When faced with chronic stress, why do some people develop anxiety and depressive symptoms while others show resilience? A protein that acts as a cannabinoid receptor and is present in the structure controlling exchanges between the bloodstream and the brain could be part of the answer, according to a study published today in Nature Neuroscience.

The protein, called cannabinoid receptor type 1 (CB1), is part of the blood-brain barrier, the dynamic structure that protects the brain by regulating the passage of molecules between the bloodstream and the brain. In the context of chronic social stress, the integrity of this barrier is altered, inflammatory molecules make their way into the brain, and anxiety and depressive symptoms appear.”

Caroline Ménard, study leader, professor at Université Laval’s Faculty of Medicine and researcher at the CERVO Brain Research Centre

CB1 receptors are abundant in neurons, but they’re also found in astrocytes, star-shaped cells allowing communication between the brain’s blood vessels and neurons. “Astrocytes are an essential component of the barrier, explains Prof. Ménard. We noticed that mice resilient to stress had more CB1 receptors in the barrier than mice with depressive-like behavior or mice not exposed to stress. That gave us the idea to investigate the role of astrocytic CB1 receptors in the response to chronic stress.”

The research team first induced an increase in CB1 receptor abundance in mouse astrocytes by developing a viral vector that contained the genetic material coding for the CB1 receptor as well as a mechanism that limited its expression only to astrocytes. When injected, this virus increased the levels of CB1 receptors in the mice’s astrocytes but not in their neurons.

These mice were then subjected to chronic social stress. “Each day, for five minutes, they were brought into direct contact with a dominant male. The rest of the time, a transparent divider was placed in the cage. The mice could see their bully without any physical interaction so it was essentially a psychosocial stress,” says Ménard.

Three weeks after the injections, the level of CB1 receptors had more than doubled in the astrocytes of mice in the experimental group. “In these mice, baseline anxiety levels-those observed in the absence of stress-were reduced, as were symptoms of anxiety and depression-like behaviors induced by social stress. Overexpression of CB1 receptors leads to resilience by promoting vascular health in the brain”, summarizes the researcher.

Other experiments carried out by her team showed that mice that had access to an exercise wheel or those given antidepressants also had higher levels of CB1 receptors in their astrocytes.

In addition, examination of human brains from the Douglas-Bell Canada Brain Bank in Montreal confirmed the association between CB1 receptors and depressive symptoms. “We found that the level of CB1 receptors in astrocytes was lower in people with major depression at the time of death than in people without depression or those treated with antidepressants,” says Caroline Ménard.

These results suggest the possibility of using molecules capable of activating CB1 receptors in astrocytes to reduce anxiety and depressive symptoms, and to increase resilience in the face of stress, the researcher suggests. “The challenge, however, is to limit their effects to astrocytes, because strong and prolonged activation of the same receptors in neurons can have side effects, notably on alertness, anxiety and appetite. Until we find a molecule that acts specifically on CB1 receptors in astrocytes, we can mitigate the negative repercussions of stress by taking advantage of the protective effect of physical activity”.

In addition to Caroline Ménard, the study’s coauthors associated with Université Laval are Katarzyna Dudek, Sam Paton, Luisa Bandeira Binder, Adeline Collignon, Laurence Dion-Albert, Alice Cadoret, Manon Lebel, Olivier Lavoie, Jonathan Bouchard, Fernanda Neutzling Kaufmann, Valérie Clavet-Fournier, Claudia Manca, Nicolas Flamand, Flavie Lavoie-Cardinal, Cristoforo Silvestri, and Vicenzo Di Marzo. The study is also coauthored by researchers from McGill University, the University of Madrid and Trinity College Dublin.