The Contribution of the Circadian Gene Bmal1 to Female Fertility and the Generation of the Preovulatory Luteinizing Hormone Surge

Abstract

In rodents, the preovulatory LH surge is temporally gated, but the timing cue is unknown. Estrogen primes neurons in the anteroventral periventricular nucleus (AVPV) to secrete kisspeptin, which potently activates GnRH neurons to release GnRH, eliciting a surge of LH to induce ovulation. Deletion of the circadian clock gene Bmal1 results in infertility. Previous studies have found that Bmal1 knockout (KO) females do not display an LH surge at any time of day. We sought to determine whether neuroendocrine disruption contributes to the absence of the LH surge. Because Kiss1 expression in the AVPV is critical for regulating ovulation, we hypothesized that this population is disrupted in Bmal1 KO females. However, we found an appropriate rise in AVPV Kiss1 and Fos mRNA at the time of lights out in ovariectomized estrogen-treated animals, despite the absence of a measureable increase in LH. Furthermore, Bmal1 KO females have significantly increased LH response to kiss-10 administration, although the LH response to GnRH was unchanged. We then created Kiss1- and GnRH-specific Bmal1 KO mice to examine whether Bmal1 expression is necessary within either kisspeptin or GnRH neurons. We detected no significant differences in any measured reproductive parameter. Our results indicate that disruption of the hypothalamic regulation of fertility in the Bmal1 KO females is not dependent on endogenous clocks within either the GnRH or kisspeptin neurons.

Insulin‐induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice

“…injection of either saline or insulin, and then 45 min later challenged with i.p. kisspeptin as described previously (25) (2 μg/g; rat Kisspeptin-10; Cat: 4243, Tocris). Blood samples were collected at 6-min intervals for 30 min before and after kisspeptin injection for LH assay.…”

The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function

“…4a, c), suggesting that the reduced activity in Vax1 Gnrh-cre is not solely caused by reduced sex steroid levels. To establish to what degree the impaired wheel running activity in Vax1 Gnrh-cre was due to impaired SCN circadian rhythms, we deleted the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a required transcription factor for circadian rhythm generation, using the Gnrh cre (Bmal Gnrh-cre ; [62]). Bmal Gnrh-cre males entrained normally to LD12:12, and had comparable wheel running activity to controls in constant darkness (Fig.…”

Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids

“… 88 , 89 ). This is surprising as disrupting brain clocks in other neuroendocrine circuits, such as those in kisspeptin or GnRH neurons, has little to no effect on physiology 90 , 91 . Importantly, the irregular, low daily surge in corticosterone we found in our Crh Cre/Cre ; Bmal1 fl/fl mice is distinct from Crh knockout mice, which have chronically low levels of corticosterone 92 .…”