Central Rhythmogenesis and Behavior

描述（由申请人提供）：本项目将重点研究以下假设：N-甲基-D-天冬氨酸（NMDA）谷氨酸受体和神经元间隙连接协同作用，以确定脑中电耦合网络内活动的时空动力学。该假设将在下橄榄中进行测试，下橄榄是小脑的主要传入神经，在成人大脑中具有最高密度的电突触。我们实验室以前的工作表明，NMDA受体激活诱导下橄榄核神经元膜电位的高阈值振荡，连接蛋白36介导的神经元间隙连接对于下橄榄核相干振荡的连续性和强度至关重要。有四个目标。目的1将确定NMDA受体是否通过作用于神经元间隙连接来调节体内耦合网络中的电相干性和节律。目的二是确定NMDA受体是否影响电偶联的空间动力学。目的3：探讨下橄榄核NMDA受体表达上调与缺氧诱导的小脑神经元死亡之间是否存在对应关系。目的4将确定是否在下橄榄单独或与神经元间隙连接的NMDA受体功能的阻断，将防止在小脑缺氧后迟发性神经元死亡。这些目标将与多电极记录，多束多光子显微镜，和基因转移的组合进行，以表达蛋白质的显性负效应和RNA抑制剂序列在下橄榄。最近，上调NMDA受体在下橄榄和浦肯野细胞的死亡是独立相关的婴儿猝死综合征。这项研究将确定这些临床相关现象是如何相互关联的。公共卫生相关性本申请中提出的研究将提供关于称为下橄榄的特定脑区域中的神经元振荡的机制以及该脑区域中的病理活动触发小脑中的神经元死亡的可能性的重要信息。这些研究的结果不仅有助于我们对大脑功能的全面了解，而且可能与婴儿猝死综合征有关，这是大脑累积缺氧损伤的悲惨结果。这些研究的长期目标是确定大脑中正常和病理性振荡的细胞生物学和神经元系综机制。

DESCRIPTION (provided by applicant): 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 and RNA inhibitor sequences 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. PUBLIC HEALTH RELEVANCE The studies proposed in the present application will provide important information about the mechanisms of neuronal oscillation in a specific brain region named the inferior olive, and the potential for pathological activity in that brain area for triggering neuronal death in the cerebellum. The results of these studies will be useful not only for our general understanding of brain function but may be relevant to the sudden infant death syndrome, a tragic result of cumulative hypoxic damage to the brain. The long term goal of these studies is to determine the cell biological and neuronal ensemble mechanisms of normal and pathological oscillations in the brain.