Circadian rhythmicity is a critically important component of the temporal organization of most living things. Work with mammalian models has established that the circadian pacemaking system, located in the suprachiasmatic nucleus, influences the timing of many behavioral, physiological and endocrinological processes. In humans, disruption of the circadian system produced by travel across time zones causes jet lag, fatigue and general decline in alertness and performance. The circadian system is affected adversely in old people, and such effects may well underlie the almost universal difficulties with insomnia experienced by the aged. Abnormalities in circadian physiology which may result from environmental insult or from genetic anomalies are thought to be partially responsible for much more serious pathologies such as some forms of severe depression. Until the discovery of the tau mutant hamster, there have been no genetic models available with which to investigate the many roles of the mammalian circadian system. The tau gene is a single, co-dominant, autosomal gene: wild-type hamsters have free-running circadian periods of 24 hours, hamsters heterozygous for the mutant allele have periods of 22 hours, and homozygous mutants have periods of 20 hours. We propose to use the mutation to study the roles played by the circadian system in the regulation or modulation of other non-circadian aspects of mammalian temporal organization. We will determine how the changes in the circadian system that is produced by the tau mutation affect three endocrine- mediated rhythms of very different frequencies: LH pulses produced at roughly 20 minute intervals by the pituitary; estrous cyclicity which in wild-type hamsters has a period of four days; and the annual reproductive cycle which is regulated by the seasonal changes in daylength (photoperiod). We have preliminary evidence which indicates that each of these three processes is affected by the mutation. Our experiments are directed toward understanding of the mechanisms that are responsible for these effects. This knowledge will deepen our understanding of mammalian temporal organization by defining the place of the circadian pacemaker in the temporal hierarchy and the ways in which it interacts with other biological oscillations.
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