Chemoanatomic bases for peripheral vestibular function

外周前庭功能的化学解剖学基础

• 批准号: 6868768
• 负责人: Gay R Holstein
• 金额: $ 50.83万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-05 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868768
• 关键词: afferent nerve; alternatives to animals in research; biological models; biological signal transduction; cell morphology; cellular polarity; dendrites; ear hair cell; fish; gamma aminobutyrate; glutamates; immunocytochemistry; laboratory mouse; neural information processing; neural transmission; neuroanatomy; neurochemistry; neurons; neuropharmacology; neurophysiology; neurotransmitter receptor; phenotype; protein localization; semicircular duct; vestibular apparatus

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.

描述（由申请人提供）：搜索主要前庭传入反应动态多样性的起源一直是前庭研究的主要主题，并且是本提案的主要主题。这项工作的长期目标是研究发射机系统在塑造传入响应中的作用，而直接目标是将GABA和谷氨酸的影响确定为毛细胞发射机。这项研究的中心假设是，Crista在处理收敛兴奋剂（谷氨酸能）和抑制性（GABAERGAGIC）毛细胞突触中对某些速度敏感输入信号的数学分化（差分计算）进行了对单个相关神经元的树突的突变，并至少会遇到了范围的范围，至少会均应构成一定的反应。将追求三个具体目标。这些目的采用了采用技术和实验模型的多学科方法，以特殊的适用性，研究人员的研究经验以及结果适用于理解人类前庭疾病的适用性。解剖学，生理，药理和数学工具同时采用了从多个角度解决目标和检验假设。第一个目的是将水平运河Crista ampullaris中毛细胞的化学解剖学与一级传入反应动力学联系起来。第二个目的是确定毛细胞发射机表型，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GABA传播对水平管神经和个体传入纤维的药理操作的影响。发射机表型在塑造主要传入活性中的作用是前庭功能的根本和临床重要方面，知之甚少。大多数研究都将在蟾蜍中进行，由于它们的可用性，易于暴露和提取迷宫的易用性以及整个脊椎动物门的前庭内虫的相似性，它们在实验上具有优势。提出了对小鼠的其他研究，以将蟾蜍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，将直接与外围前庭疾病的更有效的治疗干预措施的发展有关。