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形成传入反应中的作用，近期目标是确定GABA和谷氨酸作为毛细胞递质的影响。该研究的中心假设是，嵴执行一些速度敏感的输入信号的数学微分（微分）在处理会聚兴奋性（多巴胺能）和抑制性（GABA能）毛细胞突触到单个传入神经元的树突上，并且这种推拉输入至少部分地解释了所观察到的传入反应的广泛范围。将追求三个具体目标。这些目标包括一个多学科的方法，利用技术和实验模型，选择他们的特别适合的实验，研究人员的研究经验，并了解人类前庭疾病的结果的适用性。解剖学，生理学，药理学和数学的工具，同时从多个角度来解决的目标和测试假设。第一个目的是与化学解剖的毛细胞在水平管嵴壶腹初级传入反应动力学。第二个目的是确定毛细胞递质表型，毛细胞形态，毛细胞活化和反应动力学之间的关系。第三个具体目标是评估GABA传输的药理学操作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和临床重要方面，但人们对此知之甚少。大多数研究将在蟾鱼中进行，这在实验上是有利的，因为它们的可用性，易于暴露和提取它们的触角，以及整个脊椎动物门前庭终器的相似性。提出了在小鼠中进行的其他研究，以便将蟾鱼中的发现与哺乳动物前庭系统联系起来，从而建立结果的一般性和人类健康相关性。拟议的研究是独一无二的，将直接关系到更有效的治疗干预措施的发展，无论是药物和设备为导向，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.