Central Rhythmogenesis and Behavior

中枢节律发生和行为

• 批准号: 7625329
• 负责人: John P Welsh
• 金额: $ 37.5万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-03-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625329
• 关键词: Adult; Attenuated; Behavior; Biological Assay; Brain; Brain Hypoxia-Ischemia; Cell Death; Cerebellum; Cessation of life; Coupled; Coupling; Dendrites; Dominant-Negative Mutation; Electrical Synapse; Gap Junctions; Gene Transfer; Genetic; Glutamate Receptor; Hypoxia; Image; Immunofluorescence Microscopy; In Vitro; Inferior; Laboratories; Mediating; Membrane Potentials; Microscopy; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurons; Normal Range; Olives - dietary; Proteins; Purkinje Cells; Rattus; Receptor Activation; Research; Shapes; Structure; Sudden infant death syndrome; Testing; Up-Regulation; Western Blotting; Work; attenuation; clinically relevant; connexin 36; density; human NR1 protein; in vivo; killings; mutant; prevent; receptor function; receptor upregulation

This project will focus on the hypothesis that N-methyl-D-aspartate (NMDA) glutamate receptors and neuronal gap junctions act concertedly to determine the spatio-temporal dynamics of activity within electrically coupled networks in brain. The hypothesis will be tested in the inferior olive, a major afferent of the cerebellum that has the highest density of electrical synapses in the adult brain. Previous work from our laboratory showed that NMDA receptor activation induces high-threshold oscillations in membrane potential in inferior olive neurons and that neuronal gap junctions mediated by connexin36 are critical for the continuity and strength of coherent oscillations in the inferior olive. There are 4 aims. Aim 1 will determine whether NMDA receptors regulate electrical coherence and rhythm within a coupled network by acting on neuronal gap junctions in vivo. Aim 2 will determine whether NMDA receptors shape the spatial dynamics of electrical coupling in vitro. Aim 3 will determine whether there is a correspondence between NMDA receptor upregulation in the inferior olive and hypoxia-induced death of cerebellar neurons. Aim 4 will determine whether the block of NMDA receptor function in the inferior olive alone, or with neuronal gap junctions, will prevent delayed neuronal death in the cerebellum after hypoxia. These aims will be carried out with a combination of multielectrode recording, multibeam multiphoton microscopy, and gene transfer to express proteins with dominant-negative effect in the inferior olive. Recently, the upregulation of the NMDA receptor in the inferior olive and the death of Purkinje cells were independently related to sudden infant death syndrome. The research will establish how these clinically-relevant phenomena are related to one another.

这个项目的重点是假设N-甲基-D-天冬氨酸(NMDA)谷氨酸 受体和神经元缝隙连接共同作用决定时空 大脑中电耦合网络的活动动力学。假设将是 在下橄榄中测试，下橄榄是小脑的一种主要传入神经，密度最高 成人大脑中的电子突触。我们实验室以前的工作表明， N-甲基-D-天冬氨酸受体激活诱导膜电位高阈值振荡 下橄榄神经元和连接蛋白36介导的神经元缝隙连接 对下位橄榄中相干振荡的连续性和强度至关重要。那里 有四个目标。目标1将确定NMDA受体是否调节电连贯性 以及通过作用于体内神经元缝隙连接的耦合网络中的节律。目标2 将决定NMDA受体是否塑造了电信号的空间动力学 体外偶联。目标3将确定两者之间是否对应 下橄榄核NMDA受体上调与缺氧性小脑死亡 神经元。Aim 4将确定NMDA受体的阻断是否在 单独使用下橄榄或与神经元缝隙连接可以防止迟发性神经元死亡。 在缺氧后的小脑中。这些目标的实现将结合以下几个方面 多电极记录、多光束多光子显微镜和基因转移 在下位橄榄中表达具有显性负效应的蛋白质。最近， 下橄榄NMDA受体上调与浦肯野细胞死亡 与婴儿猝死综合征独立相关。这项研究将 确定这些与临床相关的现象是如何相互联系的。