Understanding our brains during puberty

How sex differences in brain development affect mental health

There are many neurological and neuropsychiatric diseases that affect men and women differently, but we don’t have a clear picture as to why.

One factor that may be important is the influence of hormones during puberty, which can change the way in which genes are used by brain cells, affecting their function.

“There are some baseline differences between males and females that suggest we shouldn’t be given the same pharmacological interventions. We are trying to identify what changes are occurring at the molecular level so we can figure out how to target those specifically.”

Dr. Corina Nagy, Assistant Professor in the Department of Psychiatry at McGill University and a Future Leader in Canadian Brain Research.

The Future Leaders in Canadian Brain Research Program is one of several Brain Canada flagship programs that focuses on building capacity within the brain research landscape. By providing funding to early-career researchers at critical junctures in their careers, Brain Canada is building Canada’s pipeline of neuroscience leaders and a foundation of research excellence and innovation.

“Supporting the next generation of scientists is a key focus for Brain Canada as we believe they have the talent and ingenuity to move the needle in Canadian brain research. We are investing directly in trainees and early-career researchers so that we can catalyze their potential and foster bold, unorthodox, and exploratory research that is poised to have a positive impact on the lives of all people in Canada,” says neuroscientist Dr. Viviane Poupon, Brain Canada President and CEO.

Dr. Nagy is one of 88 Canadian researchers to have received funding to date through Brain Canada’s Future Leaders in Canadian Brain Research program since 2019. Dr. Nagy’s award is made possible by the Canada Brain Research Fund (CBRF), an innovative arrangement between the Government of Canada (through Health Canada), Brain Canada Foundation, and Hewitt Foundation.

At the Douglas Research Centre, Dr. Nagy and her team are using a four-core genotype (FCG) mouse model, which allows them to decouple the effect of gonadal hormones from the underlying chromosomal contributions. This approach enables them to examine the interactions between sex chromosomes and hormones in various combinations and examine their sex-specific effects on the brain. 

“My research explores sex differences in brain development,” she says. “I’m investigating this in the context of major depressive disorder, as it is twice as common in females compared to males.”

Ultimately, Dr. Nagy is using the FCG mouse model to determine how sex hormones and genetics influence gene function and brain development during puberty.

“We have two main driving factors regarding our biological sex: our genes and the hormones produced by our sex organs. Our genome transcribes differently based on our sex, and these hormones affect our bodies in distinct ways.”

Funding for early-career researchers

Anchored by a lead gift from the Azrieli Foundation, the Future Leaders in Canadian Brain Research program aims to accelerate novel and transformative research that will fundamentally change our understanding of nervous system function and dysfunction and their impact on health. Since its inception, the program has invested $8 million to advance the search for answers to brain diseases and disorders, including Parkinson’s, Alzheimer’s, brain cancer, autism, substance use disorders, mental illnesses and more. To date, at least eight patents have been filed for discoveries resulting from Future Leader projects, and more than $64 million in additional funding has been awarded to recipients to amplify their research.

According to Dr. Nagy, Brain Canada’s Future Leaders in Canadian Brain Research program offers more than just financial support. She appreciates Brain Canada’s efforts to share research with the public and the program’s focus on early-career researchers, who face intense competition for grants.

“Knowledge translation is a very important factor that I appreciate, as it helps get this type of research off the ground, paving the way for larger funding opportunities,” she explains.

Since the start of her Future Leaders funding in late 2023, Dr. Nagy has made significant strides. Using a normative mouse model, she has identified the critical time points within puberty to focus on. Concurrently, her team is analyzing hormones directly from the same brain tissue to determine how estrogen and testosterone levels influence gene transcription.

Georgia Kruck, a master’s student in Nagy’s lab, is now working on analyzing the data at the level of individual cells.

“Georgia is very excited about this,” says Dr. Nagy. “She had the opportunity to present in Munich earlier this year. This project is a great chance for her to focus on a major biomedical question that has been overlooked for so long.”

The Big Question

But why does most research focus on males when major depression is more prevalent in females?

“We already have some evidence that the treatments we use are more efficacious in one sex than the other,” says Dr. Nagy.

Incorporating sex-specific biological considerations in brain development is crucial for understanding the biological roots of mental illness. These sex differences can significantly influence how brain conditions manifest, progress, and respond to treatment.

“There is a misconception that females have a cycle so complex that it’s impossible to study, and that that we should just apply everything we learn from males to females. It’s not true. Males also experience significant hormonal cycles that follow a daily rhythm. It’s also important to note that many of the findings from studies conducted in males simply do not generalize to females.”

Dr. Corina Nagy

Dr. Nagy describes that many brain disorders exhibit clear sex differences: Alzheimer’s is more common in females, while Parkinson’s disease is more prevalent in males, for example. These differences are prominent across various disorders but have been ignored for the sake of convenience.

“The research community has finally realized that this doesn’t work,” explains Dr. Nagy.

Thanks to her work, the Douglas Bell Canada Brain Bank, funded in part through support from Brain Canada, is taking steps to address gender gaps in their processes as well.

“Gender was never part of our questionnaire when we recruited for the brain bank before,” she says. “But I’ve changed that now, and we ask this question. I hope that moving forward many brain banks will do the same.”

Dr. Nagy is optimistic that her research will show that there are divergent mechanisms in how we develop pathologies and develop in general. Males and females use different cell types in different ways, which is fascinating.

“I hope this research opens people’s eyes to the fact that developing differently is just that—developing differently. We are all biologically unique, and that doesn’t mean one is better or worse than the other.”

Dr. Corina Nagy

If there’s one key takeaway from this, it’s that we all have unique needs, and we need to start tailoring our approaches to meet those differences now.