Griesgraber Max J, Coolen Lique M, Onslow Kayla M, Corey Jacob R, Rice Rachel E, Aerts Eliana G, Bowdridge Elizabeth C, Hardy Steven L, Lehman Michael N, Goodman Robert L, Hileman Stanley M
Department of Physiology, Pharmacology and Toxicology, West Virginia University, Morgantown, West Virginia, USA.
Brain Health Research Institute, Kent State University, Kent, Ohio, USA.
J Neuroendocrinol. 2025 May;37(5):e70010. doi: 10.1111/jne.70010. Epub 2025 Mar 3.
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.
弓状核（ARC）中的下丘脑促性腺激素释放激素（Kiss）、神经激肽B（NKB）和含强啡肽（KNDy）的神经元一直被证明是哺乳动物促性腺激素释放激素（GnRH）和相应促黄体生成素（LH）脉冲的中央发生器，并且可能也有助于高峰分泌。此外，最近来自绵羊实验的证据表明，ARC中含Kiss1R的神经元在调节LH脉冲的时间和幅度方面发挥重要作用。在本研究中，我们通过注射皂草素-配体偶联物（SAP）来消融这些神经群体，从而研究ARC中KNDy和含Kiss1R的神经元在绵羊LH高峰分泌中的功能作用。与对照动物相比，注射NKB-SAP可显著降低ARC Kiss1细胞的百分比（降低约65%），并且在Kiss1细胞消融程度最大的母羊中可防止LH出现类似高峰的增加。与对照相比，注射Kiss-SAP对Kiss1细胞百分比或ARC Kiss1R细胞数量没有影响，后者可能是由于在LH高峰期间对照动物中雌二醇浓度升高导致Kiss1R受到抑制。然而，注射Kiss-SAP持续且显著降低LH高峰幅度，80%接受Kiss-SAP处理的母羊未能产生高峰。虽然这些ARC Kiss1R神经元的确切身份尚未完全阐明，但它们可能在KNDy神经元的下游起作用或与之协同作用，并可能整合其他以高峰为中心的信号通路来产生绵羊的LH高峰。这些结果支持以下结论：KNDy神经元对绵羊LH高峰有显著贡献，而ARC Kiss1R神经元似乎是绵羊发生功能性高峰所必需的。
