Chemoanatomic bases for peripheral vestibular function

描述(由申请人提供)：寻找初级前庭传入反应动力学多样性的起源一直是前庭研究的主导主题，也是本提案的主要主题。这项工作的长期目标是研究递质系统在塑造传入反应中的作用，近期目标是确定GABA和谷氨酸作为毛细胞递质的影响。这项研究的中心假设是，在处理汇聚的兴奋性(谷氨酸能)和抑制性(GABA能)毛细胞突触到单个传入神经元的树突上时，Crista对一些速度敏感的输入信号进行了数学微分(微积分)，这种推拉输入至少部分解释了观察到的广泛的传入反应。将追求三个具体目标。这些目标包括一种多学科的方法，利用技术和实验模型，因为它们特别适合实验，研究人员的研究经验，以及结果对理解人类前庭疾病的适用性。同时使用解剖学、生理学、药理学和数学工具来解决这些目标，并从多个角度检验假说。第一个目的是将壶腹水平管内毛细胞的化学解剖与初级传入反应动力学联系起来。第二个目的是确定毛细胞递质表型、毛细胞形态和毛细胞激活和反应动力学之间的关系。第三个具体目的是评估药物操纵GABA传递对水平管神经和单个传入纤维的影响。递质表型在形成初级传入活动中的作用是前庭功能的一个基本的和临床上重要的方面，人们对此知之甚少。大多数研究将在蟾鱼身上进行，这在实验上是有利的，因为它们的可用性，容易暴露和提取它们的迷路，以及整个脊椎动物门的前庭内脏的相似性。建议在小鼠身上进行更多的研究，以将在蟾鱼中的发现与哺乳动物的前庭系统联系起来，从而确立结果的普遍性和与人类健康的相关性。这项拟议的研究是独一无二的，将直接关系到开发更有效的治疗干预措施，包括药物和设备导向的外周前庭疾病。

DESCRIPTION (provided by applicant): The search for the origins of diversity in primary vestibular afferent response dynamics has been a dominant theme of vestibular research and is the major subject of the present proposal. The long-term goal of the work is to study the role of transmitter systems in shaping afferent responses, and the immediate objective is to identify the impact of GABA and glutamate as hair cell transmitters. The central hypothesis of the research is that the crista performs a mathematical differentiation (differential calculus) of some velocity-sensitive input signals in processing convergent excitatory (glutamatergic) and inhibitory (GABAergic) hair cell synapses onto dendrites of single afferent neurons and that this push-pull input accounts, at least in part, for the wide range of observed afferent responses. Three specific aims will be pursued. These aims embrace a multidisciplinary approach utilizing techniques and experimental models selected for their particular suitability for the experiments, the research experience of the investigators, and the applicability of the results to understanding human vestibular disorders. Anatomical, physiological, pharmacological and mathematical tools are employed concomitantly to address the aims and test hypotheses from multiple perspectives. The first aim is to relate the chemical anatomy of the hair cells in the horizontal canal crista ampullaris to primary afferent response dynamics. The second aim is to identify the relationship between hair cell transmitter phenotype, hair cell morphology, and hair cell activation and response kinetics. The third specific aim is to evaluate the effects of pharmacological manipulation of GABA transmission on the horizontal canal nerve and on individual afferent fibers. The role of transmitter phenotype in shaping primary afferent activity is a fundamentally and clinically important aspect of vestibular function that is poorly understood. Most studies will be conducted in toadfish, which are experimentally advantageous because of their availability, the ease of exposing and extracting their labyrinths, and the similarity of vestibular endorgans throughout the vertebrate phyla. Additional studies in mouse are proposed in order to relate findings in toadfish to a mammalian vestibular system, thus establishing the generality and human health relevance of the results. The proposed research is unique, and will have direct bearing on the development of more effective therapeutic interventions, both medicinal and device-oriented, for peripheral vestibular disorders.