Figure 6.

A proposed model depicting circadian control of the preovulatory LH surge and ovulation. A, Estrogen responsive circuitry. These cell populations integrate estrogenic, SCN-derived, and local endogenous circadian cues to appropriately time the preovulatory LH surge. B, Loci receiving direct and indirect input from the master clock in the SCN. In this model, the SCN projects directly to GnRH, kisspeptin, and RFRP-3 cells. Additionally, the SCN projects to a putative interneuron to drive the removal of RFRP-3 inhibition by SCN-derived VIP at the time of the surge. Clock icons indicate neural populations exhibiting circadian oscillations in clock genes/proteins and time-dependent sensitivity to SCN signaling, including the GnRH (35, 42, 43) and RFRP-3 systems (46). C, Estrogen- and clock-controlled hierarchy. RFRP-3 neurons project to GnRH cells and to the median eminence to regulate gonadotropin secretion. It is proposed that RFRP-3 neurons respond to estradiol by inhibiting the reproductive axis throughout most of the estrous cycle. At the time of the LH surge, the SCN inhibits the RFRP-3 system through indirect VIP-ergic signaling, removing negative feedback to allow concomitant, SCN-controlled surge generation. oc, optic chiasm; MPO, medial preoptic area; ARC, arcuate nucleus; PIT, pituitary; SON, supraoptic nucleus.