During fetal life, a biological clock located in the hypothalamic suprachasmatic nuclei (SCN) is oscillating. The mother coordinates (entrains) the timing of the fetal biological clock to ambient light-dark conditions. The experiments proposed in this application use physiological, and newly developed cellular and molecular approaches to probe the biology of the fetal SCN. Our long-term goal is to better understand the basic mechanisms underlying biological clock function. First , the signals communicating circadian phase information to the fetal SCN will be examined. Periodic feeding or pharmacological doses of the pineal hormone, melatonin, can entrain the fetuses of SCN-lesioned pregnant rodents. Experiments will investigate which aspect of periodic food presentation entrains the rat fetus. It will also be determined whether a physiological pattern of melatonin administration entrains the fetus. Potential fetal entraining agents will be examined in vitro by monitoring the electrical activity rhythm in brains slices containing fetal SCN. Second, a dopamine system within the fetal SCN will be defined. The expression of c-fos in the fetal SCN can be activated through a Dl-dopamine receptor suggesting that a functional dopamine system exists within the fetal SCN. Experiments will characterize the components of a dopamine system in the fetal hypothalamus, assess the functional significance of this dopamine system, and investigate the potential role of other transmitter systems in the fetal SCN. Third, the functional properties of migrating SCN neurons will be elucidated. Dopamine Dl- receptor mRNA will be used to identify SCN neurons during migration. This will permit investigation of the circadian properties of migrating SCN neurons. Fourth, the oscillatory properties of the developing SCN will be investigated, utilizing multimicroelectrode plates to record electrical activity from cultured neurons. The ability of fetal SCN cells to form a functional circadian clock following dissociation will be used to examine the functional interactions among SCN cells which develop to form, a circadian clock in vitro. This system will also be used to determine whether single SCN cells express circadian oscillations in firing rate in vitro. Circadian variations affect virtually all aspects of human physiology and can contribute to pathophysiological states. Thus, increased understanding of the basic mechanisms of biological clock function may facilitate the development of better treatment strategies for a wide range of disorders.
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