Circadian rhythms regulate the function of living systems at virtually every level of organization - from molecular to organismal. The long- term objectives of our research are to understand the cellular and molecular events that underlie circadian rhythms among the vertebrates. We have extensively studied the photoreceptive system that mediates entrainment to light in the golden hamster. Using these quantitative behavioral experiments as a framework, we have recently shown that a number of cellular immediate-early genes (IEGs) are induced by light in the suprachiasmatic nucleus (SCN) and that the induction of these IEGs is correlated with circadian behavior. Light exposure of hamsters during the subjective night causes a profound induction of c-fos and jun-B mRNA levels as well as AP-1 DNA binding in the SCN. the induction of c-fos mRNA is directly correlated with the phase-shifting effects of light on the circadian behavior of the animal in two ways. First, the photic induction of c-fos is phase-dependent: the ability of light to stimulate c-fos is restricted to those phases at which light can reset the circadian oscillator. Second, the photic induction of c-fos and the phase-shifting response have the same photic threshold. Taken together these experiments suggest that photic entrainment in mammals may involve transcriptionally regulated signal transduction processes. In this proposal we will investigate the role of IEGs in the SCN. Specifically, our goals are: 1) To characterize of the effects of light upon immediate-early gene expression int he SCN; 2) To identify neurotransmitters that regulate c-fos in the SCN; and 3) To describe how circadian gating of c-fos induction by light is regulated. The results from the proposed experiments should provide new information on the role of gene expression in the entrainment and generation of circadian rhythms in mammals, and should ultimately lead to an understanding of the molecular components of the mammalian circadian clock. An understanding of the biological basis of circadian rhythms in mammals may lead to procedures useful in the diagnosis and treatment of pathophysiologic conditions associated with circadian rhythm dysfunctions such as sleep disorders, mental health and endocrine abnormalities.
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