When faced with chronic stress, some people develop anxiety and depressive symptoms, while others show great resilience. How can such differences be explained? It could be attributable, at least in part, to a protein that acts as a cannabinoid receptor and is present in the structure that controls exchanges between the bloodstream and the brain, suggests a study just published in Nature Neuroscience.
The protein in question, cannabinoid receptor type 1 (CB1), is part of the blood-brain barrier, the dynamic structure that protects the brain by controlling the passage of molecules between the bloodstream and the brain," explains study leader Caroline Ménard , a professor at Université Laval’s Faculty of Medicine and researcher at the CERVO research center. In situations of chronic social stress, we observe that the tightness of this barrier is affected, that inflammatory molecules make their way to the brain, and that anxiety and depressive symptoms appear."
CB1 receptors are abundant in neurons, but are also present in astrocytes, the star-shaped cells that bridge the gap between the brain’s blood vessels and neurons. Astrocytes are one of the essential components of the barrier," explains Prof. Ménard. We noticed that mice resilient to stress had more CB1 receptors at the barrier than mice with depressive behavior or mice not exposed to stress. This convinced us to investigate the role of astrocyte CB1 receptors in the chronic stress response."
To achieve this, the research team first induced an increase in CB1 receptor abundance in mouse astrocytes using a viral vector. We use a virus into which we have inserted the genetic material coding for the CB1 receptor, as well as a primer which limits its expression in astrocytes," explains the researcher. When this virus is injected into mice, they produce more CB1 receptors in their astrocytes."
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’s essentially psychosocial stress," says Prof. Ménard.
Three weeks after injection of the viruses, 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 - had decreased, as had symptoms of anxiety and depression induced by social stress. Overexpression of CB1 receptors leads to resilience by promoting vascular health in the brain", summarizes the researcher.
Beneficial effect of exercise
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 brain bank of Montreal’s Douglas Mental Health University Institute 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 argues. "The challenge, however, is to limit their effects to astrocytes, because strong and prolonged activation of the same receptors on neurons can have undesirable repercussions, notably on alertness, anxiety and appetite. Until we find a molecule that acts specifically on CB1 receptors in astrocytes, it is possible to mitigate the negative repercussions of stress by taking advantage of the protective effect of physical activity."
"Until we find a molecule that acts specifically on CB1 receptors in astrocytes, it is possible to mitigate the negative repercussions of stress by taking advantage of the protective effect of physical activity."
-- Caroline Ménard In addition to Caroline Ménard, the signatories of the Nature Neuroscience study (hyperlink coming soon) associated with Université Laval areUniversité 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. Other signatories are from McGill University, the University of Madrid and Trinity College Dublin.
