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 美国大约有800万成年人因损坏外围而遭受平衡损伤 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 前庭管和耳石器官将运动转换为受体电位，感官信息被传达到 前庭传入神经中的动作电位（AP）的大脑。前庭中央区域（CZ）的传入 与外围区（PZ）中的传入相比，神经上皮对前庭刺激的反应不同。这 神经代码的性质传达了不同传播类型中前庭信息的性质。那里 是三种前庭传入类型：仅花萼的传入剂支配一个或多个I型毛细胞，胸部树突 支配II型毛细胞和二态传入剂与两种毛细胞类型接触。我们的目标是阐明独特的 具有花萼端子传入的AP发射机制，以更好地了解前庭编码。仅花萼 传入仅存在于CZ中，并且具有不规则的射击模式，而双态传入都存在 CZ和PZ具有规则的触发方式。为了实现我们的目标，我们将完善前庭的新颖准备 由我们的实验室开发的Cristae和Utrect 沙鼠神经上皮。电生理，发束刺激，免疫组织化学和药理 方法将使传入纤维中的离子通道在发育和成熟的上皮中表征。在 AIM 1我们将确定K+通道和超极化激活的环状核苷酸的贡献 在CZ和PZ传入中，通向AP射击的通道。 AIM 2将测试NAV1.6通道的假设 瞬态和复兴的特征性有助于成熟的PZ Dimorphs中的AP触发。在目标3中，我们将 将目标1和2的离子频道数据纳入一个新颖的，定制的三维数学 花萼的模型，可深入了解我们的区域驱动的实验发现。确定如何通道 本地化直接影响AP射击，确定的频道类型将在策略上放置在内部和外部 花萼端子的面和相关的轴突和通道密度各不相同。我们的结果将阐明感觉如何 传达信息以及如何在隔离的前庭传入中生成区域编码。我们的数据 将告知针对传入中离子渠道的特定组的前庭神经疗法的开发 神经。现有的前庭假体植入物试图通过直接电气恢复正常的前庭功能 刺激前庭传入。对前庭内AP的产生和传播的更清晰了解 需要传入的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，并告知开发 对抗前庭功能障碍的药物和电气策略。