Editors' ChoiceDepression

Brain leak, mind bleak

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Science Translational Medicine  06 Dec 2017:
Vol. 9, Issue 419, eaar4429
DOI: 10.1126/scitranslmed.aar4429

Abstract

Stress-induced changes in blood-brain barrier permeability contribute to depression pathology.

Peripheral immune system activation has been implicated in the pathophysiology of major depressive disorder; however, the mechanisms by which circulating immune mediators interact with the central nervous system remain to be clarified. Menard et al. used a rodent model of depression to begin to uncover such mechanisms, focusing on the effects of stress on blood-brain barrier (BBB) permeability.

Transcriptomic analysis in Nucleus Accumbens (NAc), a brain region linked to depression behavior, showed that stress-induced depression resulted in decreased levels of Claudin 5 (Cld5), a tight junction protein implicated in BBB permeability in mice. Importantly, the authors also showed that Cld5 expression was reduced in the NAc of human subjects with major depressive disorder.

Chronic antidepressant treatment reversed the depression-related behavior in mice and increased Cld5 levels in their NAc. To establish a causal role of Cld5 suppression in mediating depression behavior, the authors then infected mice with a short hairpin RNA (shRNA)-Cld5 viral vector to silence the gene. Viral-induced suppression of Cld5 in NAc increased stress-induced depression susceptibility. Using a peripheral dye with low BBB permeability, the authors showed that Cld5-depleted mice also exhibited increased BBB permeability. Thus, this manipulation mirrored the phenotype observed in stress-induced depression in mice.

Last, the authors showed that higher levels of interleukin-6 (IL-6) were observed in the Nucleus Accumbens in mice with depressive phenotype. Tagged IL-6 injected peripherally also showed increased accumulation in NAc, confirming that stress-induced brain inflammation was at least partially mediated by alteration of BBB permeability.

Stress-induced changes in BBB permeability failed to explain the emergence of anxiety-related behaviors in the animal model. Nevertheless, these findings establish a new mechanism linking neurovascular alteration to depression that might help to explain the relationship between peripheral immune activation and stress-related disorders.

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