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

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 coordinate β-endorphin release with ejaculation, shedding light on the neurobiological basis of the post-ejaculation affective state.