Chronic stress-induced depression and neurovascular health Ana Pavlovic, Endji Enfole Bampoka, Ellen Tusk, Juliette Paul, Manon Lebel, Caroline Menard Université Laval & CERVO Brain Resear
Depression will affect 20% of individuals and is considered the leading cause of disabilities worldwide. Chronic stress is depression’s main environmental risk factor and thus, both these conditions have been studied in conjunction countless times, yet, the exact nature of the relationship uniting them remained misunderstood. This could be attributable to inter-individual differences since not every individual submitted to chronic stress develops depression. We recently showed that chronic social stress can promote the establishment of depressive behaviors in mice through opening of the blood-brain barrier (BBB). These effects were also observed in postmortem human brains from depressed patients, adding translational value to our findings. Here, we aim at characterizing the astrocyte-BBB interface. We proposed that astrocytes, sealing endothelial cells and controlling the neurovascular unit, could be actively involved in stress responses and depression. Method: The main objective of this study was to identify differences in the expression of proteins linked to the integrity of the neurovascular system in brain regions known to regulate mood and development of depressive behaviors (nucleus accumbens, hippocampus, prefrontal cortex). We compare the neurovascular network of three mice groups established by subjecting animals to chronic social defeat stress and social interaction test. Stress-susceptible (SS) mice developed social avoidance while resilient mice did not, and acted like unstressed controls (CTRL). We compare several BBB- and astrocyte-related proteins such as claudin-5, CD-31, glial fibrillary acidic protein and aquaporin 4, at protein and gene levels by using immunofluorescence (IF) and quantitative PCR (qPCR), respectively. Results: IF revealed significant alterations in the expression of BBB tight junction protein cldn5 and a reduced presence of astrocytic end-feet surrounding blood vessels in the NAc of SS mice compared to CTRL and RES animals. qPCR analysis confirmed gene downregulation of astrocyte end-foot aqp4 in SS mice. These results opened a door to understanding the biological mechanisms underlying stress resilience. We hypothesized that BBB integrity is a marker of mental health wellness and promoting the neurovascular health could represent a promising avenue to treat depression which is especially relevant since 30–50% of patients with major depressive disorder are unresponsive to antidepressant medications.