The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Why do birds sing in the morning and frogs call at night?  Why do most heart attacks strike before dawn, while asthmatic attacks generally occur after sunset? Or, why do we feel that the short, dark days of winter are dreary and the long, sunny days of summer are cheerful and bright? The answer to each of these questions lies in understanding the central role that biological clocks play in organizing the internal environment of the cell or organism around the major variable in the external world, the daily cycle of light and darkness. We now know that all eukaryotic organisms possess cellular clocks that mark the passage of time in near 24-hr cycles, even in an environment devoid of any time cues. How 24-hr time-keeping is accomplished is currently the topic of intense investigation in chronobiological paradigms ranging from protozoan luminescence rhythms to human sleep patterns.

Our research program is aimed at understanding the cellular mechanisms underlying the circadian clock in the mammalian brain. The suprachiasmatic nucleus (SCN) of the hypothalamus sustains a stable circadian rhythm of neuronal activity for up to 3 days in vitro. The phase of this rhythm can be reset by neural signals from other brain sites in a time-of-day dependent manner. The clock gates its own sensitivity to activation of signal transduction pathways, which imbues external signals with temporal relevance. Prominent regulators include glutamate, acetylcholine and melatonin. Our findings demonstrate that the timekeeping mechanism is comprised of dynamic cellular states in which specific events in signal transduction, kinase activation, protein phosphorylation, nuclear translocation, transcription/translation and proteolysis occur in an orderly sequence. We are probing the identity of molecules that confer this time-of-day sensitivity of the SCN clock to resetting by using cell biological, behavioral, biochemical, electrophysiological, imaging and molecular techniques. We have discovered that differential spatial and temporal patterns of intracellular Ca2+ release, assessed by 2-photon microscopy, define the direction of clock resetting. Molecular studies on immortalized clock cells are providing insights into timekeeping mechanisms. Studying genetically modified mice enables us to test our hypotheses in the organism. Through this multidisciplinary approach, we hope to understand how these changes at the cellular level generate a biological timekeeping system that orchestrates the rhythms of our physiology and behavior over the cycle of day and night.