UC Berkeley

Fertility in women and across mammalian species requires a series of temporally coordinated neuroendocrine events by the circadian timing system, with disruptions to circadian timing having a pronounced negative impact on female reproductive function across species, including humans. For example, irregular menstrual/estrous cycles, diminished fertility, and increased miscarriages/fetal resorption are associated with disrupted circadian timing. Ovulation and subsequent fertility in across spontaneously ovulating mammals require the preovulatory luteinizing hormone (LH) surge, a hormonal signaling cascade initiated prior to the onset of the activity period that is stimulated by direct and indirect neuronal signals to the reproductive axis originating from the suprachiasmatic nucleus (SCN) of the hypothalamus. Throughout most of the ovulatory cycle, the negative feedback effects of ovarian sex steroids maintain the gonadotropins, LH and follicle-stimulating hormone (FSH), at low levels prior to ovulation. However, during a brief time window on the morning of proestrus when systemic levels of estradiol peak organizing responsiveness of circuits governing reproductive axis activity, daily SCN signals to the reproductive axis drive LH surge initiation. Specifically, SCN-derived signals drive the activity of stimulatory kisspeptin neurons, while concomitantly suppressing activity of the inhibitory RFRP-3 neurons. This dissertation focuses on understanding the cellular mechanisms underlying timed-changes in reproductive axis activity in response to temporally coordinated kisspeptin and RFRP-3 signals by the circadian system in LH surge generation. Whereas most studies to date have focused on their role in LH pulse generation and as the locus for estradiol negative feedback, the stimulatory role for arcuate kisspeptin (KNDy) neurons in LH surge generation was examined in Experiment 1. Although the role in anteroventral periventricular (AVPV) kisspeptin neurons is well established for their integration of sex steroid and circadian signals for the initiation of the LH surge, the mechanisms by which estrogen, progesterone, and vasopressin are temporally integrated individually and synergistically with circadian molecular timekeeping to drive timed AVPV kisspeptin cell responsiveness to vasopressin signals for LH surge initiation was investigated in Experiment 2. Finally, because the reproductive axis exhibits time-dependent changes to Kp signals for LH surge generation, Experiment 3 examined whether the reproductive axis demonstrated daily changes sensitivity to RFRP-3 signals for LH surge generation in a similar manner to kisspeptin signaling. Taken together, findings from experiments discussed herein uncover novel cellular mechanisms for several critical signaling molecules integrated into the reproductive axis in temporally coordinated activity required for LH surge generation.