控通道。AIM 2将测试Nav1.6通道与 在成熟的PZ双晶型中，短暂和复活的特性对AP的放电有独特的贡献。在《目标3》中，我们将 将来自AIMS 1和2离子通道数据合并到新的、定制编写的三维数学中 为我们的带状驱动的实验结果提供洞察力。确定渠道的方式 本地化直接影响AP触发，确定的通道类型将战略性地放置在内部和外部 花萼末端及相关轴突和通道密度的面各不相同。我们的结果将阐明感官 信息被传达，以及在分离的前庭传入中如何产生区带编码。我们的数据 将为前庭神经疗法的发展提供信息，靶向于传入的特定离子通道组 太紧张了。现有的前庭假体试图通过直流电恢复正常的前庭功能 前庭传入神经的刺激。更清楚地了解AP在前庭内的产生和传播 需要传入子类型来通知适当的电刺激参数。这项工作的成果 可以提供关于前庭传入编码的重要新信息，并为 对抗前庭功能障碍的药物和电气策略。