Central Rhythmogenesis and Behavior

本课题将重点研究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，以确定时空 大脑中电耦合网络内的活动动力学。假设是 在下橄榄中进行了测试，下橄榄是小脑的主要传入神经，密度最高 成年人大脑中的电突触。我们实验室以前的工作表明， NMDA受体激活诱导高阈值膜电位振荡 下橄榄核神经元和由连接蛋白36介导的神经元间隙连接， 关键的连续性和强度的相干振荡在下橄榄。那里 有四个目标。目的1将确定NMDA受体是否调节电相干性 和节律在一个耦合的网络通过作用于神经元间隙连接在体内。目的2 将决定NMDA受体是否塑造电的空间动力学 体外偶联目标3将确定是否有一个对应关系， 下橄榄核NMDA受体表达上调与缺氧性小脑死亡 神经元目的4：探讨阻断NMDA受体功能是否能降低脑缺血再灌注损伤的发生率。 单独或与神经元间隙连接一起使用，可防止迟发性神经元死亡 小脑缺氧后的反应这些目标将通过以下方式实现： 多电极记录，多束多光子显微镜，和基因转移， 在下橄榄中表达显性负效应蛋白。近日 下橄榄核中NMDA受体的上调和浦肯野细胞的死亡 与婴儿猝死综合征独立相关。这项研究将 确定这些临床相关现象是如何相互关联的。

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.