Depression will affect 1 out of 5 individuals in their lifetime. Antidepressant treatments are not effective for 30-50% patients, only 30% completely remit and do not suffer from another depressive episode, suggesting that current therapies do not address important biological mechanisms involved such as neurovascular dysfunction or inflammation, which are receiving increasing attention in psychiatry. Depression is more prevalent and recurrent in patients affected by cardiovascular diseases and stroke and, conversely, depressed individuals are more at risk to develop these pathologies, suggesting a relationship between vascular dysfunction and this mood disorder.
We showed that chronic social stress induces blood-brain barrier (BBB) leakage in male mice, promoting depressive behaviors. The BBB is the ultimate frontier between the brain and harmful toxins or inflammatory signals circulating in the blood. The endocannabinoid system can regulate BBB permeability and has been associated with stress responses. It is composed of endocannabinoids, which are endogenous lipid-based neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system and peripheral organs. The endocannabinoid system is involved in the pharmacological effects of cannabis but also several biological processes including pain, immune response and changes in the intestinal microbiota. The gut microbiota is disrupted in depressed patients leading to increased inflammation and gut barrier hyperpermeability. Thus, loss of the BBB permeability induced by chronic stress could come from changes in the microbiome endocannabinoid environment leading to release of inflammatory signals in the circulation, subsequent vascular dysfunction and establishment of depressive behaviors.
We propose here to evaluate if the endocannabinoid system could represent a promising target to promote neurovascular health and stress resilience by using a multidisciplinary and translational approach combining experiments performed in mice to validation in human samples including from women and Northern populations.