Genetic dissection of circadian pacemaker function in the suprachiasmatic nucleus

生物钟以大约24小时的周期驱动生理和行为的节奏。在哺乳动物中，主昼夜节律振荡器位于视交叉上核（SCN），这是大脑底部的一个配对结构。每个半球仅由大约20，000个神经元组成，在小鼠中或45，000人中，它们同步振荡，以便在身体轴上传输连贯的定时信号，从而对太阳日所指示的环境变化做出最佳的生理和行为反应。有人建议，SCN的功能分为亚室，然而，在体内的证据支持这一观点仍然很大程度上缺乏。使用一种新的遗传策略，我们计划系统地消除或恢复从小鼠SCN的不同细分产生的节律，然后测试体内的功能后果。这些实验可能不仅揭示了关于SCN功能细分存在的基本问题，而且还可能揭示SCN神经元之间如何保持节律同步。由于SCN神经元支配各种大脑区域，因此拟议的研究可能会产生大脑中SCN起搏器目标的高分辨率功能图。最终，这些研究可能会提供关键的见解，了解哺乳动物睡眠，进食和运动行为的时间组织的基础机制知之甚少。

Circadian clocks drive rhythms in physiology and behavior with a period of about 24 hours. In mammals the master circadian oscillator is located in the suprachiasmatic nucleus (SCN), a paired structure at the base of the brain. Each hemisphere consists only of about 20,000 neurons in mice or 45,000 in humans that oscillate in synchrony in order to transmit a coherent timing signal across the body axis permitting an optimal physiological and behavioral response to the environmental changes dictated by the solar day. It is suggested that the SCN is functionally divided into subcompartments, however, in vivo evidence in support of this view is still largely lacking. Using a novel genetic strategy, we plan to systematically eliminate or restore rhythm generating from distinct subdivisions of the mouse SCN and then test for functional consequences in vivo. These experiments might not only shed light on the fundamental question regarding the existence of functional SCN subdivisions, but may also reveal how rhythmic synchrony is maintained among SCN neurons. Because SCN neurons innervate various brain areas, it is likely that the proposed research will yield a high resolution, functional map of SCN pacemaker targets in the brain. Ultimately, these studies are likely to provide critical insights into the poorly understood mechanisms underlying the temporal organization of mammalian sleep, feeding, and locomotor behavior.