Kisspeptin-Neurokinin B-Dynorphin (KNDy) neurons of the arcuate nucleus (ARC) of the hypothalamus have been proposed as a critical component regulating the pulsatile release of gonadotropin-releasing hormone (GnRH), and its modulation by endogenous steroid hormones and exogenous environmental cues.  The current working model proposes specific roles for each of the three KNDy peptides in pulse generation and/or termination, and has been the subject of active investigation in a range of species.  In this talk, we will review the role of KNDy neurons and peptides in the control of GnRH secretion in studies using adult female sheep, an animal model in which GnRH release into portal blood can be directly monitored.  Results thus far are consistent with KNDy neurons acting as a component of the “GnRH pulse generator”; however, there are significant species differences in the functional roles of individual KNDy peptides and receptors, and major unanswered questions as to how the KNDy network acts to regulate pulses.  These include the mechanisms responsible for the time lag between pulse onset and termination; as one possibility, we are exploring the hypothesis that changes in the subcellular trafficking and localization of KNDy peptide receptors contribute to pulse dynamics.  In addition, besides their role in the control of GnRH pulses, KNDy neurons and peptides in the female sheep also appear to participate in control of the GnRH/LH surge that triggers ovulation.  Specifically, neurokinin B (NKB) contributes to the generation of the estradiol-induced LH surge in the ewe, acting through hypothalamic pathways that include NK3R-containing cells of the retrochiasmatic area and KNDy neurons of the ARC.  In summary, KNDy cells and peptides appear to be involved in both pulsatile and surge modes of GnRH secretion in the sheep: in light of similarities between sheep and human reproduction, these findings may have translational importance for understanding the basis for human disorders in which central control of GnRH secretion is impaired.

Supported by NIH R01 HD039916 to M.N.L. and R.L.G.