Stress resilience and depression: a step towards personalized treatment strategies

An article by Valérie Levée, science journalist

In the face of stress, some people become anxious or even depressed, while others are resilient. Knowing the biological mechanisms underlying this resilience could lead to the discovery of new treatments for depression. This is the line of research pursued by Caroline Ménard, a professor in the Department of Psychiatry and Neurosciences at Université Laval and a researcher affiliated with the CERVO research center at CIUSSS de la Capitale-Nationale. She tracks markers of stress resilience in the brain, blood and even the intestines.

“The ultimate goal is to develop personalized medicine in psychiatry,” says Caroline Ménard, holder of the Sentinel North Research Chair in the Neurobiology of Stress and Resilience. She explains that chronic stress triggers an inflammatory response that circulates in the bloodstream. Typically, the brain is shielded from this circulating inflammation by the blood-brain barrier, which encircles the blood vessels. However, if the barrier is weakened, inflammatory signals can enter the brain. Conversely, molecules associated with barrier disruption can enter the bloodstream and break the body’s internal balance.

Ménard and her research team have already identified some of these molecules in blood samples from the Signature Bank, a biobank containing biological and psychosocial data from individuals with mental health conditions. “We found markers associated with major depression or bipolar disorder. We believe these blood biomarkers indirectly indicate blood-brain barrier vulnerability,” Ménard explains.

The gut barrier is also weakened in people experiencing stress. Notably, the markers differ between men and women.

If women and men respond differently to stress, an antidepressant that works for one group may not be effective for the other. This underscores the importance of identifying biological signatures that could lead to personalized treatments. Stress responses may also depend on the type of stress experienced, the environment, or sociocultural norms. "The resilience markers linked to psychological distress in people living in urban Montreal may differ from those in individuals from northern communities due to the specific challenges they face, particularly those related to climate change," says Ménard.

Clues to resilience in mice

Before looking for markers of resilience in human populations, Caroline Ménard looks for them in mice. Various protocols are used to stress the mice, after which behaviours are tested and tissues collected to be scrutinized from every angle. "Several students are working on various aspects of the neurobiology of stress and resilience. One is looking at the blood, another at the brain, another at the gut... We're trying to understand stress resilience in relation to vulnerability in a holistic way," describes Caroline Ménard. Resilient mice show a number of physiological and behavioral adaptations.
In the blood-brain barrier of resilient mice, astrocytes - star-shaped cells that bridge the gap between brain and blood - have more endocannabinoid receptors. “Endocannabinoids play a role in the immune system, but also in mood regulation, so they could help promote resilience to stress,” concludes Caroline Ménard. Similarly, if after stressing mice, they are given access to a wheel for exercise, they will not all behave in the same way.

"Resilient mice are more likely to use the wheel, while depressed mice avoid it. By giving them access to physical exercise, the mice naturally increase the level of cannabinoid receptors on their astrocytes, making them more resilient", describes Caroline Ménard.

This point has already been verified, not in Northern populations, but on brains from the Douglas-Bell Canada bank. "We verified that people who died by suicide had a loss of cannabinoid receptors on astrocytes," the professor continues. The team also demonstrated that the blood-brain barrier of vulnerable mice is more permeable than that of resilient mice and that this barrier fragility is associated with disturbances in omega-3 metabolism. Therefore, a diet rich in omega-3s, inspired by the Inuit diet, could promote resilience to stress by optimizing the function of the blood-brain barrier.

A North Sentinel-funded project is exploring this avenue in young and adolescent mice, ahead of more in-depth research in Nordic populations. The team used two scenarios to subject mice to stress: separating the offspring from their mothers for a brief period to induce stress early in life, or disrupting the hierarchy of a group of adolescent mice. These mice are fed an omega-3 enriched diet, and their resilience to stress is assessed in adulthood.

“We want to see whether the omega-3s the mice received when they were young protected their blood-brain barrier, making them more resilient to future stresses,” explains Caroline Ménard.

The study is still ongoing, but as previous research has shown that certain stress markers identified in mice are also present in humans, Caroline Ménard hopes to eventually identify markers, or even a biological signature of stress resilience possibly unique to northern populations.

🔎 To learn more

Dion-Albert, L., Cadoret, A., Doney, E., Kaufmann, F.N, Dudek, K.A., Daigle, B., Parise, L.F., Cathomas, F., Samba, N., Hudson, N., Lebel, M., Signature Consortium, Campbell, M., Turecki, G., Mechawar, N., and Menard, C. (2022). Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue. Nature Communications, 13(1), article 164.
https://doi.org/10.1038/s41467-021-27604-x

Doney, E., Dion-Albert, L., Coulombe-Rozon, F., Osborne, N., Bernatchez, R., Paton, S.E.J, Kaufmann, F.N., Agomma, R.O., Solano, J.L., Gaumond, R., Dudek, K.A., Szyszkowicz, J.K., Cecile Lepage on behalf of Signature Consortium, Lebel, M., Doyen, A., Durand, A., Lavoie-Cardinal, F., Audet, M.-C., and Menard, C. (2023). Chronic Stress Exposure Alters the Gut Barrier: Sex-Specific Effects on Microbiota and Jejunum Tight Junctions. Biological Psychiatry Global Open Science, 4(1), 213-228.
https://doi.org/10.1016/j.bpsgos.2023.04.007

Dudek, K.A., Paton, S.E.J, Binder, L.B., Collignon, A., Dion-Albert, L., Cadoret, A., Lebel, M., Lavoie, O., Bouchard, J., Kaufmann, F.N., Clavet-Fournier, V., Manca, C., Guzmán, M., Campbell, M., Turecki, G., Mechawar, N., Flamand, N., Lavoie-Cardinal, F., Silvestri, C., Di Marzo, V., and Menard, C. (2025). Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood-brain barrier alterations. Nature Neuroscience, 28(4), 766-782.
https://doi.org/10.1038/s41593-025-01891-9

Paton, S.E.J., Solano, J.L., Collignon, A., Richer, E., Coulombe-Rozon, F., Dion-Albert, L., Bandeira Binder, L., Dudek, K.A., Cadoret, A., Signature Consortium, Lebel, M., and Ménard, C. Environmental enrichment and physical exercise prevent stress-induced behavioral and blood-brain barrier alterations via Fgf2. BioRXiv 
https://doi.org/10.1101/2023.11.08.566229.

Cover photo: Visualization of barrier epithelial cells in a mouse intestine (by Ellen Doney).