Brainstem Gap Junctions in Respiratory Control

呼吸控制中的脑干间隙连接

• 批准号: 6780491
• 负责人: IRENE C SOLOMON
• 金额: $ 27.84万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780491
• 关键词: brain stem; carbon dioxide; cell cell interaction; central nervous system; chemoreceptors; electromyography; gap junctions; gene deletion mutation; genetically modified animals; glia; hypercapnia; immunocytochemistry; laboratory mouse; laboratory rat; perfusion; plethysmography; pulmonary respiration

DESCRIPTION (provided by applicant): Recent evidence indicates that gap junctions play a more prominent role in normal functioning of the mammalian central nervous system (CNS) than was once believed. Accumulating evidence from both neonatal and adult rodents indicates that gap junctions participate in multiple aspects of respiratory control, including central CO2 chemoreception. Central CO2 chemoreceptors have been demonstrated to be distributed at several sites in the mammalian brainstem, and respiratory neurophysiologists have gained tremendous insight as to how presumptive central CO2 chemoreceptor neurons work by studying the electrophysiological and anatomical properties of cells in in vitro preparations of the mammalian CNS. One feature that has been identified in CO2-chemosensitive neurons is cell-to-cell coupling which occurs via gap junctions. The presence of gap junctions between adjoining CO2-chemosensitive neurons and the demonstration of neuronal expression of the gap junction proteins (connexin; Cx) Cx26 and Cx32 in CO2-chemosensitive brainstem regions suggest that either electrical coupling and/or metabolic coupling is/are involved in respiratory control. The principle hypothesis of this proposal is that gap junctional communication plays an important role in mediating and maintaining the ventilatory response to elevated levels of CO2 (i.e., hypercapnia). The experiments proposed in this application will use both in vitro and in vivo models along with biochemical and immunohistochemical procedures to further define the role of gap junctions in CO2 chemoreception. The specific aims of the project are: (1) investigate the effects of pharmacological blockade (i.e., uncoupling) of brainstem gap junctions on CO2-chemoreception, (2) investigate the effects of genetic manipulation (deletion) of the neuronal gap junction proteins Cx32 and Cx 36 on CO2-chemoreception in vivo, (3) identify the repertoire of neuronal and glial gap junction proteins, including regional and postnatal developmental expression, in putative CO2-chemosensitive brainstem regions, (4) investigate the effects of hypercapnia on modulation of gap junction protein expression in putative CO2-chemosensitivie regions and (5) investigate the effects of a prior hypercapnia conditioning exposure on CO2 chemoreception.

描述（由申请人提供）：最近的证据表明，间隙连接在哺乳动物中枢神经系统（CNS）的正常功能中起着比以前认为的更重要的作用。来自新生儿和成年啮齿动物的累积证据表明，间隙连接参与呼吸控制的多个方面，包括中央二氧化碳化学感受。已经证明，中央二氧化碳化学感受器分布在哺乳动物脑干的多个部位，呼吸神经生理学家已经获得了关于假定的中央二氧化碳化学感受器神经元如何通过研究乳腺科制剂中细胞的电学生理学和解剖学特性来获得的推定中心CO2化学感受器神经元的巨大见解。在CO2-化学敏感的神经元中已鉴定的一个特征是通过间隙连接发生的细胞对细胞耦合。在二氧化碳连接蛋白（Connexin; CX）CX26和CX32中，在二氧化碳连接蛋白（CO2-化学敏感性脑干区域）之间的神经元表达之间存在间隙连接的存在表明，这表明要么是电耦合和/或代谢耦合的电气偶联性和/或代谢耦合性的。该提议的主要假设是，间隙连接通信在介导和维持对二氧化碳水平升高（即高碳酸盐）的通气反应中起着重要作用。本应用中提出的实验将同时使用体外和体内模型以及生化和免疫组织化学程序，以进一步定义GAP连接在CO2化学感受中的作用。该项目的具体目的是：（1）研究脑部间隙连接对CO2-肌受感受的药理阻滞（即解开）的影响，（2）研究神经元间隙差异蛋白CX32和CX 36对CO2-核能的遗传操纵（缺失）的影响（vivo）（3） （4）（4）研究过度capnia对假定的CO2-CO2-CEMOSENSENSITIVIE区域间隙连接蛋白表达的调节的影响，以及（5）研究先前的超碳酸酯条件曝光对Co2 Chem2化学的影响。