Central Rhythmogenesis and Behavior

描述(申请人提供)：这个项目将集中在下橄榄内神经元同步和振荡的重要性，下橄榄是小脑的两个主要传入系统之一。在成年哺乳动物的大脑中，下橄榄具有最高密度的电紧张性突触和缝隙连接，但它们的功能仍然难以捉摸。我们的研究将使用一种新的遗传工具，涉及连接蛋白36的点突变-连接蛋白36是一种组装神经元缝隙连接的蛋白质-在体内以显性-负向的方式起作用，以防止内在的连接蛋白36在橄榄状神经元的树突中组装缝隙连接。基本的工作假设是，下橄榄核神经元之间的电紧张性突触是小脑运动协调的基础。有四个具体目标。目的我将确定抑制连接蛋白36介导的缝隙连接是否能阻断下橄榄核神经元的膜电位阈值下振荡，从而纠正病理性震颤。目的2将确定抑制连接蛋白36介导的下橄榄内缝隙连接如何改变小脑皮质内的同步性和神经元之间的相互作用。目标3将确定抑制下橄榄核内神经元的同步性是否会改变空间引导运动的时间和轨迹，包括条件性舌头突出行为。目的4将确定阻断下橄榄内连接蛋白36介导的缝隙连接是否能防止脑缺血后浦肯野细胞的死亡。这项研究将提供有关神经元同步性在运动控制中的作用以及在脑缺血后驱动浦肯野细胞死亡的基本信息。此外，这项研究可能会提供对特发性震颤的更多了解，特发性震颤与病理性下橄榄震荡有关。

DESCRIPTION (provided by applicant): This project will focus on the importance of neuronal synchrony and oscillation within the inferior olive, one of the two major afferent systems of the cerebellum. The inferior olive has the highest density of electrotonic synapses and gap junctions in the adult mammalian brain, but their function remains elusive. Our studies will employ a novel genetic tool involving a point-mutation in connexin36 - the protein that assembles neuronal gap junctions - that acts in a dominant-negative manner in vivo to prevent intrinsic connexin36 from assembling gap junctions in dendritic spines of olivary neurons. The basic working hypothesis is that electrotonic synapses among inferior olivary neurons are fundamental for cerebellar coordination of movement. There are four specific aims. Aim I will determine whether inhibition of connexin36-mediated gap junctions blocks inferior olivary neurons' sub-threshold oscillations in membrane potential and remediates a pathological tremor. Aim 2 will determine how inhibition of connexin36-mediated gap junctions within the inferior olive will alter synchrony and neuronal interaction within cerebellar cortex. Aim 3 will determine whether inhibition of neuronal synchrony within the inferior olive will alter the timing and trajectory of a spatially-guided movement involving a conditioned tongue protrusion behavior. Aim 4 will determine whether blockade of connexin36 mediated gap junctions within the inferior olive will prevent the death of Purkinje cells after brain ischemia. The research will provide fundamental information regarding the role of neuronal synchrony in motor control and for driving Purkinje cells into death after brain ischemia. Moreover, the research is likely to provide a greater understanding of essential tremor, which has been associated with pathological inferior olivary oscillation