ESTROGEN IN THE AGING HYPOTHALAMUS

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DESCRIPTION: (adapted from the application). Estrogen influence on synaptic connectivity in the aging hypothalamus of the female rat may be via modulation of neuromodulin (GAP-43) expression. Estrogen regulates reproductive activity throughout the lifetime of the female animal and is involved in neurite outgrowth during development, onset of the ovarian cycle, ovarian cycle regularity, and synaptic remodelling in the hypothalamus. Constant and high dosages of estradiol administered to female rats result in constant vaginal estrus, an age- related stage in reproductive senescence in which the ovaries are anovulatory, little steroidal hormones are secreted, and cyclicity ceases. It has been observed that increases and decreases in the concentration of specific proteins isolated from prepuberal female rats administered estrogen. One of the isolated proteins that showed a significant increase in expression levels, biochemically resembled neuromodulin, GAP-43 (kDa=4.3; pI=5.4). Neuromodulin is found in the developing rat nervous system, in neurite outgrowth of regenerating neurons and has also been shown to be involved in neuronal plasticity in the hippocampus. Recent studies have indicated that GAP-43 expression increases in the steroid primed animal. To date, the mechanism by which estrogen influences synaptic connectivity is unknown. It is our belief that estrogen facilitates this occurrence via modulation of neuromodulin, since neuromodulin is highly expressed in axons during neurite outgrowth in development and regeneration. We propose to determine whether aging or estrogen modulates changes in synaptic connectivity and GAP-43 expression in the aging hypothalamus. We aim to identify any changes in synaptic connectivity in the hypothalamus of the aging female rat which may be representative of changes in the ovarian cycle and vaginal epithelium and that those changes correlate with estrogen modulation of GAP-43 expression in neurons in the aging hypothalamus. Studies will be conducted in sexually mature adult (3 - 5 months) and older (8 - 10 months) female ovariectomized Sprague Dawley rats pretreated with estrogen or vehicle for 48 hours.