Grant: Project Grant

Depression is the leading cause of disabilities worldwide and will affect 1 out of 5 individuals in their lifetime. Antidepressant treatments are not effective for 30-50% of patients, only 30% completely remit and do not suffer from another depressive episode, suggesting that current therapies do not address important biological mechanisms involved. 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, indicating that vascular dysfunction may contribute to the development of depression. We showed that chronic social stress induces blood-brain barrier (BBB) leakage in male mice, promoting depressive behaviors. Chronic stress is depression's main risk factor and the BBB is an active barrier preventing harmful circulating signals to penetrate the healthy brain. Here we propose to investigate if stress-induced loss of BBB integrity is occurring in a sex- and region-specific manner. We hypothesize that BBB integrity may be affected in different brain regions in females explaining sex-specific symptoms. We will also define critical time points and evaluate if vulnerability to depression can be predicted by testing BBB integrity before stress exposure. Effects of chronic stress on BBB-astrocyte interface will be characterized as well. Astrocytes are part of the neurovascular unit and maintain BBB integrity in the healthy brain. Finally, we will test prevention strategies to promote neurovascular health and stress resilience. The strength of our approach is a reverse translational strategy that consists in studying stress responses in mice to unravel novel biological mechanisms underlying depression in humans. Depression is more prevalent in women and correlated with reported stress levels in daily life. It is imperative to explore stress-induced vascular maladaptive responses to develop innovative therapeutic strategies.