The pattern of expression of several neurotransmitters that regulate the cyclic release of GnRH and LH become desynchronized with each other and with the light-dark cycle during the initial stages of reproductive decline. Further, estradiol's ability to modulate these rhythms deteriorates during middle age. Changes in this broad spectrum of neurochemical rhythms may result from a fundamental change in the circadian pacemaker in the hypothalamic suprachiasmatic nuclei (SCN). Such a fundamental deterioration in the pacemaker may initiate the gradual disintegration of temporal organization of neurotransmitter rhythms critical for stable, precise and regular cyclic LH secretion. The long-term objectives are to understand the neural, cellular and molecular mechanisms by which the SCN influence cyclic GnRH activity leading to cyclic LH secretion and how these mechanisms change with age. In addition, the investigators wish to understand the mechanisms by which estradiol couples circadian temporal information to the GnRH/LH axis and how this changes with age. Attention will be focused on vasoactive intestinal peptide (VIP), its major afferent input, serotonin (5HT), and a major efferent target, GnRH. In the SCN, VIP is likely to be the critical link between precise circadian temporal information and the time of cyclic GnRH neuronal activity. The investigators will test the working hypothesis that changes in the rhythmicity of VIP neurons, alterations in the ability of serotonin to influence rhythmic VIP expression and/or deterioration in the ability of VIP to drive normal patterns of GnRH activity occur during middle age and lead to irregular estrous cyclicity and reproductive decline. The results of these studies will deepen the understanding of the fundamental cellular and molecular mechanisms through which the brain influences cyclic reproductive function. The findings will yield new and important information on how age-related changes in the SCN may lead to desynchronization of neuroendocrine function, resulting in deterioration of rhythmic GnRH activity. These studies will broaden the understanding of the circadian underpinning of female reproduction and may help to develop new strategies to treat some neurological disorders that often accompany the menopausal transition.
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