In mice, various instinctive behaviors can be triggered by olfactory input. Despite growing knowledge of the brain regions involved in such behaviors, the organization of the neural circuits that convert olfactory input into stereotyped behavioral output remains poorly understood. Here, we mapped the neural circuit responsible for enhancing sexual receptivity of female mice by a male pheromone, exocrine gland-secreting peptide 1 (ESP1). We revealed specific neural types and pathways by which ESP1 information is conveyed from the peripheral receptive organ to the motor-regulating midbrain via the amygdala-hypothalamus axis. In the medial amygdala, a specific type of projection neurons gated ESP1 signals to the ventromedial hypothalamus (VMH) in a sex-dependent manner. In the dorsal VMH, which has been associated with defensive behaviors, a selective neural subpopulation discriminately mediated ESP1 information from a predator cue. Together, our data illuminate a labeled-line organization for controlling pheromone-mediated sexual behavioral output in female mice.
BackgroundSexual imprinting is important for kin recognition and for promoting outbreeding, and has been a driving force for evolution; however, little is known about sexual imprinting by auditory cues in mammals. Male mice emit song-like ultrasonic vocalizations that possess strain-specific characteristics.ObjectivesIn this study, we asked whether female mice imprint and prefer specific characteristics in male songs.Methods and FindingsWe used the two-choice test to determine the song preference of female C57BL/6 and BALB/c mice. By assessing the time engaged in searching behavior towards songs played back to females, we found that female mice displayed an innate preference for the songs of males from different strains. Moreover, this song preference was regulated by female reproductive status and by male sexual cues such as the pheromone ESP1. Finally, we revealed that this preference was reversed by cross-fostering and disappeared under fatherless conditions, indicating that the behavior was learned by exposure to the father's song.ConclusionsOur results suggest that female mice can discriminate among male song characteristics and prefer songs of mice from strains that are different from their parents, and that these preferences are based on their early social experiences. This is the first study in mammals to demonstrate that male songs contribute to kin recognition and mate choice by females, thus helping to avoid inbreeding and to facilitate offspring heterozygosity.
SUMMARYActive defense against a conspecific aggressor is essential for survival. Previous studies revealed strong c-Fos expression in the ventrolateral part of the ventromedial hypothalamus (VMHvl) in defeated animals. Here, we examined the functional relevance and in vivo responses of the VMHvl during conspecific defense. We found that VMHvl cells expressing estrogen receptor α (Esr1) are acutely excited during active conspecific defense. Optogenetic inhibition of the cells compromised an animal’s ability to actively defend against an aggressor, whereas activating the cells elicited defense-like behaviors. Furthermore, the VMHvl is known for its role in aggression. In vivo recording and c-Fos mapping revealed differential organization of the defense and aggression-responsive cells in the VMHvl. Specifically, defense-activated cells are concentrated in the anterior part of the VMHvl, which preferentially targets the periaqueductal gray (PAG). Thus, our study identified an essential neural substrate for active conspecific defense and expanded the function of the VMHvl.
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.
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