Social stress induces neurovascular pathology promoting depression.

TitleSocial stress induces neurovascular pathology promoting depression.
Publication TypeJournal Article
Year of Publication2017
AuthorsMénard 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
JournalNat Neurosci
Volume20
Issue12
Pagination1752-1760
Date Published2017 Dec
ISSN1546-1726
KeywordsAdrenergic 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.

DOI10.1038/s41593-017-0010-3
Alternate JournalNat. Neurosci.
PubMed ID29184215
PubMed Central IDPMC5726568
Grant ListR01 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