Kimchi T, Xu J, Dulac C. A functional circuit underlying male sexual behvior in the female mouse brain. Nature 448: 1009-1014

Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
Nature (Impact Factor: 41.46). 09/2007; 448(7157):1009-14. DOI: 10.1038/nature06089
Source: PubMed


In mice, pheromone detection is mediated by the vomeronasal organ and the main olfactory epithelium. Male mice that are deficient for Trpc2, an ion channel specifically expressed in VNO neurons and essential for VNO sensory transduction, are impaired in sex discrimination and male-male aggression. We report here that Trpc2-/- female mice show a reduction in female-specific behaviour, including maternal aggression and lactating behaviour. Strikingly, mutant females display unique characteristics of male sexual and courtship behaviours such as mounting, pelvic thrust, solicitation, anogenital olfactory investigation, and emission of complex ultrasonic vocalizations towards male and female conspecific mice. The same behavioural phenotype is observed after VNO surgical removal in adult animals, and is not accompanied by disruption of the oestrous cycle and sex hormone levels. These findings suggest that VNO-mediated pheromone inputs act in wild-type females to repress male behaviour and activate female behaviours. Moreover, they imply that functional neuronal circuits underlying male-specific behaviours exist in the normal female mouse brain.

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    • "the establishment of GnRH neuron connections . A substantial loss of the basal neurons may cause a mis - wiring of the mating / aggression circuit . In addition , physiological changes in Trpc2 − / − mice may impact circuit development . Both male and female Trpc2 − / − mice have higher testosterone levels than wildtypes ( Leypold et al . , 2002 ; Kimchi et al . , 2007 ) . As masculinization of the brain could result from elevated testosterone or estrogen levels in adults , as well as from estrogen treatment in neonatal pups ( Paup et al . , 1972 ; Baum , 2009 ; Martel and Baum , 2009 ; Wu et al . , 2009 ) , it is possible that deficiency in pheromone detection during development could lead to brain m"
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    ABSTRACT: The vomeronasal organ (VNO) plays an important role in mediating semiochemical communications and social behaviors in terrestrial species. Genetic knockout of individual components in the signaling pathways has been used to probe vomeronasal functions, and has provided much insights into how the VNO orchestrates innate behaviors. However, all data do not agree. In particular, knocking out Trpc2, a member of the TRP family of non-selective cationic channel thought to be the main transduction channel in the VNO, results in a number of fascinating behavioral phenotypes that have not been observed in other animals whose vomeronasal function is disrupted. Recent studies have identified signaling pathways that operate in parallel of Trpc2, raising the possibility that Trpc2 mutant animals may display neomorphic behaviors. In this article, I provide a critical analysis of emerging evidence to reconcile the discrepancies and discuss their implications.
    Full-text · Article · Jun 2015 · Frontiers in Neuroscience
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    • "The results of the experiments reported above shed some light on the nature of maternal aggression and on its underlying neuroendocrine substrate. Since maternal aggression is severely reduced in mutant mice having olfactory (Cnag2 -/y , Mandiyan et al., 2005; AC3 -/-, Wang and Storm, 2011) or vomeronasal dysfunction (Leypold et al., 2002; Kimchi et al., 2007; Hasen and Gammie, 2009; Chamero et al., 2011; Leinders-Zufall et al., 2014), it seems likely that exposure to pup chemosignals detected by both the olfactory and vomeronasal epithelia is necessary for the induction of maternal aggression. However, our results indicate that virgin females that have been continuously exposed to pups for 3-4 days show negligible aggressive behaviour towards intruders approaching the nest (from which pups had been previously A C C E P T E D M A N U S C R I P T "
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    ABSTRACT: This article is part of a Special Issue "Chemosignals and Reproduction". This paper reviews the role of chemosignals in the socio-sexual interactions of female mice, and reports two experiments testing the role of pup-derived chemosignals and the male sexual pheromone darcin in inducing and promoting maternal aggression. Female mice are attracted to urine-borne male pheromones. Volatile and non-volatile urine fractions have been proposed to contain olfactory and vomeronasal pheromones. In particular, the male-specific major urinary protein (MUP) MUP20, darcin, has been shown to be rewarding and attractive to females. Non-urinary male chemosignals, such as the lacrimal protein ESP1, promote lordosis in female mice, but its attractive properties are still to be tested. There is evidence indicating that ESP1 and MUPs are detected by vomeronasal type 2 receptors (V2R). When a female mouse becomes pregnant, she undergoes dramatic changes in her physiology and behaviour. She builds a nest for her pups and takes care of them. Dams also defend the nest against conspecific intruders, attacking especially gonadally intact males. Maternal behaviour is dependent on a functional olfactory system, thus suggesting a role of chemosignals in the development of maternal behaviour. Our first experiment demonstrates, however, that pup chemosignals are not sufficient to induce maternal aggression in virgin females. In addition, it is known that vomeronasal stimuli are needed for maternal aggression. Since MUPs (and other molecules) are able to promote intermale aggression, in our second experiment we test if the attractive MUP darcin also promotes attacks on castrated male intruders by lactating dams. Our findings demonstrate that the same chemosignal, darcin, promotes attraction or aggression according to female reproductive state.
    Full-text · Article · Aug 2014 · Hormones and Behavior
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    • "Furthermore, genetic inactivation of the transient receptor potential channel Trpc2, the primary sensory ion channel of the VNO [12-14], results in a number of alterations in female reproductive behaviors, such as the absence of puberty acceleration, maternal aggression, and lordosis, and an increase in male-like sex behaviors [1,14-17]. However, experiments using either surgical VNO removal [18-21] or deletion of Trpc2 [13,14,16] led to a number of phenotypic discrepancies including unusual mounting levels toward males, and ultrasonic vocalizations and sex behavior toward females. Moreover, at least a portion of basal vomeronasal sensory neurons (VSNs) in Trpc2-/- mice seem to retain some level of sensory responsiveness [11,22], possibly because of parallel signal amplification mechanisms [23-25], which makes Trpc2-/- mice a much more complicated model to examine VNO-mediated function and behavior than previously anticipated. "
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    ABSTRACT: Background Optimal reproductive fitness is essential for the biological success and survival of species. The vomeronasal organ is strongly implicated in the display of sexual and reproductive behaviors in female mice, yet the roles that apical and basal vomeronasal neuron populations play in controlling these gender-specific behaviors remain largely unclear. Results To dissect the neural pathways underlying these functions, we genetically inactivated the basal vomeronasal organ layer using conditional, cell-specific ablation of the G protein Gαo. Female mice mutant for Gαo show severe alterations in sexual and reproductive behaviors, timing of puberty onset, and estrous cycle. These mutant mice are insensitive to reproductive facilitation stimulated by male pheromones that accelerate puberty and induce ovulation. Gαo-mutant females exhibit a striking reduction in sexual receptivity or lordosis behavior to males, but gender discrimination seems to be intact. These mice also show a loss in male scent preference, which requires a learned association for volatile olfactory signals with other nonvolatile ownership signals that are contained in the high molecular weight fraction of male urine. Thus, Gαo impacts on both instinctive and learned social responses to pheromones. Conclusions These results highlight that sensory neurons of the Gαo-expressing vomeronasal subsystem, together with the receptors they express and the molecular cues they detect, control a wide range of fundamental mating and reproductive behaviors in female mice.
    Full-text · Article · May 2014 · BMC Biology
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