Social stress induces neurovascular pathology promoting depression.
Title | Social stress induces neurovascular pathology promoting depression. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Ménard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, Takahashi A, Flanigan ME, Aleyasin H, LeClair KB, Janssen WG, Labonte B, Parise EM, Lorsch ZS, Golden SA, Heshmati M, Tamminga C, Turecki G, Campbell M, Fayad ZA, Tang CYing, Merad M, Russo SJ |
Journal | Nat Neurosci |
Volume | 20 |
Issue | 12 |
Pagination | 1752-1760 |
Date Published | 2017 Dec |
ISSN | 1546-1726 |
Keywords | Adrenergic Uptake Inhibitors, Animals, Anxiety, Behavior, Animal, Blood-Brain Barrier, Claudin-5, Depression, Feeding Behavior, Food Preferences, Imipramine, Interleukin-6, Male, Mice, Mice, Inbred C57BL, Nucleus Accumbens, Social Environment, Stress, Psychological, Swimming, Tight Junction Proteins |
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. |
DOI | 10.1038/s41593-017-0010-3 |
Alternate Journal | Nat. Neurosci. |
PubMed ID | 29184215 |
PubMed Central ID | PMC5726568 |
Grant List | R01 MH104559 / MH / NIMH NIH HHS / United States F31 MH111108 / MH / NIMH NIH HHS / United States T32 MH087004 / MH / NIMH NIH HHS / United States R01 MH114882 / MH / NIMH NIH HHS / United States R01 MH090264 / MH / NIMH NIH HHS / United States P50 AT008661 / AT / NCCIH NIH HHS / United States T32 MH096678 / MH / NIMH NIH HHS / United States |