Exercise and a good environment strengthen the integrity of the brain's protective barrier against stress

A research team at Université Laval may have discovered why physical exercise and living in favorable socioeconomic conditions reduce the risk of depression. In lab animals exposed to chronic social stress—one of the main causes of depression—, physical activity and an enriched environment helped maintain the integrity of the blood-brain barrier in areas of the brain associated with mood and emotion regulation.

The research, which has just been published in the journal Nature Communications, has highlighted the key role played by a brain protein, Fgf2, in this protective mechanism and its potential as a biomarker for mood disorders.

Social stress weakens the brain's barrier

"The blood-brain barrier has lines of defense formed by several types of cells that are not glued together. The protein claudin-5 closes the gaps between the cells in the first line of defense. Without it, the barrier loses its integrity," explains study leader Caroline Ménard, professor at Université Laval's Faculty of Medicine and researcher at the CERVO Brain Research Centre.

Previous work by Ménard’s team had shown that, in mice, chronic stress leads to a loss of claudin-5, which promotes the entry of pro-inflammatory molecules into regions of the brain associated with mood and, subsequently, the onset of anxiety and depressive symptoms. The team confirmed that this loss of claudin-5 also occurred in the brains of depressed men and women.

The benefits of exercise and an enriched environment

“We wanted to see if physical activity or environmental quality could prevent the harmful effects of stress on the blood-brain barrier,” explains Professor Ménard. To do this, her team induced chronic social stress in mice by exposing them to a dominant male. These mice were divided into three groups. The first group enjoyed an enriched environment with shelter, toys, and nesting materials. The second group had access to an exercise wheel that they could use at will. The third group served as a control.

“We observed a 50% reduction in claudin-5 in stressed mice in the control group, whereas mice that benefited from an enriched environment or exercise wheel lost little or no claudin-5. Anxious and depressive behaviors were also significantly reduced,” summarizes Ménard.

A key protein in resilience

The research team found that these changes were linked to increased levels of the Fgf2 protein in the mice's brains. To determine whether there was a causal link, the scientists used viral vectors to increase or decrease Fgf2 production.

"Following exposure to chronic social stress, mice that produced more Fgf2 protein did not isolate themselves, suggesting that they are more resilient and less anxious. Conversely, mice in which we had lowered Fgf2 levels were more prone to stress, avoided social interactions, and experienced fewer benefits from exercise," the researcher reports.

A promising biomarker for depression

Fgf2 proteins are released into the brain, but because the barrier is weakened, they end up in the bloodstream and can be detected. Caroline Ménard and her team therefore tested the potential of the Fgf2 protein as a biomarker for depression, since there are currently no biomarkers available to facilitate diagnosis or treatment choice.

To do this, the scientists used about 100 blood samples from the Signature Biobank at the Institut universitaire en santé mentale de Montréal. The team measured the presence of Fgf2 protein in the blood of people with and without depression. They observed that Fgf2 levels increase with the severity of depression and appear to be influenced by environmental factors such as employment or educational attainment. The researcher would now like to test whether the protein could serve as a marker of response to treatment or for other mental disorders such as schizophrenia.

The authors of the study published in Nature Communications are Sam Paton, José Solano, Alice Cadoret, Adeline Collignon, Luisa Bandeira-Binder, Béatrice Daigle, Laura Menegatti Bevilacqua, Émanuelle Richer, François Coulombe-Rozon, Laurence Dion-Albert, Katarzyna Dudek, Manon Lebel, and Caroline Ménard.