ESTROGEN INFLUENCES ON NEUROENDOCRINE AGING

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The goal of the proposed studies is to determine effects of ovarian steroid hormones, aging, and their interactions on the function, neuroanatomy, and neuropharmacology of GnRH neurons, and their regulation by NMDA receptors (NMDAR). GnRH neurons are the key cells regulating reproduction, and inputs from glutamate to GnRH perikarya and neuroterminals, mediated by the NMDAR, play important regulatory roles in GnRH synthesis and secretion. These processes are altered by age-related changes in circulating gonadal steroid hormones, which in turn have profound effects on neuroendocrine brain regions. The proposed studies will utilize ovariectomized female rats (young, middle-aged and old) and monkeys (young and old), given hormone (estrogen +/- progesterone) or vehicle replacement. The reproductive status of all animals is characterized prior to ovariectomy, and circulating estradiol and progesterone concentrations will be monitored during (in monkeys) or at the termination (rats) of each experiment. We will test the hypotheses that GnRH neurons express NMDAR subunits, that this expression is altered by hormones and/or aging, and that this has functional consequences. Aim 1 will utilize light microscopy to examine effects of hormones and aging on the anatomical relationships between NMDAR subunits and GnRH perikarya in rat and monkey hypothalamus preoptic area. In Aim 2, we will examine effects of hormones and aging on GnRH neuroterminats and their expression of NMDAR subunits in the median eminence of rats and monkeys, using light and electron microscopy. Data from Aims 1 and 2 will provide a comprehensive understanding of the interactions of GnRH neurons and NMDAR, and their hormonal and age regulation, at both GnRH pedkarya and terminals. In Aim 3 we will utilize a neuropharmacological approach to examine effects of NMDAR activation or antagonism on the ultrastructure of GnRH neuroterminals, and on GnRH gene expression. As a whole, these three Specific Aims will provide novel information on effects of hormones, aging, and their interactions on GnRH neurons. The experimental design will facilitate comparisons between female rats and monkeys. The outcomes of these studies will have considerable relevance to understanding the causes and consequences of menopause in women and in informing future studies on postmenopausal hormone replacement therapy.