The overall goal of this new grant proposal is to elucidate the physiological mechanisms by which undernutrition leads to a suppression of reproductive function in primate species. All studies in this proposal will utilize adult male rhesus monkeys that are fasted for one day. We have previously shown that this short period of fasting leads to a decrease in the frequency of pulsatile LH and testosterone secretion, which appears to result from a decrease in the frequency of GnRH secretion. Thus the locus of dysfunction in the reproductive axis during both chronic and acute periods of undernutrition appears to be at the level of the GnRH pulse generator, however use of the short-term fasting model will allow us to study how nutrition affects reproductive function without ill effects on the health and well-being of the experimental animals. Two specific hypotheses will be tested by the projects in this proposal: (1) that metabolic changes occurring as a direct result of the state of undernutrition suppress GnRH neuronal activity, and (2) that a general stress response occurring during undernutrition suppresses GnRH neuronal activity. Projects 1-4 are designed to identify """"""""signals"""""""" that are leading to the suppressed activity of the GnRH pulse generator in undernourished states. Project 1 will determine whether the slowing of LH pulse frequency during short-term fasting can be reversed by (a) administering nutrients intravenously to provide nutrition without relieving the psychological stress of withholding food, and (b) providing noncaloric pellets to relieve the psychological stress of food deprivation without increasing nutrient intake. Projects 2-4 are designed to isolate signals which serve to link GnRH neuronal activity to the nutritional state of the body by (a) examining the ability of the GnRH neuronal system to respond to short-term fasting when it has been surgically disconnected from other neuronal input, (b) measuring neuronal and metabolic changes occurring in the vicinity of the GnRH neurons using push-pull perfusion techniques, and (c) determining whether administration of specific pharmacological agonists and antagonists can reverse the effects of short-term fasting on pulsatile LH secretion. Project 5 will involve measurement of GnRH and POMC mRNA levels during short-term fasting to begin to determine whether changes in neuropeptide synthesis are involved in the slowing of the GnRH neuronal activity, but that they will also increase our understanding of the general mechanisms leading to quiescence of the GnRH neuronal system in other physiological and pathological conditions (i.e., during normal childhood, anorexia nervosa, spontaneous hypothalamic-hypophyseal dysfunction, stress, and participation in chronic vigorous exercise programs).
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