Molecular dissection of the mammalian circadian clock: The roles of the deubiquitinase USP2 in the central clock and in brain function

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Looking for new gears of the biological clock in the brain Numerous aspects of physiology present 24-hour (or circadian) rhythms: sleep-wake cycles, feeding, hormones, body temperature, etc. These circadian rhythms allow the organism to adapt properly to cyclic variations of the environment (day-night cycles, seasons). Circadian rhythms are generated by "biological clocks", which are located in the brain as well as in various other organs. In recent years, many so-called "clock genes" have been discovered; these genes constitute the cogwheels of the biological clocks. The general objective of my research program is to understand exactly how these circadian clocks function and how they control physiology and behaviour. Recently, we found a new component of the biological clock, a protein called USP2. This protein seems to modify how other clock components work. Thus, this proposal describes the work of the next five years aiming at finding the exact role of USP2 within the clocks that are located in the brain. More specifically, we wish to find out how USP2 works in concert with other gears of the biological clock in the brain, and how it helps the clock to respond to environmental day-night cycles. We also plan to extend this research program to ask what else USP2 could do in the brain besides controlling daily rhythms. Our initial work suggest that it might be important for controlling other behaviours such as anxiety behaviour. Overall the work described here will shed new light on important mechanisms that directly link molecular brain events with behaviour.