Balanced release of neuropeptide FF and gonadotropin-releasing hormone 3 modulates male sexual behavior

Animals properly perform sexual behaviors by using multiple sensory cues. However, neural mechanisms integrating multiple sensory cues and regulating motivation for sexual behaviors remain unclear. Here, we focused on peptidergic neurons, terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons, which receive inputs from various sensory systems and co-express neuropeptide FF (NPFF) in addition to GnRH. Our behavioral analyses using knockout medaka of GnRH (gnrh3) and/or NPFF (npff) demonstrated that some sexual behavioral repertoires were 9delayed9, not disrupted, in gnrh3-/- and npff-/- males, while the double knockout showed normal behaviors. We also found anatomical evidence to show that both neuropeptides modulate the sexual behavior-controlling brain areas. Furthermore, we demonstrated that NPFF activates neurons in the preoptic area via indirect pathway, which is considered to induce the increase in the motivation for male sexual behaviors. Considering these results, we propose a novel mechanism by which balanced release of co-existing peptides is important for the neuromodulatory function of TN-GnRH neurons in the control of behavioral motivation. Our results may go a long way toward understanding the functional significance of peptidergic neuromodulation in response to external environments.