Neural Basis of Mammalian Circadian Organization

哺乳动物下丘脑的视交叉上核(SCN)是一种主要的生物钟，它 调节生理和行为。现在人们普遍认为昼夜节律是由 在SCN的单个神经元中，通过涉及转录的分子反馈环网络 基因时钟和基因产物反馈。膜现象，包括膜电位， 电脉冲和电压控制的离子通量通常不被认为是 核心时钟机制，而不是参与时间信息到达的路径的过程 时钟来自环境，以及进程中的核心分子所通过的路径计时 Loop将节律信号传输到SCN组织内外的其他振荡器。最近，在中国的研究 果蝇和哺乳动物提出了膜可能发挥更核心作用的问题 电导，特别是钙在目前的提案中，我们概述了一系列实验，将允许 US将表征膜电位和钙内流在调节和恢复钙离子中的确切作用 SCN节律性的产生。将解决三个具体目标。首先，我们将检验一个假设 哺乳动物时钟基因的节律性需要每日的钙离子流量。其次，我们将探索时间- 钙内流对起搏器功能的依赖性。最后，在第三个具体目标中，我们将探索 钙离子介导的时钟基因表达幅度变化的功能意义。一起， 这三项实验工作应该会对昼夜节律系统的关键方面提供新的见解 同步和节奏生成。

The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is a major circadian clock that regulates both physiology and behavior. It is now commonly accepted that circadian rhythms are generated within individual neurons in the SCN through a network of molecular feedback loops involving transcription of clock genes and feedback by gene products. Membrane phenomena, including membrane potential, electrical impulses and voltage-controlled ionic fluxes, have generally not been considered to be part of the core clock mechanism but rather processes involved in the pathways by which temporal information reaches the clock from the environment, as well as processes in the pathways by which the core molecular timing loop transmits rhythmic signals to other oscillators within the SCN tissue and beyond. Recently, studies in Drosophila and in mammals have raised the issue of a potentially more central role for membrane conductances, specifically calcium In the current proposal we outline a series of experiments that will allow us to characterize the precise role played by membrane potential and calcium influx in the regulation and generation of SCN rhythmicity. Three specific aims will be addressed. First, we will test the hypothesis that a daily calcium flux is required for rhyhthmicity in mammalian clock genes. Secondly, we will explore the time- dependency of calcium influx on pacemaker function. Finally, in a third specific aim we will explore the functional significance of calcium-mediated changes in the amplitude of expression of clock genes. Together, the three experimental efforts should provide new insights into critical aspects of circadian system synchronization and rhythm generation.