Central Rhythmogenesis and Behavior

描述（由申请人提供）：本项目将重点研究小脑两大传入系统之一的下橄榄内神经元同步和振荡的重要性。下橄榄是成年哺乳动物大脑中密度最高的电紧张突触和间隙连接，但它们的功能尚不清楚。我们的研究将采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是一种组装神经元间隙连接的蛋白质——它在体内以显性负向方式起作用，阻止内在连接蛋白36在橄榄树神经元树突棘中组装间隙连接。基本的工作假设是，下橄榄神经元之间的电紧张突触是小脑运动协调的基础。有四个具体目标。目的：研究连接蛋白36介导的间隙连接的抑制是否会阻断下橄榄神经元的膜电位阈下振荡并修复病理性震颤。目的2将确定下橄榄内连接蛋白36介导的间隙连接的抑制如何改变小脑皮层内的同步性和神经元相互作用。目的3将确定抑制下橄榄内的神经元同步性是否会改变涉及条件舌头突出行为的空间引导运动的时间和轨迹。目的4将确定下橄榄内连接蛋白36介导的间隙连接的阻断是否会阻止脑缺血后浦肯野细胞的死亡。这项研究将提供关于神经元同步在运动控制中的作用和脑缺血后浦肯野细胞死亡的基本信息。此外，该研究可能提供对特发性震颤的更深入的了解，特发性震颤与病理性下橄榄振荡有关

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