Circadian rhythms regulate the function of living systems at virtually every level of organization - from molecular to organismal. Previous studies on this project have demonstrated that the photic threshold for phase-shifting a behavioral circadian rhythm in ld hamsters is increased about 20-fold, and similarly, the photic induction of a transcription factor, Fos, and the light-induced phosphorylation of CREB are also attenuated in the central circadian pacemaker located in the suprachiasmatic nucleus (SCN). Studies in the present project will build on these findings to examine in depth the extent of these age-related changes in response to light, and the chronology for the development of these changes. Other studies will determine if age-related increases in photic threshold are specific to the Fos/phase-shifting pathway, whether these changes influence the ability of animals to entrain to light cycles, and whether the age-related changes are due to changes in the expression of glutamate receptors in the SCN/ On addition, the laboratory mouse will be utilized as a model system to further study the mechanisms underlying age- related changes in the photic entrainment of mammalian circadian rhythms. The recent isolation of the Clock mutant mouse opens up a new set of questions that can be addressed with respect to interactions between the circadian system and aging. Of particular interest is the finding that the Clock mutation in the heterozygous condition has effects on rhythmicity that are similar to those observed in old wild-type mice. Thus, studies in the mouse will characterize in detail circadian changes associated with aging in mice, determine whether the Clock mutation affects these changes, either in degree or in time of appearance, and whether the clock mutation and aging alter the circadian clock system through similar mechanisms. 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.
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