Heterogeneity of responses in vestibular primary afferents

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，具有花萼终末的传入神经的动作电位放电机制。 仅有花瓣的传入传入仅存在于CZ，并具有不规则的放电模式，而二态传入传入 在CZ和PZ中都存在，并有规则的激发模式。为了实现我们的目标，我们将改进新的准备工作 前庭、前庭、前庭 和啮齿动物神经上皮细胞的PZ。我们将使用电生理，发束刺激，免疫- 大鼠CZ和PZ传入纤维离子通道的组织化学和药理学研究 发育成熟的上皮细胞。在目标1中，我们将确定K通道对动作电位的贡献 在CZ和PZ传入区开火。Aim 2将测试河豚毒素(TTX)敏感的Nav1.6 Na 在成熟的PZ二型体中，通道对动作电位的激发具有独特的贡献，而TTX不敏感的Na 通道是在发育过程中瞬时表达的。在目标3中，我们将合并来自 目标1和2成为一个新颖的、定制编写的花萼三维数学模型，以提供洞察力 进入我们的地带性实验发现。确定渠道定位如何直接影响行动 潜在的射击，确定的通道类型将战略性地放置在花萼的内、外表面上 终末及相关轴突和通道密度不同。我们的结果将阐明感官信息是如何 以及在分离的前庭传入中如何产生区带编码。我们的数据会告诉你 针对传入神经中特定离子通道组的前庭神经疗法的发展。 现有的前庭假体试图通过直流电恢复正常的前庭功能 刺激前庭传入，但植入可恢复耳石和半规管功能的植入物 传入神经元还不存在。我们的结果将为前庭传入提供重要的新信息 编码可以为前庭植入物的发展提供信息并推动新的范例。

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.