Heterogeneity of responses in vestibular primary afferents

前庭初级传入反应的异质性

• 批准号: 9933645
• 负责人: Katherine Janet Rennie
• 金额: $ 15.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9933645
• 关键词: 3-Dimensional; Action Potentials; Adult; Afferent Neurons; Automobile Driving; Axon; Biophysics; Brain; Cells; Characteristics; Code; Crista ampullaris; Custom; Data; Dendrites; Development; Dimensions; Electric Stimulation; Electrophysiology (science); Epithelium; Equilibrium; Exhibits; Face; Fiber; Frequencies; Functional disorder; Future; Generations; Geometry; Glutamates; Goals; Hair; Hair Cells; Heterogeneity; Implant; Individual; Ion Channel; Kinetics; Label; Laboratories; Location; Mechanics; Mediating; Modeling; Motion; Nature; Nerve Fibers; Neuroepithelial; Organ; Patients; Pattern; Peripheral; Pharmacology; Pharmacotherapy; Phase; Physiologic pulse; Physiological; Population; Potassium Channel; Preparation; Process; Property; Prosthesis; Protocols documentation; Regulation; Rodent; Role; Semicircular canal structure; 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; afferent nerve; cell type; density; dimorphism; effective therapy; electrical property; equilibration disorder; functional restoration; implant design; indium arsenide; insight; mathematical model; novel; novel therapeutics; otoconia; patch clamp; postnatal development; receptor; regional difference; relating to nervous system; response; ribbon synapse; therapeutic target; tool; transmission process; 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 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 action potential 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 rodent neuroepithelia. We will employ electrophysiological, hair bundle stimulation, immuno- histochemical and pharmacological approaches to characterize ion channels in CZ and PZ afferent fibers in developing and mature epithelia. In Aim 1 we will determine the contributions of K+ channels to action potential firing in CZ and PZ afferents. Aim 2 will test the hypotheses that tetrodotoxin (TTX)-sensitive Nav1.6 Na+ channels contribute uniquely to action potential firing in mature PZ dimorphs, and that TTX-insensitive Na+ channels are transiently expressed during development. 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 action potential 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, but implants that restore function to both otolith and semicircular canal afferent neurons do not yet exist. Our results will provide important new information on vestibular afferent coding that could inform development of and drive new paradigms in vestibular implants.

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。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 带有萼末梢的传入神经的动作电位放电机制，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，而二形传入神经 存在于 CZ 和 PZ 中并且具有规则的发射模式。为了实现我们的目标，我们将完善新颖的制剂 由我们实验室开发的前庭嵴和椭圆囊，作为研究 CZ 中萼轴承传入的工具 和啮齿动物神经上皮的 PZ。我们将采用电生理学、发束刺激、免疫- 组织化学和药理学方法来表征 CZ 和 PZ 传入纤维中的离子通道 发育和成熟的上皮。在目标 1 中，我们将确定 K+ 通道对动作电位的贡献 CZ 和 PZ 传入神经放电。目标 2 将检验河豚毒素 (TTX) 敏感 Nav1.6 Na+ 的假设 通道对成熟 PZ 二晶型的动作电位放电有独特贡献，并且 TTX 不敏感的 Na+ 通道在发育过程中短暂表达。在目标 3 中，我们将合并来自的离子通道数据 目标 1 和 2 成为一种新颖的、定制的花萼三维数学模型，以提供洞察力 进入我们的区域驱动的实验结果。确定渠道本地化如何直接影响行动 潜在的发射，确定的通道类型将战略性地放置在花萼的内表面和外表面上 末端和相关的轴突和通道密度各不相同。我们的结果将阐明感官信息是如何产生的 传递以及区域编码如何在分离的前庭传入神经中生成。我们的数据将告知 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。 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，但植入物可恢复耳石和半规管的功能 传入神经元还不存在。我们的结果将提供有关前庭传入的重要新信息 可以为前庭植入物的开发提供信息并推动新范例的编码。