Neural Basis of Mammalian Circadian Organization

哺乳动物下丘脑的视交叉上核（SCN）是一个主要的昼夜节律钟， 调节生理和行为。现在人们普遍认为，昼夜节律是由 在SCN中的单个神经元内，通过涉及转录的分子反馈回路网络， 生物钟基因和基因产物的反馈。膜现象，包括膜电位， 电脉冲和电压控制的离子流，通常不被认为是 核心时钟机制，而是涉及时间信息到达的途径的过程 来自环境的时钟，以及核心分子计时的途径中的过程 环将节律信号传输到SCN组织内和更远的其他振荡器。最近，研究在 在果蝇和哺乳动物中， 在目前的建议中，我们概述了一系列实验，将允许 我们来描述膜电位和钙内流在调节中所起的确切作用， SCN节律性的产生。将讨论三个具体目标。首先，我们将测试假设， 哺乳动物生物钟基因的节律性需要每天的钙流。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，我们将探讨 钙介导的时钟基因表达幅度变化的功能意义。在一起， 这三项实验努力应该为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.