Immune Mechanisms of Depression

抄録

Multiple clinical studies suggest that heightened peripheral inflammation contributes to major depression disorder (MDD) pathogenesis. Co-morbidity of inflammatory diseases is highly prevalent in MDD patients, and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating inflammatory molecules are released following chronic stress, where they penetrate the brain to 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. Here we evaluated the effect of CSDS on endothelial tight junction expression and astrocyte complexity in the nucleus accumbens (NAc), a brain region integrally involved in depression symptomatology. We found that after 10 days of CSDS, Cldn5 mRNA and protein expression is reduced in the NAc of stress-susceptible mice, that exhibit depression-related behavioral phenotypes, when compared to resilient mice and unstressed controls. We also found a similar decrease of Cldn5 mRNA in the NAc of depressed patients. Interestingly, in mice, chronic treatment with the antidepressant imipramine promotes resilience and rescues Cldn5 expression in the NAc. Moreover, chronic down-regulation of Cldn5 expression with an adeno associated virus including a short hairpin RNA specific to Cldn5 was sufficient to induce social avoidance and depression-like behaviors as assessed with sucrose preference and forced swim tests. Magnetic resonance imaging scans revealed higher penetration of a gadolinium-based contrasting agent in stress-related brain regions of defeated animals suggesting reduced BBB integrity. In addition, we find a concomitant decrease in expression of astrocytic proteins as well as the complexity of astrocytes themselves. We are currently testing the functional relevance of this loss of astrocyte complexity as well as their role in producing stress-related neuroinflammation. Our studies highlight a functional role for the BBB in development of depression-like behaviors related to MDD. 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.