Critical role of arcuate nucleus kisspeptin and Kiss1R in regulation of the ovine luteinizing hormone surge

Abstract

Hypothalamic kisspeptin (Kiss), neurokinin B (NKB), and dynorphin-containing (KNDy) neurons in the arcuate nucleus (ARC) have consistently been shown to be the central generator of gonadotropin-releasing hormone (GnRH) and corresponding luteinizing hormone (LH) pulses in mammals and possibly contribute to surge secretion as well. Additionally, recent evidence from experiments in sheep suggests that ARC Kiss1R-containing neurons play an important role in regulating the timing and amplitude of LH pulses. In this study, we examined the functional role of ARC KNDy and Kiss1R-containing neurons in ovine LH surge secretion via injection of saporin–ligand conjugates (SAP) to ablate these neural populations. NKB-SAP injections significantly reduced the percentage of ARC Kiss1 (~65% decrease) cells compared to control animals, and a surge-like increase of LH was prevented in ewes with the greatest degree of Kiss1 cell ablation. Kiss-SAP injections had no effect on Kiss1 cell percentage or ARC Kiss1R cell number compared to controls, the latter perhaps due to Kiss1R suppression in control animals from elevated estradiol concentrations during the LH surge. However, Kiss-SAP injections consistently and robustly decreased LH surge amplitude, with 80% of Kiss-SAP-treated ewes failing to generate a surge. While the exact identity of these ARC Kiss1R neurons has yet to be fully elucidated, they likely act downstream or in concert with KNDy neurons and possibly integrate other surge-centric signaling pathways to generate the ovine LH surge. These results support the conclusion that KNDy neurons contribute significantly to the ovine LH surge, while ARC Kiss1R neurons appear to be necessary for a functional surge to occur in sheep.