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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS055361-06
Application #
7491329
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Mitler, Merrill
Project Start
2000-12-22
Project End
2009-03-31
Budget Start
2007-08-01
Budget End
2008-03-31
Support Year
6
Fiscal Year
2007
Total Cost
$250,418
Indirect Cost
Name
University of California Los Angeles
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Nakamura, Takahiro J; Sellix, Michael T; Menaker, Michael et al. (2008) Estrogen directly modulates circadian rhythms of PER2 expression in the uterus. Am J Physiol Endocrinol Metab 295:E1025-31
Nakamura, Wataru; Yamazaki, Shin; Nakamura, Takahiro J et al. (2008) In vivo monitoring of circadian timing in freely moving mice. Curr Biol 18:381-5
Davidson, Alec J; Yamazaki, Shin; Arble, Deanna M et al. (2008) Resetting of central and peripheral circadian oscillators in aged rats. Neurobiol Aging 29:471-7
Lundkvist, Gabriella B; Kwak, Yongho; Davis, Erin K et al. (2005) A calcium flux is required for circadian rhythm generation in mammalian pacemaker neurons. J Neurosci 25:7682-6