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.
Highlights
Mating drive is balanced by a need to safeguard resources for offspring, yet the neural basis for negative regulation of mating remains poorly understood
A wellcharacterized facilitatory center of lordosis is located in the ventromedial hypothalamus (VMH), in particular, in the steroid hormone receptor-expressing neurons located in the ventrolateral area of the VMH (VMHvl)
How does the same brain region (MeA) control female sexual behavior in contrary ways? To address this question, we examined how the two pheromonal signals are represented within the medial amygdala posteroventral part (MeApv) by using cellular compartment analysis of temporal activity with fluorescent in situ hybridization (ISH)
Summary
Mating drive is balanced by a need to safeguard resources for offspring, yet the neural basis for negative regulation of mating remains poorly understood. Genetic tracing of ESP22-responsive neural circuits reveals a critical limbic system connection that inhibits reproductive behavior. V2Rp4 counteracts a highly related vomeronasal receptor, V2Rp5, that detects the male sex pheromone ESP1. 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. Classic studies using lesioning and electrical stimulation of brain areas in rats have identified facilitatory, and inhibitory systems, that control female sexual receptivity. A recent study made progress in characterizing the neural activities of VMHvl neurons in female mice[16], it is largely unclear what external stimuli drive lordosis-inhibiting systems to negatively influence female reproduction. The vomeronasal organ (VNO) plays a critical role in mediating chemosensory signals that influence sexual behaviors[17]
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