Many living systems including humans express physiological and behavioral rhythms that vary with a 24-hour period. These rhythms are regulated by an internal circadian clock that is synchronized to the environmental light-dark cycle. Efforts to elucidate the physiological mechanisms underlying the generation of circadian rhythms in mammal have focused on the suprachiasmatic nucleus (SCN) of the hypothalamus as a site of a circadian pacemaker. However, little information exists concerning the cellular and molecular mechanisms responsible for the generation of circadian rhythms in the SCN. Our long term objectives are to understand the cellular and biochemical events that underlie circadian rhythms in mammals. The mechanisms that generate circadian rhythms will be studied in vivo using microinjection of pharmacological agents directly into the SCN of hamsters as a model for investigating the role of protein synthesis in a mammalian circadian pacemaker. The site of action of protein synthesis inhibitors on the circadian oscillator will be localized by microinjection of these agents into specific brain regions. We will test the hypothesis that protein synthesis inhibitors alter circadian rhythmicity by a direct action on SCN cells. The phase dependence of the effects of protein synthesis inhibitors in the SCN will be determined. The pharmacological specificity of protein synthesis inhibitors will be defined by examining the effectiveness of other inhibitors that have different molecular mechanisms of action, inactive analogues, and other agents that control for the known side effects of these inhibitors. Finally, the correlation between the amount of protein synthesis inhibition and the magnitude of perturbation of the circadian pacemaker will be studied. Taken together, these experiments would establish that protein synthesis is required for the generation of mammalian circadian oscillations and provide a foundation for future work to identify the proteins and elucidate their function. Although there is a fairly extensive literature in the field of circadian rhythms on the effects of protein synthesis inhibitors, there are no studies in a vertebrate preparation. The elucidation of the role of protein synthesis should aid ultimately in the search for the molecular components of the 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 dysfunction such as sleep disorders, mental health and endocrine abnormalities.
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