Genetic dissection of circadian pacemaker function in the suprachiasmatic nucleus

生物钟驱动生理和行为的节律，周期约为24小时。在哺乳动物中，主要的昼夜节律振荡器位于视交叉上核(SCN)，这是大脑底部的一对结构。每个大脑半球只有大约2万个神经元组成，老鼠只有45000个神经元，人类只有大约45000个神经元，它们同步振荡，以便在体轴上传输一致的定时信号，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。有人认为，SCN在功能上被划分为不同的亚室，然而，体内证据仍然很少支持这一观点。使用一种新的遗传策略，我们计划系统地消除或恢复小鼠SCN不同细分产生的节律，然后在体内测试功能后果。这些实验不仅可能阐明有关SCN功能亚群存在的根本问题，还可能揭示SCN神经元之间如何维持节律同步。由于SCN神经元支配着大脑的不同区域，因此这项拟议的研究很可能会产生大脑中SCN起搏器靶标的高分辨率、功能图。最终，这些研究可能会对哺乳动物睡眠、进食和运动行为的时间组织背后鲜为人知的机制提供关键的见解。

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.