Social Stress Induces Neurovascular Pathology Promoting Depression

Nat Neurosci. 2017 Dec;20(12):1752-1760. doi: 10.1038/s41593-017-0010-3. Epub 2017 Nov 13.

Abstract

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Anxiety / psychology
  • Behavior, Animal
  • Blood-Brain Barrier / pathology
  • Claudin-5 / biosynthesis
  • Claudin-5 / genetics
  • Depression / pathology*
  • Depression / psychology*
  • Feeding Behavior
  • Food Preferences
  • Imipramine / pharmacology
  • Interleukin-6 / biosynthesis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens / pathology
  • Social Environment*
  • Stress, Psychological / pathology*
  • Stress, Psychological / psychology*
  • Swimming / psychology
  • Tight Junction Proteins / metabolism

Substances

  • Adrenergic Uptake Inhibitors
  • Claudin-5
  • Cldn5 protein, mouse
  • Interleukin-6
  • Tight Junction Proteins
  • interleukin-6, mouse
  • Imipramine