Circadian rhythms regulate the function of living systems at virtually every level of organization - from molecular to organismal. In this proposal we will specifically examine whether aging influences two levels within the circadian system of mammals: 1) the photic entrainment behavior of hamsters; and 2) the photic induction of immediate-early genes in the hypothalamic suprachiasmatic nucleus (SCN). We have extensively studied the photoreceptive system that mediates entrainment to light in young golden hamsters. 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 SCN and that the induction of these IEGs is correlated with circadian behavior. Light exposure of young hamsters during the subjective night causes a profound induction of c-fos and jun-B mRNA levels, AP-1 DNA binding, and CREB phosphorylation in the SCN. The induction of c-fos mRNA is directly correlated with the phase-shifting effects of light on the circadian behavior in two ways. First, 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. In this proposal we will investigate the effects of aging on photic entrainment behavior and on photic induction of immediate-early genes in the SCN. Our preliminary results indicate that the thresholds for both phase shifting and Fos induction are increased about 1.5 log units (30-fold) in old animals. Specifically, our goals are: 1) To complete our analysis of whether aging influences the threshold to light for phase-shifting behavior; 2) To determine whether aging alters the integration properties of the photic entrainment pathway; 3) To analyze the effects of aging upon the Fos pathway as well as other immediate-early gene pathways in the SCN; 4) To determine at what level of the photic input pathway aging attenuates the photic induction of c-fos in the SCN; and 5) To determine whether aging effects circadian gating of c-fos induction by light. The results from the proposed experiments should provide new information on the influence of aging on gene expression and its role in the entrainment and generation of circadian rhythms in mammals, and should ultimately aid in an understanding of the molecular components of the mammalian circadian clock. An understanding of the biological basis of aging and 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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