Neural Basis of Mammalian Circadian Organization

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The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is a major circadian clock that regulates both physiology and behavior. It is now commonly accepted that circadian rhythms are generated within individual neurons in the SCN through a network of molecular feedback loops involving transcription of clock genes and feedback by gene products. Membrane phenomena, including membrane potential, electrical impulses and voltage-controlled ionic fluxes, have generally not been considered to be part of the core clock mechanism but rather processes involved in the pathways by which temporal information reaches the clock from the environment, as well as processes in the pathways by which the core molecular timing loop transmits rhythmic signals to other oscillators within the SCN tissue and beyond. Recently, studies in Drosophila and in mammals have raised the issue of a potentially more central role for membrane conductances, specifically calcium In the current proposal we outline a series of experiments that will allow us to characterize the precise role played by membrane potential and calcium influx in the regulation and generation of SCN rhythmicity. Three specific aims will be addressed. First, we will test the hypothesis that a daily calcium flux is required for rhyhthmicity in mammalian clock genes. Secondly, we will explore the time- dependency of calcium influx on pacemaker function. Finally, in a third specific aim we will explore the functional significance of calcium-mediated changes in the amplitude of expression of clock genes. Together, the three experimental efforts should provide new insights into critical aspects of circadian system synchronization and rhythm generation.