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: 10219544
• 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/10219544
• 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800万成年人由于外周神经损伤而患有平衡障碍。 前庭系统，但缺乏有效的治疗平衡功能障碍。前庭毛细胞 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 通过前庭传入神经中的动作电位（AP）来观察大脑。前庭中枢传入纤维 神经上皮对前庭刺激的反应与外周区（PZ）的传入神经不同。的 在不同的传入类型中传递前庭信息的神经代码的性质知之甚少。那里 有3种类型的前庭传入：仅花萼传入神经支配一个或多个I型毛细胞， 受神经支配的II型毛细胞和二型传入纤维接触两种类型的毛细胞。我们的目标是阐明 AP放电机制与花萼终端传入更好地了解前庭编码。只有花萼 传入只存在于CZ中，并且具有不规则的放电模式，而两种传入都存在于CZ中。 CZ和PZ有规律的射击模式。为了实现我们的目标，我们将改进前庭的新制剂， 嵴和胞果，作为工具，研究花萼轴承传入的CZ和PZ的 沙鼠神经上皮电生理学、毛束刺激、免疫组织化学和药理学 这些方法将允许表征发育和成熟上皮中传入纤维中的离子通道。在 目的1研究钾离子通道和超极化激活的环核苷酸通道在心肌细胞中的作用。 门控通道到CZ和PZ传入中的AP放电。目标2将检验Nav1.6通道与 在成熟的PZ二型体中，短暂和复活的特征对AP放电有独特的贡献。在目标3中， 将来自目标1和2离子通道数据结合到新颖的定制编写的三维数学模型中， 模型的花萼，以提供深入了解我们的区域驱动的实验结果。要确定通道如何 定位直接影响AP发射，识别的通道类型将被战略性地放置在内部和外部 花萼顶面及相关轴突和通道密度变化。我们的研究结果将阐明感官 信息的传递以及在分离的前庭传入内如何产生区域编码。我们的数据 将告知前庭神经治疗剂的发展，靶向传入神经中的特定离子通道组。 神经现有的前庭假体植入物试图通过直接电刺激来恢复正常的前庭功能。 前庭传入神经的刺激。更清楚地了解前庭内AP的产生和传播 需要传入子类型来通知适当的电刺激参数。这项工作的结果 可以提供关于前庭传入编码的重要新信息，并为 药物和电策略来对抗前庭功能障碍。