Figure 1.

The multi-oscillatory network of the female hypothalamic–pituitary gonadal axis in rodents. (A) Schematic representation of the neuroendocrine pathway timing female reproduction: the master circadian clock located in the hypothalamic suprachiasmatic nucleus (SCN) is synchronized to the daily cycle mostly via the light/dark cycle and to a less extend by other time cues (food intake and sleep/wake activity); two SCN peptidergic transmitters forward the daily information to the reproductive axis: arginine vasopressin (AVP) is the most essential daily transmitter projecting to the kisspeptin (Kp) neurons of the anteroventral periventricular nuclei (AVPV), which in turn strongly activate the GnRH neurons located in the preoptic area (POA); vasoactive intestinal peptide (VIP) directly modulates GnRH neuron activity and possibly indirectly via neurons of the dorsomedial hypothalamus (DMH), which express RF-related peptide (RFRP); GnRH released in the portal blood system activates the synthesis and release of the gonadotropins luteinizing hormone (LH) and folliculo-stimulating hormone (FSH), which in turn regulate oocyte maturation, estradiol synthesis, and finally ovulation triggered by the LH surge; throughout the estrous cycle, estradiol feeds back onto different levels of the reproductive axis principally via the nuclear estrogen receptor α (ERα) and to a less extend via ERβ. Kp neurons are the main estradiol targets with an inhibitory effect of low estradiol on Kp neurons of the arcuate nucleus (ARN) and a stimulatory action of high estradiol on AVPV Kp neurons. In addition to the master SCN clock, peripheral clocks are located in the AVPV Kp neurons, GnRH neurons, pituitary gonadotrophs, and the different cell types of the ovary. (B) Representative pictures showing PER1 immunoreactivity (green) in Kp immunoreactive neurons (red) in the AVPV of female mice sampled at zeitgeber time 20 (8 h after lights off on a 12 h light/12 h dark schedule) on the day of proestrus [adapted from Ref. (9)]. (C) Representative bioluminescence traces from isolated AVPV explants of PER2:LUCIFERASE female mice, in absence (0 E2, light gray line) or in presence of estradiol (1 μM E2, black line) in the culture medium; τ indicates the period of the circadian AVPV oscillations in both conditions [adapted from Ref. (9)]. (D) Schematic representation of the mouse estrus cycle including the four stages: metestrus, diestrus, proestrus (the stage at which the LH concentration raises as an LH surge), and estrus; during the first part of the reproductive cycle, low circulating level of estradiol displays a negative feedback, whereas at proestrus, high estradiol levels exert a positive feedback, causing a synchronized activation of GnRH neurons leading to the preovulatory surge of LH; notably, the LH surge occurs at the end of the resting period, which is late day in nocturnal species.