The brain clearly plays a critical role in the transition to reproductive senescence. During the past funding period, we have found that during middle age, estradiol's ability to modulate the rhythmic neurochemical events, which are required for preovulatory GnRH/LH surges, diminishes. In addition, changes within the suprachiasmatic nucleus (SCN), the major circadian pacemaker, and its ability to drive diurnal neurochemical events lead to declining precision in the timing of the GnRH/LH surge. Our long-term objectives are to underatand the neural, cellular and molecular mechanisms by which estradiol and the circadian pacemaker act and interact to yield cyclic GnRH neuronal activity leading to LH surges at the proper time and of the proper amplitude and how these mechanisms change with age. This proposal focuses on events that occur in three regions of the hypothalamus: (a) the anteroventral periventicular. nucleus/periventricular preoptic area, (b) the organum vasculosum of the lamina terminalis/rostral medial preoptic nucleus and (c) the SCN. These three regions play critical and interactive roles regulating cyclic GnRH/LH surge& Together, the integrity of these regions is essential to maintain regular cyclic LH release and regular estrous cycles. The principal investigator will test the working hypothesis that changes in the ability of these brain regions to coordinate daily signals, respond to estracliol and/or communicate with GnRH neurons occur during middle age and lead to irregular esirous cycicity and reproductive decline. The investigators will address the following specific aims: (1) determine whether the diurnal patterns. of expression of key neuromodulators and/or their ability to cormmunicate with GnRH neurons are attenuated with age. Further, the investigators will assess whether these changes result from attenuated responsiveness to estradiOL (2) determine whether SCN neurons commulicate directly with GnRH neurons or indirectly through other neuronal phenotypes. The investigators will determine whether these direct and indirect connections to GnRH neurons change with age. (3) evaluate the role of astrocyte/neuron interactions in the age-related diminishing ability of estradiol or neuromodulators to influence GnRH expression and release. (4) assess whether age-related changes in responsiveness to estradiol result from changes in the receptor (ERa or ERb) and/or the ability of estrogen receptors to cross-talk with second messenger signaling systems.
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