Neural Basis of Mammalian Circadian Organization

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DESCRIPTION (provided by applicant): 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 the 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 involved in the pathway by which temporal information reaches the clock from the environment and the pathway 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 possibility of a 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. Four specific aims will be addressed. First, an hypothesis will be tested that a daily transmembrane calcium flux is required for sustained rhythmicity in the SCN and peripheral oscillators and, also, whether there is a phase dependency for the action of calcium on pacemaker function. Second, the functional significance of calcium regulation of the amplitude of clock gene rhythms will be explored. Third, the role of calcium in mammalian circadian entrainment will be addressed. Finally, the underlying mechanisms governing the effects of calcium conductance on the circadian clock will be studied. Together, the four experimental efforts should provide new insights into critical aspects of circadian system synchronization and rhythm generation. There is significant health relevancy to the study of mechanisms underlying mammalian circadian rhythms. Sleep quality during disease states and in human aging can have a profound effect on human health. Complex shift work schedules and trans-meridian light create physiological disruption that needs to be understood in order to be effectively addressed. Human physiology is profoundly rhythmic and the mechanisms governing this rhythmicity need to be understood.