How Sex-Based Analysis Can Drive Neuroscience Research Forward

Historically, sex differences have captivated the interests of researchers from many realms of academia. Evolutionary biologists have come a long way in investigating the link between species survival, sexual dimorphism, and mate choice. Physiologists have been pivotal in elucidating the divergent bodily functions of the different human sexes. Sociologists have even examined the roles of the different sexes in society, paving the way for foundational pieces of feminist literature, such as those by Simone de Beauvoir and Mary Wollstonecraft. But how is sex research done in neuroscience? Apart from studying sexually dimorphic brain regions, what more do researchers look at? In the Einstein Lab, cognitive neuroscience is investigated from the lens of sex and gender, and these terms are thoroughly discussed and examined before being incorporated into research. Dr. Nicole Gervais, a post-doctoral researcher in the lab, discusses her work in cognitive and behavioral neuroscience and how she integrates sex into her own work.

Dr. Gervais, who is interested in answering questions related to the effects of hormones on memory and sleep, started working with rats during her PhD at Concordia University in Montréal, QC. She investigated the functional role of brain areas that are within the medial temporal lobe, on memory. (While the brains of rats do not have lobes, they have the same brain structures). “That’s when I got interested in working with females,” she recalls. “I actually switched focus to look exclusively at female rats and how they remember.” At the time, while there were quite a few researchers investigating female rats and memory, the Canadian Institute for Health Research (CIHR) did not have the focus of sex and gender in their grants, as they do now. “In my lab, my research supervisor, Dr. Dave Mumby, had [previously] looked exclusively at male rats,” she remembers. “People who study memory do not typically study females, himself included. But he was open to the idea, and now continues to include females in his research. And I think it has since received growing interest.” As a Postdoctoral Research Associate working with Dr. Agnès Lacreuse at the University of Massachusetts Amherst, Dr. Gervais continued investigating memory in females, but moved on to a completely different species: marmosets, a New World monkey. “I started looking at how hormones can modulate memory in middle-aged marmosets,” Dr. Gervais explains, expressing her love for the animals. “I also conducted sex difference studies looking at the importance of brain-derived estrogens in modulating the memory of males and females.” Alongside studying memory in marmosets, Dr. Gervais also worked on a sleep study, where she learned to score sleep in the monkeys. “They have a wireless telemetry system so you can record what they’re doing at any time of day, including their brain activity while they’re asleep,” she details.  She then brought her expertise on ovarian hormones, memory, and sleep to her post-doctoral position at the University of Toronto, where she currently researches hormones and memories – but in humans this time. She received a grant co-sponsored by the Alzheimer’s Association and Brain Canada Foundation to investigate why women have higher dementia risk, and the impact of menopause on memory, brain structure, and sleep.

How do Sex Differences Affect Research in Neuroscience?

Sex plays a large role in Dr. Gervais’ research, which is also centered around hormones and sleep. “Women have more sleep problems than men,” she professes. “We don’t really know why and we haven’t delved deeper beyond sleep staging, so a lot of the analysis is from a superficial standpoint.” Dr. Gervais is interested in interpreting the subtle signals from EEG recordings to explain why women will report more sleep problems than men. “We can observe slight changes in the frequency and amplitude of waves in different stages of sleep,” she explains, “which the EEG might be sensitive enough to pick up.”

Dr. Gervais goes on to dismantling preconceived notions of sex. When asked about the belief that sex is thought to be a binary characteristic determined by an X or Y chromosome before birth, whereas gender is viewed as a social construct, she replies, “Sex is a biological characteristic but it’s not binary. While for a majority of cases, there will be either an XX or XY [predetermination], there are also alternatives.” She further expands, “We also know that biological sex can be defined in ways other than chromosomes: it can be defined by a hormonal definition, such as during prenatal development, or also during puberty.

How do researchers study sex differences?

There are certain questions scientists could not have asked earlier but can ask now about how sex impacts the brain. “People who study sex differences  have come up with a really nice definition of how sex differences exist in the brain,” Dr. Gervais affirms. “There are sexually dimorphic areas, which is probably the classic thing we think of when we think about sex differences in the brain. But that’s rare and only a certain number of brain areas actually show sexually dimorphic effects.” She clarifies that there are more subtle sex differences, which can be observed and investigated. “For example, females tend to be at a slight advantage at verbal memory skills, but the opposite holds true for spatial memory,” she states. Furthermore, sex differences might appear in one study but not on others, which could be attributed to the samples of both studies – each cohort will include different people, which might slightly alter each average, but that doesn’t mean that the sex difference doesn’t exist – it’s just more of a subtle difference. “Then, there’s a third kind of sex difference that might arise, in which there might be differences in gene expression or memory mechanisms, but the outcome is exactly the same,” Dr. Gervais explains. “So if you were to look at behavior, females and males would perform the same but how they got there is going to be different.”

 If sex differences can exist in the brain in so many ways and forms, why doesn’t more research include them? While a growing body of research is now starting to incorporate sex differences into studies, Dr. Gervais still believes that there might be some obstacles along the way. “I don’t think there have been too many challenges with my own work, but what I’m struggling with now is convincing people it’s worth the effort,” she admits. “When you work with people who normally do rodent research, you budget for a certain number of rats. But you need to double that number if you’re working with females, and suddenly a grant becomes more expensive. There’s also a kind of stress for people who have never worked with female rodents before. All these questions come up – How do you properly conduct experiments with hormones and keep the females intact? How do you track the estrous cycle? Do you take the ovaries out? If you do, how do you replace the hormones in a controlled manner?” Dr. Gervais acknowledges that its challenging for researchers to incorporate females into their research program when sex has not been a variable addressed in their work before. “But I see that there are more and more scientists willing to put in the effort,” she notes.

 Human neuroscience, on the other hand, is a slightly different situation. “People will often test a sample that includes both men and women,” Dr. Gervais explains. “While most researchers will at least mention the sex distribution of their studies, many will either covary sex out of their analysis (remove the effect of sex) or not address sex at all. While this is a result of oversight (researcher didn’t think to study sex), some researchers are now going back to old data and re-analyzing and seeing sex differences. This is very positive news for us!”

Going forward, Dr. Gervais plans to keep exploring sex differences and investigate how hormones regulate the memory-promoting effects of sleep. But her work with sex differences and her knowledge on how gender impacts changes in the brain have led her to think more about shared knowledge and collaboration on these subjects within the scientific community. “I wonder what scientists that care about sex and gender can do to encourage other researchers to start thinking about these areas too,” she wonders aloud. “And what are some of the things that we haven’t considered and that are also important – like sex and gender – that we should probably integrate into our research?”

Sex and gender analysis in neuroscience has come a long way – but also has a long way to go. And as we continue to think about sex, gender, and the brain, what other influencers of neurobiology can we consider that we haven’t and couldn’t before?

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