Genetic dissection of circadian pacemaker function in the suprachiasmatic nucleus

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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.