A recent study has identified the cannabinoid receptor type 1 (CB1) as critical in promoting resilience to chronic stress, offering hope for new mental health treatments.
In a groundbreaking study published in Nature Neuroscience, researchers have identified a protein that could be the key to understanding why some people are more resilient to chronic stress than others. This protein, known as cannabinoid receptor type 1 (CB1), plays a crucial role in the blood-brain barrier, the structure that regulates the passage of molecules between the bloodstream and the brain.
“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,” study leader Caroline Ménard, a professor at Université Laval’s Faculty of Medicine and researcher at the CERVO Brain Research Centre, said in a news release. “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.”
CB1 receptors are found in abundance in neurons, but more intriguingly, they are also present in astrocytes. These star-shaped cells facilitate communication between the brain’s blood vessels and neurons.
“Astrocytes are an essential component of the barrier,” Ménard added. “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 study’s research team engineered a viral vector carrying genetic material that coded for the CB1 receptor, ensuring its expression was limited to astrocytes. After injecting this virus into mice, the levels of CB1 receptors in the astrocytes more than doubled, but there was no increase in neurons.
Subsequently, these genetically modified mice were exposed 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,” added Ménard.
Three weeks post-injection, the experimental mice exhibited reduced baseline anxiety levels and diminished 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,” summarized the researchers.
Additional experiments demonstrated that mice with access to exercise wheels or those treated with antidepressants also exhibited elevated CB1 receptor levels in their astrocytes.
The study extended its findings to humans by analyzing brains from the Douglas-Bell Canada Brain Bank. The analysis confirmed a clear 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,” Ménard added.
This discovery hints that molecules capable of activating CB1 receptors in astrocytes could potentially reduce anxiety and depressive symptoms, thereby increasing resilience to stress.
“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,” Ménard added.
The study’s co-authors from Université Laval include Katarzyna Dudek, Sam Paton, Luisa Bandeira Binder, and others. Researchers from McGill University, the University of Madrid, and Trinity College Dublin also contributed to this pioneering research.
This breakthrough not only advances our understanding of stress resilience but also opens new avenues for treating mood disorders, potentially transforming mental health care in the future.