Intra-hypothalamic circuit orchestrates β-endorphin release following coital ejaculation in male mice

作者：Xi Zha, Zhuolei Jiao, Shuaishuai Li, Xiao-Yao Liu, Xingyu Li, Yi-Zhuo Sun, Xiao‐Jing Ding, Meng-Tong Gao, Shu-Chen Gao, Ai-Xiao Chen, Jun-Kai Lin, Wen Zhang, Xuan-Zi Cao, Yanli Zhang, Rongrong Yang, Chunping Xu, Xiaohong Xu · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.09.18.613624 · 研究领域：Sexual function and dysfunction studies、Hormonal and reproductive studies、Hypothalamic control of reproductive hormones

Abstract Survey-based evidence suggests that men experience a distinct post-ejaculation affective state 1,2 , marked by intense pleasure sometimes compared to the euphoric rush from intravenous injection of opioid drugs such as heroin 3 . However, the intrinsic neural circuit mechanisms underlying the ejaculation-triggered affective state remain unclear. Here, we discovered that Calbindin1 -expressing ( Calb1+ ) neurons in the preoptic area (POA) of the hypothalamus, an evolutionarily conserved regulatory region for male mating behavior 4 , are specifically activated during ejaculation in male mice. Inhibiting POA Calb1+ neurons prolongs mating and delays ejaculation. Importantly, POA Calb1+ neurons transmit the ejaculation signal and activate proopiomelanocortin-expressing ( Pomc+ ) neurons in the arcuate nucleus of the hypothalamus, which show robust and sustained activity lasting for tens of seconds, specifically upon ejaculation. This activity is accompanied by elevated levels of β-endorphins 5 , opioid peptides secreted by Pomc+ neurons, post-ejaculation in male mice. Optogenetic activation of Pomc+ neurons increases β-endorphins levels and conditioned placed preference, similar to ejaculation. Conversely, intracerebroventricular (i.c.v.) infusion of drugs blocking Pomc neuropeptides signaling eliminates ejaculation-conditioned place preference. Collectively, these results elucidate an intra-hypothalamic circuit from POA Calb1+ neurons to arcuate Pomc+ neurons that coord...