There is staggering evidence pointing to crucial distinction between disease pathologies and their manifestations between the sexes. These differences, and their underlying roots, remained largely understudied throughout the 20th century. But thankfully, that has been changing.
Today, scientists are engaged in exploring sex differences in the prevalence and manifestation of a number of diseases, including depression. In the laboratory of Corina Nagy, Ph.D., at the Douglas Research Centre, researchers are working to bridge the existing gap in knowledge by exploring sex differences at the molecular level. Gladi Thng, Ph.D., and Elizabeth DeSouza, two members in the Nagy lab, sat down with us to provide an overview of their respective groundwork, and how their research is helping shape the future of neuropsychiatric research through Sex and Gender Based Analysis (SGBA), using both animal and human models.
Starting before the beginning
“Life events often act as key triggers for depression; but fundamentally, there are baseline molecular differences between males and females that can influence underlying risk,”says Thng, a postdoctoral researcher who joined the Nagy lab in 2024. “Currently, there’s a lot of focus on what happens after the diagnosis of depression. But what if we can find ways to mitigate risk at the root before the manifestation of the disease?”
Using healthy mouse models, Thng investigated how baseline sex differences in gene expression and transcriptional regulation emerge across normal brain development.
DeSouza started her journey in the Nagy lab as a research technician with the Douglas Brain Bank, an experience that inspired her to pursue her own research project. In May 2026, she completed her master’s degree. For her project, she decided to explore the DNA methylation landscape and steroid hormone levels in the prefrontal cortex during adolescence, using postmortem human brain tissue.
The aim for both researchers was to understand sex dependent differences prior to the manifestation of depression or psychopathology: one looked at the gene expression and gene regulatory networks, while the other looked at methylation and hormones.
“Adolescence is a sensitive period of brain development during which internal and external stimuli can have an important outcome. It’s also a period of heightened risk for developing psychopathologies, such as depression and anxiety related disorders. Therefore, this period was of great interest to us,” says DeSouza.
Their findings clearly suggest that studying both male and female brain mechanisms is crucial in paving the path forward in understanding disease manifestation.
What the science shows
In adolescent mouse models, Thng uncovered sex-specific developmental trajectories of immediate early genes, a class of genes rapidly activated in response to neuronal activity and stress. Her findings also suggest distinct sex-specific regulatory programs underlying the response to stress, with male regulatory networks oriented toward neuronal stability and female regulatory networks oriented toward hormonal sensitivity. These differences suggest distinct entry points for stress-induced pathology and may explain how shared risk factors produce divergent biological and clinical outcomes across sexes.
DNA methylation is a process that regulates how and if genes are expressed. This can in-turn influence how an individual expresses their emotions and behaves in response to adversity. In her research, DeSouza found that sex differences started to show in older adolescence (15 years and older) in both hormone expression and DNA methylation. Interestingly, they found that male brains showed more regions with higher methylation in early adolescence; but by mid-adolescence, this was more prevalent in females.
“This sex-bias reversal in early and mid-adolescence could be due to fluctuations in steroid hormone levels triggered by the onset of menstruation,” says DeSouza.
“This data is the first of its kind,” she adds. “Future studies can now include other brain regions, and we can then connect these findings together in a cohesive and holistic way.” Measuring hormone levels in postmortem brain tissue was done in collaboration with Kiran Soma, PhD, Professor in the Department of Psychology at the University of British Columbia.
“Depression is often thought of as being more common in women, but current diagnostic criteria may not fully capture how the disorder presents in men,” says Thng. “Our findings suggest that males and females may arrive at depression through different molecular pathways, which could help explain why symptoms can differ between the sexes.”
Empowering future researchers
These findings are only scratching at the surface of sex differences in adolescent brains. We are still far away from understanding the implications of these molecular and regulatory pathways in the manifestation of psychopathologies. Understanding these core differences can help inform future research directions. In addition to these projects, the Nagy lab is establishing a pipeline from other brain regions. The goal is to identify brain structures where changes happen, and how that affects neural network.
“We hope that these findings inspire people to think about inequities in research. Beyond our lab, I hope to see more misrepresented or understudied groups taken into consideration,” says DeSouza.
“I hope that findings like ours inspire governmental programs that are aimed at prevention, and at mitigating mental health risks early on, rather than waiting for the disease to develop and rely on the willingness of the individuals to seek therapy and treatment,” says Thng.
Both researchers are preparing to launch the next step of their career: DeSouza hopes to pursue research opportunities in industry, and Thng is planning to return to Singapore where she aspires to shape the research landscape.
