Szentkirályi-Tóth Soma, Göcz Balázs, Takács Szabolcs, Sárvári Miklós, Farkas Imre, Skrapits Katalin, Rumpler Éva, Póliska Szilárd, Rácz Gergely, Matolcsy András, Ternier Gaëtan, Fernandois Daniela, Giacobini Paolo, Prévot Vincent, Colledge William H, Wittmann Gábor, Kádár Andrea, Mohácsik Petra, Gereben Balázs, Fekete Csaba, Hrabovszky Erik
Laboratory of Reproductive Neurobiology, HUN-REN Institute of Experimental Medicine, Budapest 1083, Hungary.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
J Neurosci. 2025 Feb 19;45(8):e1307242024. doi: 10.1523/JNEUROSCI.1307-24.2024.
While hypothalamic kisspeptin (KP) neurons play well-established roles in the estrogen-dependent regulation of reproduction, little is known about extrahypothalamic KP-producing (KP) neurons of the lateral septum. As established previously, expression in this region is low and regulated by estrogen receptor- and GABA receptor-dependent mechanisms. Our present experiments on knock-in mice revealed that transgene expression in the LS begins at Postnatal Day (P)33-36 in females and P40-45 in males and is stimulated by estrogen receptor signaling. Fluorescent cell numbers continue to increase in adulthood and are higher in females. Viral tracing uncovered that the bulk of KP fibers joins the medial forebrain bundle and terminates in the hypothalamic supramammillary nucleus. Smaller subsets innervate the medial amygdala or project to other limbic structures. One-quarter of gonadotropin-releasing hormone (GnRH)-immunoreactive perikarya in the preoptic area and their dendrites receive appositions from KP axons. OVX adult mice treated for 4 d with 17β-estradiol or vehicle were used for RNA sequencing studies of laser-microdissected KP neurons. The transcriptome included markers of GABAergic and neuropeptidergic (, , ) cotransmission and 571 estrogen-regulated transcripts. Estrogen treatment upregulated the acetylcholine receptor transcript and, in slice electrophysiology experiments, caused enhanced muscarinic inhibition of KP neurons. Finally, we provided immunohistochemical evidence for homologous neurons in the postmortem human brain, suggesting that KP neurons may contribute to evolutionarily conserved regulatory mechanisms. Future studies will need to investigate the putative roles of KP neurons in the estrogen-dependent control of GnRH neurons and/or various hypothalamic/limbic functions.
虽然下丘脑促性腺激素释放激素（KP）神经元在雌激素依赖的生殖调节中发挥着既定作用，但对于外侧隔的下丘脑外KP产生神经元知之甚少。如先前所述，该区域的表达较低，并受雌激素受体和GABA受体依赖机制的调节。我们目前对敲入小鼠的实验表明，LS中的转基因表达在雌性出生后第（P）33 - 36天开始，在雄性中在P40 - 45天开始，并受雌激素受体信号刺激。成年期荧光细胞数量持续增加，且雌性更高。病毒示踪发现，大部分KP纤维加入内侧前脑束并终止于下丘脑乳头体上核。较小的亚群支配内侧杏仁核或投射到其他边缘结构。视前区四分之一的促性腺激素释放激素（GnRH）免疫反应性核周体及其树突接受来自KP轴突的附着。用17β - 雌二醇或赋形剂处理4天的去卵巢成年小鼠用于激光显微切割的KP神经元的RNA测序研究。转录组包括GABA能和神经肽能（，，）共传递的标记以及571个雌激素调节的转录本。雌激素处理上调了乙酰胆碱受体转录本，并且在切片电生理实验中，导致对KP神经元的毒蕈碱抑制增强。最后，我们提供了死后人类大脑中同源神经元的免疫组化证据，表明KP神经元可能有助于进化上保守的调节机制。未来的研究需要调查KP神经元在雌激素依赖的GnRH神经元控制和/或各种下丘脑/边缘功能中的假定作用。
