• Contributed by Troy Shirangi

Sexual orientation and the rewarding brain

When Michael Stipe of the alternative band R.E.M. wrote, ‘sexuality isn’t just black and white, or simple—it is every shade and gradation of the rainbow,’ he very well could have been writing about the animal kingdom at large.

Sexual orientation is remarkably fluid—not just in humans, but in all kinds of animals [1]. Female bonobos, for instance, will lie on top of one another rubbing genitalia. Male Adelie penguins from Antarctica routinely take turns copulating with each other. Bottle-nosed dolphins are known to have sex with turtles, sharks and even eels. (Yes, eels). And more recently, female Japanese macaques were observed to ride male sika deer and sexually grind their genitals against the deer’s back.

How does the brain control sexual orientation, and why is it that orientation is so flexible? Insights into these questions began to unfold in 2007 from work by a neuroscientist and her colleagues in Catherine Dulac’s laboratory at Harvard University [2]. Tali Kimchi was studying the sexual behaviors of mice when one day a certain strain of mice caught her attention. Male mice are typically heterosexual, but the males of this strain made sexual advances towards both females and males. Kimchi later discovered that the difference between the bisexual and heterosexual male mice was genetic, and it came down to a change in just a single gene called trpC2 (pronounced trip-c-2).

Ten years after her discovery of the trpC2 gene, Tali Kimchi’s research has given a unique glimpse into how the mouse’s brain controls sexual preference. In an article published recently in the journal Cell Reports, Kimchi’s research group reports that heterosexual behavior in male mice emerges in part because their brain assigns positive rewarding properties to pheromones from female mice [3]. The male mice with an altered trpC2 gene are bisexual because their brain no longer associates a sense of reward with female pheromones.

Mice spend much of their social life sniffing one another. They use their sense of smell to recognize gender and species, among other social cues. Females, for example, emit a suite of odors and pheromones that act as aphrodisiacs for heterosexual male mice. A few years ago, a study at University of North Carolina showed that heterosexual mice secrete a chemical called dopamine in certain areas of their brain when they encounter female pheromones [4]. The release of dopamine in the brain has been linked to the sensation of reward, leading some neuroscientists to believe that female pheromones are rewarding for heterosexual male mice.

Kimchi’s laboratory was curious to find out if the bisexual mice they were studying would release dopamine like their heterosexual counterparts when they chanced upon a female mouse. They reasoned that an altered trpC2 gene in these mice could lead to male bisexuality if it somehow uncoupled a sense of reward from female pheromones.

When scientists in Kimchi’s laboratory measured dopamine levels in the brains of their bisexual mice, they found, lo and behold, that their hypothesis was correct: the bisexual mice did not release dopamine when they encountered a female mouse, suggesting that their bisexual mice no longer equate a rewarding sensation with females.

The results of this experiment suggested that the release of dopamine and the association of reward with female pheromones may regulate sexual preference in male mice. To test this idea further, Kimchi’s laboratory thought of an ingenious experiment. They wondered, would it be possible to induce heterosexual behavior in their bisexual mice by stimulating the dopamine pathway as the male mouse encountered a female?

The scientists in Kimchi’s laboratory genetically engineered a new strain of their bisexual mice. By shining blue light on the heads of these mice, they could artificially stimulate the dopamine pathway in their brains while the male interacted with a female. Remarkably, when the researchers did the experiment, the male mice that were formerly bisexual became exclusively heterosexual.

Tali Kimchi and the researchers in her laboratory must have popped the champagne bottle after that experiment. It provided compelling evidence that heterosexual behavior in male mice is controlled at least in part by their brain’s ability to ascribe a positive rewarding sensation female pheromones.

While this study tells us a lot about the biological basis of heterosexual behavior, many questions remain. It’s not clear, for example, why the inability to link reward to female pheromones would cause males to gain an attraction towards other males. Perhaps it suggests that males with a modified trpC2 gene have other neurological changes beyond a change in the rewarding properties of female pheromones. All the same, work from Tali Kimchi’s laboratory and others have begun to lift the mystery behind the biology of sexual orientation.

1. Judson, O., Dr. Tatiana's sex advice to all creation: the definitive guide to the evolutionary biology of sex.

2. Kimchi T, Xu J, Dulac C. A functional circuit underlying male sexual behaviour in the female mouse brain. Nature. 2007 Aug 30;448(7157):1009-14.

3. Beny-Shefer Y, Zilkha N, Lavi-Avnon Y, Bezalel N, Rogachev I, Brandis A, Dayan M, Kimchi T. Nucleus Accumbens Dopamine Signaling Regulates Sexual Preference for Females in Male Mice. Cell Rep. 2017 Dec 12;21(11):3079-3088.

4. Robinson, D.L., Phillips, P.E., Budygin, E.A., Trafton, B.J., Garris, P.A., and Wightman, R.M. (2001). Sub-second changes in accumbal dopamine during sexual behavior in male rats. Neuroreport 12, 2549–2552.