Circadian Regulation of Kiss1 Neurons: Implications for Timing the Preovulatory Gonadotropin-Releasing Hormone/Luteinizing Hormone Surge

Abstract

The preovulatory GnRH/LH surge depends on the presence of estradiol (E(2)) and is gated by a circadian oscillator in the suprachiasmatic nucleus (SCN) that causes the surge to occur within a specific temporal window. Although the mechanisms by which the clock times the LH surge are unclear, evidence suggests that the SCN is linked to GnRH neurons through a multisynaptic pathway that includes neurons in the anteroventral periventricular nucleus (AVPV). Recently, Kiss1 neurons in the AVPV have been implicated in the surge mechanism, suggesting that they may integrate circadian and E(2) signals to generate the LH surge. We tested whether Kiss1 neurons display circadian patterns of regulation in synchrony with the temporal pattern of LH secretion. Mice housed in 14 h light, 10 h dark were ovariectomized, given E(2) capsules (or nothing), and transferred into constant darkness. Two days later, the mice were killed at various times of day and their LH and Kiss1 levels assessed. In E(2)-treated females, LH levels were low except during late subjective day (indicative of an LH surge). Similarly, AVPV Kiss1 expression and c-fos coexpression in Kiss1 neurons showed circadian patterns that peaked coincident with LH. These temporal changes in Kiss1 neurons occurred under steady-state E(2) and constant environmental conditions, suggesting that Kiss1 neurons are regulated by circadian signals. In the absence of E(2), animals displayed no circadian pattern in LH secretion or Kiss1 expression. Collectively, these findings suggest that the LH surge is controlled by AVPV Kiss1 neurons whose activity is gated by SCN signals in an E(2)-dependent manner.

Diurnal regulation of hypothalamic kisspeptin is disrupted during mouse pregnancy

“…Kiss1 gene expression in the AVPV peaked at ZT13 during proestrus, 4 h before the LH peak at ZT17, which is consistent with that reported in the literature, although the peak in Kiss1 mRNA levels has previously been found to be roughly coincident with the LH surge (Smith et al 2006, Robertson et al 2009). We also found that AVP receptor Avpr1a increased in expression in the AVPV at ZT5 during proestrus, before the rise in Kiss1 expression and the LH surge.…”

“…In this study, both Kiss1 and Avpr1a mRNAs in the anterior hypothalamus exhibited a peak in expression during proestrus that was absent at diestrus. These estrous cycle differences in expression profiles do not appear to be driven by clock genes as the rhythms of Bmal1 and Rev-erbα were unchanged between diestrus and proestrus, suggesting that the likely major stimulus for the increase in Kiss1 and Avpr1a expression at proestrus is rising estradiol levels (Robertson et al 2009, Williams et al 2011, Smarr et al 2013. Unlike Kiss1 expression in the AVPV, Kiss1 expression in the ARC was not different between proestrus and diestrus, exhibiting no diurnal variation on either day.…”

“…Despite the rise in estradiol levels throughout pregnancy, established in the literature and confirmed by our data, the surge in kisspeptin and LH does not occur at any stage of pregnancy. As both the LH surge and AVPV Kiss1 levels require the combination of elevated estradiol and a circadian signal (Robertson et al 2009), the lack of an LH surge in the face of peak estradiol concentrations would indicate a disruption of the circadian signal.…”

“…In female rodents, the LH surge is precisely timed to occur in the late afternoon of proestrus, being tightly controlled by the master circadian oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Kisspeptin also appears to be under the circadian control, as evidenced by studies showing that increases in kisspeptin expression in the AVPV of the hypothalamus are synchronous with the LH surge during proestrus in female rats (Smith et al 2006), mice (Robertson et al 2009), and hamsters (Williams et al 2011). Furthermore, studies in hamsters have shown that RFRP-3 cells are indirectly modulated via SCN vasoactive intestinal peptide (VIP)-ergic neurons (Russo et al 2015) and act directly on GnRH neurons to inhibit their activity (Gibson et al 2008).…”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…These findings were further confirmed by studies performed in rats [25,78], which also revealed increased activation of kisspeptin neurons at AVPV (measured by increased c-fos expression) preceding oestrogen-induced preovulatory LH surges [78,79]. Recent studies in rodents have also shown that kisspeptin neurons activation at AVPV follows an oestrogen-dependent circadian pattern [80][81][82], which receives its input from the suprachiasmatic nucleus (SCN) as evidenced by vasopressinergic (AVP) neuronal projections to kisspeptin neurons and the ability of AVP to augment their neuronal activity [80,83].…”