Pheromone for the Young

Researchers identify a compound in juvenile mice that inhibits the sexual advances of adult males.

By | October 2, 2013

Fluorescently labeled vomeronasal neurons recorded from adult male mice exposed to ESP22MARC SPEHR, RWTH AACHEN UNIVERSITYThe tears of two- to three-week-old mice contain a pheromone that deters adult males from sexual contact, according to a study published today (October 2) in Nature. In young mice lacking exocrine-gland secreting peptide 22 (ESP22), males made unwanted sexual advances, but painting the compound on the fur of juveniles inhibited this behavior.

“In the past, people actually thought that the lack of [sexual] reaction to young was due to the lack of pheromones. No pheromones, no behavioral responses—that was the common thinking,” said neuroscientist Roberto Tirindelli of the University of Parma in Italy, who did not participate in the study. “Now, for the first time, they show that there is a specific pheromone which is actually active, preventing sexual contact. The inhibition of sexual contact is due to the presence of this pheromone and not to the absence of other pheromones.”

In the last several years, researchers have begun to identify more and more putative pheromones in mice. Specifically, three large gene families, including ESPs, have been recognized to activate the vomeronasal organ (VNO), an olfactory structure located just above the roof of the mouth. But identifying the functions of these dozens of compounds has proven much harder. The first study to link an ESP to function, for example, was published in 2010, when the University of Tokyo’s Kazushige Touhara, an author on the present study, and colleagues found that ESP1 induces lordosis, a sexually receptive posture in females.

Interested in better characterizing the growing number of compounds that may be mouse pheromones, Stephen Liberles’s lab at Harvard Medical School developed a screen to look for differential expression of pheromone homologs across mice, already identifying a predator odor found in carnivores that causes an avoidance response, and an attractive mouse odor. But when the researchers identified a compound that was expressed almost exclusively in juvenile mice, they were intrigued.

Without any preconceived notion of what a juvenile compound might be doing, Liberles’s group “took a Jane Goodall-inspired approach, where we just observed the behavior” of adult males with young mice. They compared wild-type mice with males harboring a genetic mutation that resulted in a largely dysfunctional VNO. Surprisingly, these knockout males displayed increased sexual behavior towards the juveniles. David Ferrero, the graduate student who ran the experiments, told Liberles that he “had never observed a stronger [behavioral] effect in any of his research,” Liberles said. “It was a very striking phenotype . . . suggesting that the juveniles were releasing some sort of protective pheromone that blocked these normally unproductive advances.”

The team confirmed the findings observing the interactions of adult males with juveniles from strains that did not express ESP22. Sure enough, without the behavior-suppressing signal, the males tried to mount the young mice. Painting ESP22 onto the mice inhibited the sexual behavior, however.

“[It’s] a pretty unique finding,” said geneticist Robert Karn of the University of Arizona College of Medicine, who was not involved in the work. “The little bit of juvenile-adult interactions [studied so far] seem to work the other way,” he noted, such as evidence that newborn mice use pheromones secreted in their mother’s milk to help find their first meals. “In this case, it appears that the signal is being produced in the pups [and eliciting] a behavioral response [in the adults]—or, you might say, a lack of behavioral response.”

“I think the data is quite convincing,” added C. Ron Yu, neuroscientist at the Stowers Institute for Medical Research, who recently authored a feature story on mammalian pheromones in The Scientist. “By painting an exogenously expressed peptide directly onto the mouse and inhibiting mating, that is quite striking.”

Electrophysiology and immunohistochemistry analyses confirmed that ESP22 activated a small subset of cells in the VNO and revealed downstream processing in the medial amygdala, a bit of a pheromone “hub” that mediates a range of behavioral responses, said Liberles, who noted that one direction of future research will be to further dissect the neural circuitry underlying such behaviors. Additionally, the researchers would like to identify the receptor that ESP22 binds to in the VNO. “We don’t understand how instinctive neural circuits are formed,” said Liberles. “So I think if you know what receptors are responding to these cues, that sort of gives you a handle on the neural circuit.”

And there are still dozens of other putative pheromones to be further explored, meaning more age-related compounds will likely be uncovered. “We know that male pheromones in mice are incredibly complex,” said Liberles. “There’s not a single cue that indicates maleness. I think something similar could occur with age.”

 “I’d be very surprised if there weren’t [more],” agreed Karn.

