Cellular analysis of mammalian circadian rhythms

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The primary focus of work in this laboratory is on how daily rhythms of behavior and physiology are generated. This includes research into the biology of the central clock in the hypothalamus, the suprachiasmatic nucleus, as well as how a hierarchy of clocks throughout the body are controlled either by the central clock or directly by sensory input. The proposed research therefore follows two interrelated approaches. The first is aimed at an understanding of how the central clock produces circadian rhythms. When we switch on a gene (casein kinase-1-epsilon) within this clock in a mouse, the period of the animal's behavioral rhythm shortens. We will now produce mice where the gene is switched on only in specific cells, to see how these cells are involved in rhythm generation. The second approach is aimed at understanding how animals adjust their daily rhythms by learning the time of day that significant events occur. This will be accomplished by teaching animals to expect appetitive or aversive conditions at defined times of day, then examining how and where the cellular activity responsible for the time of day memory occurs in the brain. Finally, we will ask how the central clock is able to synchronize the time learning system in the absence of significant event. The work will contribute to our understanding of how multiple timing mechanisms in the body are coordinated. Time of day conditioning is thought to underlie the rhythms of craving seen in addiction, and internal disorganization of the many clocks throughout the body has been shown to lead to physical and mental issues such as cardiovascular disease and depressive disorders, as well as cognitive impairment.