Reproductive Aging and the Human Hypothalamus

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DESCRIPTION (provided by applicant): Our overall goal is to characterize and understand the events that occur in the human central nervous system in response to menopause. We have found that human menopause is associated with a striking hypertrophy and increase in neurokinin B (NKB) gene expression in the hypothalamic infundibular (arcuate) nucleus. During the last funding period, we showed that the changes in NKB gene expression and cell size could by duplicated by ovariectomy of young cynomolgus monkeys and provided strong evidence that arcuate NKB neurons participate in the hypothalamic regulation of reproduction. In this renewal, we will begin to relate the changes in hypothalamic NKB gene expression to one of the most prominent symptoms in postmenopausal women, the hot flush. Hot flushes, a disorder of central thermoregulation, are characterized by activation of the physiologic mechanisms to dissipate heat (cutaneous vasodilatation, sweating and behavioral changes). Integration of the hypothalamic control centers for reproduction and thermoregulation appears to be a key element in the mechanism of flushes. We hypothesize that arcuate NKB neurons participate in the estrogen modulation of body temperature and LH secretion and therefore could be involved in the generation of flushes. In support of this hypothesis, our pilot studies in the rat demonstrate tail vasodilatation in response to central injection of an NK3 receptor agonist and localization of NK3 receptors in the median preoptic nucleus, a major integrating center for thermoregulatory vasodilation. Specific aim 1 will use pharmacological tools in a rat model to test the hypothesis that NKB neurons participate in the regulation of thermoregulation and reproduction. Specific aim 2 will characterize the anatomic relationship between arcuate NKB neurons and the thermoregulatory axis. Specific aim 3 will test our hypothesis that NKB neurons in the arcuate nucleus or NK3R-expressing neurons in the median preoptic nucleus play an important role in thermoregulatory vasodilation by determining the effects of selective ablation of these neurons on the thermoregulatory axis. Specific aim 4 will explore the morphologic relationship between NKB, kisspeptin and dynorphin mRNAs in the human hypothalamus and determine if the receptor mRNAs for these peptides are expressed by GnRH neurons. Our studies provide an exceptional opportunity to address basic biological issues directly relevant to the physiology of postmenopausal women.