D.M. Ferrero et al., “A juvenile mouse pheromone inhibits sexual behaviour through the vomeronasal system,” Nature, doi:10.1038/nature12579, 2013.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 435

October 2, 2013

Stephen Liberles has co-authored with 2004 Nobel Laureate Linda Buck who co-authored Feedback loops link odor and pheromone signaling with reproduction. These feedback loops link the epigenetic effects of olfactory/pheromonal input directly to the de novo creation of olfactory receptor genes and  receptor-mediated changes in gonadotropin-releasing hormone (GnRH).  It seems likely Liberles knows that modulation by GnRH of other hormones such as sex steroid hormones affects the development of  mammalian behavior, which includes behaviors associated with the development of sexual orientation and with age-related changes in sexual function. This suggests that pheromones epigenetically effect the development of sexual orientation and adult sexual function.

There's a model for that!


In Gay, Straight, and the Reason Why: The Science of Sexual Orientation, Simon Le Vay wrote:

"This model is attractive in that it solves the "binding problem" of sexual attraction. By that I mean the problem of why all the different features of men or women (visual appearance and feel of face, body, and genitals; voice quality, smell; personality and behavior, etc.) attract people as a more or less coherent package representing one sex, rather than as an arbitrary collage of male and female characteristics. If all these characteristics come to be attractive because they were experienced in association with a male- or female-specific pheromone, then they will naturally go together even in the absence of complex genetically coded instructions."


Adding evidence of a pheromone in juvenile mice that inhibits sexual behavior in adult males suggests that the inhibition is due to an epigenetic effect on GnRH pulse frequency in my model of Nutrient-dependent / pheromone-controlled adaptive evolution. Including evidence that males harboring a genetic mutation, and that males with a largely dysfunctional VNO displayed increased sexual behavior towards the juveniles, appears to link genetic mutations to sexual orientation in mammals and perhaps even to pedophilia in humans.

It seems likely that trouble lies ahead for those willing to use models of the hormone-organized and hormone-activated  development of sexual orientation in some animals, or of mutation-driven evolution in others, but who also try avoid a Nobel Laureate's link from pheromones to GnRH and its modulation of the human hypothalamic-pituitary-gonadal-adrenal (HPGA) axis. Are we being inadvertently led to believe in mutation-caused human sexual orientation and pedophilia, or can we avoid that link via the lack of a functional human VNO and claims by human pheromone-deniers that human pheromones don't exist? Can we also avoid any link from the epigenetic effects of olfactory/pheromonal input on GnRH and its nutrient-dependent pheromone-controlled modulation of the HPGA axis and behavior in other mammals?

 I don't think so. Sex Differences and the FDA Critical Path Initiative cites a report recommending that research on sex diff erences be conducted at every level—gene, cell, tissue, organ, and organism—and that sex differences be studied at every stage of life, from conception through death. How are researchers going to avoid discussion of epigenetic effects of olfactory/pheromonal input in humans after showing that a juvenile mouse pheromone inhibits sexual behavior (in a model organism of mammalian behavior)? Does anyone else think that this a juvenile mouse pheromone has the potential to confuse people about biologically-based cause and effect?



Avatar of: Roy Niles

Roy Niles

Posts: 107

October 3, 2013

Commenters like Kohl have a vested interest in getting the development sequence for pherenomes backwards.  Behavioral purposes developed chemical responses, not the responses developing the behaviors that they then supposedly found they needed to assist.

Avatar of: James V. Kohl

James V. Kohl

Posts: 435

Replied to a comment from Roy Niles made on October 3, 2013

October 3, 2013

Commenters like Niles never comment on my published works or reasons why they disagree with representations made by others in the context of the nutrient-dependent physiology of reproduction. They might just as well argue that the president of the International Union of Physiological Sciences has a vested interest in misrepresentations of fact, like those addressed in Physiology is rocking the foundations of evolutionary biology.

Abstract: "The 'Modern Synthesis' (Neo-Darwinism) is a mid-twentieth century gene-centric view of evolution, based on random mutations accumulating to produce gradual change through natural selection. Any role of physiological function in influencing genetic inheritance was excluded. The organism became a mere carrier of the real objects of selection: its genes. We now know that genetic change is far from random and often not gradual. Molecular genetics and genome sequencing have deconstructed this unnecessarily restrictive view of evolution in a way that reintroduces physiological function and interactions with the environment as factors influencing the speed and nature of inherited change. Acquired characteristics can be inherited, and in a few but growing number of cases that inheritance has now been shown to be robust for many generations. The twenty-first century can look forward to a new synthesis that will reintegrate physiology with evolutionary biology."

The environmental factors that epigenetically and directly effect the nutrient-dependent pheromone-controlled hormone-organized and hormone-activated physiology of invertebrate and vertebrate reproduction are olfactory input and pheromonal input. Niles is probably still touting random mutations theory despite the works of Liberles, Le Vay, and Nobel Laureate Linda Buck.

It is no wonder he doesn't pose a coherant objection to my representations in my published works. He's stuck in the twentieth century and can't get out.

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