The battle of the sexes may still be raging in the media, but as far as neuroscientist Catherine Dulac is concerned, it has no place in the brain. Though her research has shed light on behavioral differences in male and female mice when it comes to reproduction and aggression, “the idea of the gendered brain is largely wrong.” That is because, for mouse or human, new research shows that the brains of males and females are likely to be quite similar. Canonical female and male behaviors like nurturing young, or attacking them, stem instead from a combination of hormonal and environmental triggers that in turn differentially activate still incompletely understood circuits that are present in both female and male brains. It is these circuits, and more widely the brain structures that determine social behaviors, that continue to fascinate Dulac.

The Harvard professor’s career began, and has largely remained, in the vicinity of the nose, particularly in the vomeronasal organ, a nasal sidekick in some animals that detects the social signals known as pheromones. Smells and pheromones are gateways to instinctive behaviors in many species, and Dulac was the first to identify the genes responsible for encoding pheromone receptors in mammals — mice especially rely on pheromones to identify mates and predators. During a visit to the RIKEN Brain Science Institute in Japan, Dulac discussed the sex bias in biomedical research, the genderless brain and the media, and the demise of the dreaded ‘third reviewer’.

There is no male brain or female brain

What are the broad goals of your research?

I am interested in the social brain. What is special about detecting other individuals, as opposed to objects? There is something very special about social interactions, and humans especially are extremely sensitive to a range of signals emitted by other human beings. All animals of course need to interact, and they treat information about other individuals in special ways. Various species use different stimuli to recognize each other— for mice it’s olfaction, for humans it’s visual and auditory cues, but the central brain processes are likely to be similar.

When we started looking at the brains of male and female mice, we did not find that many differences, which came as a total surprise, because if their behaviors are sexually dimorphic, one could expect to find that the brain areas controlling these behaviors are also different in males and females. Males fight or mate, females are maternal and respond to different stimuli. The dogma was that if we see these behavioral differences, the brains must be different. But what we have found instead is that the circuitry is similar in males and females and it is the way this circuitry is controlled and modulated [for example by hormones] that is different between the sexes.

You have published research on brain circuits that determine sexual and parental behaviors in mice. Have the public or the media drawn excessive conclusions from your work?

Catherine Dulac. Image: Tomoko Nishiyama/RIKEN Brain Science Institute

First, the idea of the ‘gendered’ brain is likely to be mostly wrong. Ten or 15 years ago, we realized that the dogma that at birth male or female brains develop along different organizational schemes, we came to realize that this was not true in the mouse. We published these results in top journals, but we were careful that the data would not get hyped in media coverage; we did not want the work to be misinterpreted, for example with big headlines like “the homosexual brain” or “the bisexual brain”. My work applies to mouse behavior and says nothing about humans, so I really want to be very cautious about extrapolating our results to other species and particularly to humans.

Several years later, with more data and after extensive discussions on this topic, I think I can now place these results in a larger context. Today there are active public discussions about gender identity and transgender individuals, and scientific information about how to explain these phenomena is actively sought. When I spoke at the Harvard Medical School endocrinology grand rounds several years ago, the head of the transgender clinic remarked to me that those who came for consultation were not teenagers but very young children, two, three, four years old, who already had a strong sense that they were not a boy or a girl. This reflects a problem unrelated to sexual behavior, but rather a deep issue of gender identity. How can one explain someone’s feeling of being in a wrong body? There are a lot of open discussions on this topic nowadays, so it is easier to think about it and form hypotheses compared to the situation 10 years ago.

The principles we have discovered in the mouse may help explain some parts of the puzzle in humans or inspire some ideas. We cannot, however, make any inferences from mice to humans when it comes to sex and the brain. That being said, very recent structural and functional data from humans now show that there is no such thing as a male brain or female brain, but that brains are just a mosaic of different features. These data fit quite well with our own conclusions in rodents.

How can you study female lab mice if they don’t do anything?!

The vast majority of biomedical research is done with male animals, and even human clinical trials have skewed toward male participants. Is this an issue?

Are you sure you want to get me started on this? I could talk about this all day! … When I started as a principal investigator, as a woman I wanted to make sure that half of our experiments were done in males and half in females. But we hit two problems. First, there is almost no literature on female behavior, because only the male, historically, has been worth considering. Second, and an equally problematic issue for behavioral neuroscience, is that very few female-specific behaviors have been reported. The problem is due to the mice we are using. In work that she initiated in my lab, Tali Kimchi, a former postdoc, recently published a paper comparing the behaviors of wild — wild — mice, female and male, and laboratory female and male mice. The lab female is a total outlier, in all aspects of physiology and behavior. Wild females are as aggressive as males, they kill pups, attack both males and females, have small litters, reproduce late and are choosy with mates. One obviously cannot have a mouse colony if females behave that way. So all those female characteristics have been bred out. Now we have docile females, so how can one study their female-specific behaviors if they don’t do much of anything?!

So looking at male and female mice, I hit this problem: it’s just not easy to do. The first set of studies we did were in males. I then tried to convince someone in the lab to look at females, but they always pointed to the lack of literature. It became embarrassing, because I would give talks and someone in the audience would always ask about the female mutant behavior, and I just didn’t know. But since then some of the most interesting results have come from the study of female behavior. In neuroscience, the reaction is that there is nothing interesting in females, it’s either the same as males and not worth doing or just too complicated.

What is a structural or cultural issue in science that could be improved?

One issue that has not been evolving well until recently is the way peer review works. It’s unacceptable that the peer review and evaluation required by many journals may take six months to over a year, sometimes even longer, and require dozens of new experiments, then six months again after re-submission, only to end in a rejection. It’s hard for a principal investigator but even harder for a student or postdoc who is waiting for evidence — published papers — to advance their career.

I am a senior editor at eLife. It has been successful, and a good model that other journals are starting to pay attention to. What makes it work is the combination of not requiring additional work and the open peer reviews. The people evaluating the work are all scientists, so they feel in their heart and body the effort in requiring additional experiments — the maximum we can ask for is two more months’ worth of work. The reviewers know each other, so the famous vitriolic third reviewer no longer exists. Reviewers do not want to look like a fool in the eyes of the other two reviewers, so they pay close attention and provide constructive criticism. The eLife review provides a set of marching orders [recommendations on how to improve a submitted manuscript] that is common to all reviewers, instead of three non-overlapping reviews, and it makes a huge difference. And the process is entirely online, so publishing can be done quickly.

This interview has been edited for clarity and length.