Heterogeneity of responses in vestibular primary afferents

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 通过前庭传入神经的动作电位来控制大脑。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， 神经支配II型毛细胞，二形传入纤维接触两种毛细胞类型。我们的目标是阐明 动作电位放电机制的传入与花萼终端，以更好地了解前庭编码。 只有花萼传入只存在于CZ，并有不规则的放电模式，而二形传入 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，我们将改进新的准备工作， 我们实验室开发的前庭嵴和椭圆囊，作为研究CZ中含花萼传入的工具 和PZ。我们将采用电生理，毛束刺激，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传入中放电。目的2验证河豚毒素（TTX）敏感的Nav1.6 Na+ 通道在成熟的PZ二型体中对动作电位放电有独特的贡献，并且TTX不敏感的Na+ 通道在发育过程中瞬时表达。在目标3中，我们将结合离子通道数据， 目的1和2到一个新的，定制的书面三维数学模型的花萼，以提供洞察力 为了确定通道定位如何直接影响行动， 潜在的射击，确定通道类型将战略性地放置在花萼的内表面和外表面 终末和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是如何 以及分区编码如何在分离的前庭传入神经内产生。我们的数据将告诉 前庭神经疗法的发展靶向传入神经中的特定离子通道组。 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。 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。我们的研究结果将为前庭传入神经的研究提供重要的新信息 编码，可以告知前庭植入物的发展和驱动新的范例。

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.