Social stress induces neurovascular pathology promoting depression

Caroline Menard, Madeline L. Pfau, Georgia E. Hodes, Veronika Kana, Victoria X. Wang, Sylvain Bouchard, Aki Takahashi, Meghan E. Flanigan, Hossein Aleyasin, Katherine B. Leclair, William G. Janssen, Benoit Labonté, Eric M. Parise, Zachary S. Lorsch, Sam A. Golden, Mitra Heshmati, Carol Tamminga, Gustavo Turecki, Matthew Campbell, Zahi A. Fayad & 3 others Cheuk Ying Tang, Miriam Merad, Scott J. Russo

Research output: Contribution to journalArticle

101 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1752-1760
Number of pages9
JournalNature Neuroscience
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2017

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Claudin-5
Blood-Brain Barrier
Depression
Pathology
Nucleus Accumbens
Tight Junction Proteins
Interleukin-6
Dependovirus
Intercellular Junctions
Major Depressive Disorder
Small Interfering RNA
Antidepressive Agents
Blood Vessels
Permeability
Down-Regulation
Endothelial Cells
Cytokines
Inflammation
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Menard, C., Pfau, M. L., Hodes, G. E., Kana, V., Wang, V. X., Bouchard, S., ... Russo, S. J. (2017). Social stress induces neurovascular pathology promoting depression. Nature Neuroscience, 20(12), 1752-1760. https://doi.org/10.1038/s41593-017-0010-3

Social stress induces neurovascular pathology promoting depression. / Menard, Caroline; Pfau, Madeline L.; Hodes, Georgia E.; Kana, Veronika; Wang, Victoria X.; Bouchard, Sylvain; Takahashi, Aki; Flanigan, Meghan E.; Aleyasin, Hossein; Leclair, Katherine B.; Janssen, William G.; Labonté, Benoit; Parise, Eric M.; Lorsch, Zachary S.; Golden, Sam A.; Heshmati, Mitra; Tamminga, Carol; Turecki, Gustavo; Campbell, Matthew; Fayad, Zahi A.; Tang, Cheuk Ying; Merad, Miriam; Russo, Scott J.

In: Nature Neuroscience, Vol. 20, No. 12, 01.12.2017, p. 1752-1760.

Research output: Contribution to journalArticle

Menard, C, Pfau, ML, Hodes, GE, Kana, V, Wang, VX, Bouchard, S, Takahashi, A, Flanigan, ME, Aleyasin, H, Leclair, KB, Janssen, WG, Labonté, B, Parise, EM, Lorsch, ZS, Golden, SA, Heshmati, M, Tamminga, C, Turecki, G, Campbell, M, Fayad, ZA, Tang, CY, Merad, M & Russo, SJ 2017, 'Social stress induces neurovascular pathology promoting depression', Nature Neuroscience, vol. 20, no. 12, pp. 1752-1760. https://doi.org/10.1038/s41593-017-0010-3
Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S et al. Social stress induces neurovascular pathology promoting depression. Nature Neuroscience. 2017 Dec 1;20(12):1752-1760. https://doi.org/10.1038/s41593-017-0010-3
Menard, Caroline ; Pfau, Madeline L. ; Hodes, Georgia E. ; Kana, Veronika ; Wang, Victoria X. ; Bouchard, Sylvain ; Takahashi, Aki ; Flanigan, Meghan E. ; Aleyasin, Hossein ; Leclair, Katherine B. ; Janssen, William G. ; Labonté, Benoit ; Parise, Eric M. ; Lorsch, Zachary S. ; Golden, Sam A. ; Heshmati, Mitra ; Tamminga, Carol ; Turecki, Gustavo ; Campbell, Matthew ; Fayad, Zahi A. ; Tang, Cheuk Ying ; Merad, Miriam ; Russo, Scott J. / Social stress induces neurovascular pathology promoting depression. In: Nature Neuroscience. 2017 ; Vol. 20, No. 12. pp. 1752-1760.
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