Sexual rejection via a vomeronasal receptor-triggered limbic circuit

Abstract

Mating drive is balanced by a need to safeguard resources for offspring, yet the neural basis for negative regulation of mating remains poorly understood. In rodents, pheromones critically regulate sexual behavior. Here, we observe suppression of adult female sexual behavior in mice by exocrine gland-secreting peptide 22 (ESP22), a lacrimal protein from juvenile mice. ESP22 activates a dedicated vomeronasal receptor, V2Rp4, and V2Rp4 knockout eliminates ESP22 effects on sexual behavior. Genetic tracing of ESP22-responsive neural circuits reveals a critical limbic system connection that inhibits reproductive behavior. Furthermore, V2Rp4 counteracts a highly related vomeronasal receptor, V2Rp5, that detects the male sex pheromone ESP1. Interestingly, V2Rp4 and V2Rp5 are encoded by adjacent genes, yet couple to distinct circuits and mediate opposing effects on female sexual behavior. Collectively, our study reveals molecular and neural mechanisms underlying pheromone-mediated sexual rejection, and more generally, how inputs are routed through olfactory circuits to evoke specific behaviors.

Physiology-forward identification of bile acid sensitive vomeronasal receptors

“…We saw a very small number of VSNs that were co-activated by BAs and sulfated androgen, estrogen, and pregnanolone ligands, but given the relatively narrow focus of this panel, we cannot exclude that other non-BA steroid ligands may co-activate BA-sensitive VSNs. Overall, these studies show that the VSN sensitivity and selectivity for BAs is comparable to most of the other major known AOS ligand classes (Haga-Yamanaka et al, 2015;Kaur et al, 2014;Leinders-Zufall et al, 2000;Nodari et al, 2008;Osakada et al, 2018).…”

“…Other efforts have explored VNO ligand-receptor interactions using various approaches (Haga-Yamanaka et al, 2015;Isogai et al, 2011;Lee et al, 2019;Stein et al, 2016). Despite recent progress, a small fraction of the VR family has confirmed ligands (Haga-Yamanaka et al, 2014;Haga et al, 2010;Isogai et al, 2011;Isogai et al, 2018;Lee et al, 2019;Osakada et al, 2018).…”

Female mouse tears contain an anti-aggression pheromone

“…Moreover, the same peptide is also responsible for a long-term pheromonal response, namely the Bruce effect, that refers to the pregnancy block in recently pregnant female mice upon exposure to unfamiliar male cues 8,9 . In contrast, a juvenile lacrimal peptide, ESP22, is expressed in 2-to 3-week-old mice and exerts a strong inhibitory effect on adult male mating behavior, also promoting sexual rejection in females 10,11 . Very recently, another lacrimal protein was identified in the male rat that enhances stopping behavior in females 12 .…”

“…This finding is noteworthy as it infers the presence of pheromonal cues that operate as intraspecific and interspecific signals, at the same time. As for most urinary pheromones, all these lacrimal peptides bind receptors and activate peripheral and central brain areas that are part of the vomeronasal system 7,10,12,13 . No studies have been reported on the physiological and behavioral effects of female tears in the mouse, a species that bases the socio-sexual interactions on pheromones.…”

Nature Controls Nurture in the Development of Sexual Orientation, and Voice is Nature’s Agent

“…A third mechanism is a signal that inhibits the inhibition of an excitatory signal. All those mechanisms have been observed in the MASHA (28,29), and the model accommodates all of them. The connections where that variability in the flow of auditory information occurs are the sites that determine the sexual orientation that emerges at puberty.…”