Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

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Multiple clinical studies suggest that heightened peripheral inflammation contributes to major depressive disorder (MDD) pathogenesis. Co-morbidity of inflammatory disease with MDD is highly prevalent, and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating inflammatory molecules are released following chronic stress, penetrate the blood brain barrier (BBB), and affect neural circuits, mediating stress vulnerability and depression. However, despite years of intensive research into the role of cytokines in depression, we have very little direct evidence of how cytokines enter the brain and in which circuits they act. Recently, we have begun to investigate the effect of chronic social defeat stress (CSDS), a mouse model of stress that induces depression-like behavior, on BBB permeability. Endothelial cells and astrocytes play critical roles in maintaining vascular impermeability. Endothelial cells, via expression of tight junction proteins, establish the paracellular barrier between the perivascular space and brain parenchyma. Breakdown of the endothelial barrier can lead to infiltration of peripheral immune signals— such as IL-6—that we have shown previously to increase stress susceptibility. Our new data shows that 10 days of CSDS downregulates expression of the tight junction protein Cldn5 in the NAc of stress-susceptible mice leading to loss of integrity of the endothelial barrier, immune infiltration and expression of depression-like behaviors. Expanding upon these preliminary observations, we will probe the detailed molecular and cellular mechanisms by which peripheral immune signals interface with mood-related brain circuitry to control depression-like behaviors following social stress. By understanding how chronic stress affects the BBB we may be able to augment current antidepressant treatment or design new therapeutic strategies promoting vascular health by preventing BBB degeneration.