Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse

TLDR

Kisspeptin, encoded by Kiss1, is essential for reproduction and in rodents, arcuate nucleus kisspeptin neurons provide tonic drive to GnRH neurons that sustains basal LH secretion. The study aimed to determine coexpression of Dyn and NKB in Kiss1 neurons and to assess their physiological role, proposing that NKB and dynorphin act autosynaptically to synchronize kisspeptin pulsatility and drive GnRH release. Using in situ hybridization, the authors showed that Arc Kiss1 neurons express Dyn, NKB, NK3, and KOR, and they propose that NKB and dynorphin act autosynaptically on these neurons. Estradiol suppresses Dyn, NKB, KOR, and NK3 expression, Dyn and NKB inhibit LH secretion, and loss of Dyn/KOR signaling impairs the LH surge after ovariectomy.

Abstract

Kisspeptin is encoded by the Kiss1 gene, and kisspeptin signaling plays a critical role in reproduction. In rodents, kisspeptin neurons in the arcuate nucleus (Arc) provide tonic drive to gonadotropin-releasing hormone (GnRH) neurons, which in turn supports basal luteinizing hormone (LH) secretion. Our objectives were to determine whether preprodynorphin ( Dyn ) and neurokinin B ( NKB ) are coexpressed in Kiss1 neurons in the mouse and to evaluate its physiological significance. Using in situ hybridization, we found that Kiss1 neurons in the Arc of female mice not only express the Dyn and NKB genes but also the NKB receptor gene ( NK3 ) and the Dyn receptor [the κ opioid receptor ( KOR )] gene. We also found that expression of the Dyn , NKB , KOR , and NK3 in the Arc are inhibited by estradiol, as has been established for Kiss1 , and confirmed that Dyn and NKB inhibit LH secretion. Moreover, using Dyn and KOR knock-out mice, we found that long-term disruption of Dyn/KOR signaling compromises the rise of LH after ovariectomy. We propose a model whereby NKB and dynorphin act autosynaptically on kisspeptin neurons in the Arc to synchronize and shape the pulsatile secretion of kisspeptin and drive the release of GnRH from fibers in the median eminence.