Why do some people develop anxiety and depressive symptoms during chronic stress , while others are resilient? A protein that acts as a cannabinoid receptor and is present in the structure that controls the exchange between the bloodstream and the brain could be part of the answer, according to a study published in Nature Neuroscience.
Stress Resistance is Linked to CB1 Receptors
“The protein called cannabinoid receptor type 1 (CB1) is part of the blood-brain barrier, a dynamic structure that protects the brain by regulating the passage of molecules between the bloodstream and the brain,” explains study leader Caroline Ménard, professor at Université Laval’s Faculty of Medicine and researcher at the CERVO Brain Research Center. In chronic social stress, the integrity of this barrier is disrupted, inflammatory molecules enter the brain, and anxiety and depressive symptoms occur.”
CB1 receptors are found in large numbers in neurons, but also in astrocytes, star-shaped cells that enable communication between the blood vessels and the neurons of the brain. Astrocytes are an essential component of the barrier. The researchers found that mice that are stress-resistant have more CB1 receptors in the barrier than mice with depression-like behavior or mice that were not exposed to stress. This gave them the idea to investigate the role of astrocytic CB1 receptors in the response to chronic stress.
New Ways to Reduce Anxiety and Depressive Symptoms
The research team first induced an increase in CB1 receptor abundance in the astrocytes of mice by developing a viral vector that contained the genetic material encoding the CB1 receptor and a mechanism that restricted its expression to astrocytes only. After injection, this virus increased CB1 receptor density in the astrocytes of the mice, but not in their neurons. These mice were then exposed to chronic social stress. Each day, they were brought into direct contact with a dominant male for five minutes. The rest of the time there was a transparent partition in the cage. The mice could see their tormentor without any physical interaction, so it was essentially psychosocial stress.
Three weeks after the injections, the number of CB1 receptors in the astrocytes of the mice in the experimental group had more than doubled. “In these mice, baseline anxiety – which was observed in the absence of stress – was reduced, as were the anxiety symptoms and depression-like behaviors triggered by social stress. Overexpression of CB1 receptors leads to resilience by promoting vascular health in the brain,” summarizes the researcher. Other experiments by the team showed that mice that had access to a running wheel or received antidepressants also had higher CB1 receptor levels in their astrocytes. In addition, the study of human brains at the Douglas-Bell Canada Brain Bank in Montreal confirmed the link between CB1 receptors and depressive symptoms.
The researchers 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 in people being treated with antidepressants. These results suggest that molecules capable of activating CB1 receptors in astrocytes could be used to reduce anxiety and depressive symptoms and increase resilience to stress. However, the challenge, according to Ménard, is to limit their effect to astrocytes, as strong and sustained activation of the same receptors in neurons can have side effects, particularly in terms of alertness, anxiety and appetite. Until they find a molecule that acts specifically on CB1 receptors in astrocytes, the researchers can mitigate the negative effects of stress by harnessing the protective effects of physical activity.
Can Stress be Predicted?
Although stress resilience is a much-discussed concept, it is still very difficult to predict the individual response of people to increased stress levels. Laboratory experiments can only be used to a limited extent to reproduce the chronic stress that many people experience in their everyday lives, as the stress simulated in the laboratory is always limited in terms of exposure time and intensity. In a study, however, scientists at the University of Zurich have determined an objective neurobiological measure that can predict a person’s stress response. Before starting their internship, test subjects were given a task in which they had to process contradictory information.
This conflict task activates the locus coeruleus-norepinephrine (LC-NE) system, a brain region associated with regulating our stress response and conflict resolution. However, the intensity of LC-NE activation – often referred to as “firing rate” – varies from person to person. For example, subjects with higher LC-NE responsiveness showed more symptoms of anxiety and depression after their emergency room internship. The more responsive the LC-NE system is, the more likely a person is to develop symptoms of anxiety and depression when exposed to prolonged stress. This is the first evidence that differences in LC-NE responsiveness can be used as an indicator of stress resilience in humans.