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.

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Acknowledgements

The authors thank A. Keller for advice on BBB-related studies and the Center for Comparative Medicine and Surgery housing facilities staff for their work and support. This research was supported by Mental Health grants RO1 MH090264 (S.J.R.), P50 MH096890 (S.J.R.), P50 AT008661-01 (S.J.R.), RO1 MH114882 (S.J.R.), RO1 MH104559 (S.J.R. and M.M.), NIH/NHLBI P01 HL131478 (Z.A.F.), T32 MH087004 (M.L.P., M.H. and M.F.), T32 MH096678 (M.L.P.), F30 MH100835 (M.H.) and F31 MH105217 (M.L.P.), a Janssen/IMHRO Rising Star Translational Research Award (S.J.R.), a Swiss National Science Foundation Advanced Postdoc Mobility Fellowship (V.K.) and a Brain and Behavior Research Foundation NARSAD Young Investigator Award (G.E.H.). C.M. is supported by a Brain and Behavior Research Foundation NARSAD Young Investigator Grant sponsored by the P&S Fund.

Author information

Author notes

    • Caroline Menard

    Present address: Département de psychiatrie et neurosciences, Faculté de médecine and CERVO Brain Research Centre, Université Laval, Quebec City, QC, Canada

Affiliations

  1. Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Caroline Menard
    • , Madeline L. Pfau
    • , Georgia E. Hodes
    • , 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
    •  & Scott J. Russo
  2. Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Veronika Kana
    •  & Miriam Merad
  3. Department of Radiology, Translational and Molecular Imaging Institute at Mount Sinai, New York, NY, USA

    • Victoria X. Wang
    • , Zahi A. Fayad
    •  & Cheuk Ying Tang
  4. University of Tsukuba, Tsukuba, Japan

    • Aki Takahashi
  5. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Carol Tamminga
  6. Douglas Mental Health University Institute and McGill University, Montreal, QC, Canada

    • Gustavo Turecki
  7. Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland

    • Matthew Campbell

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Contributions

C.M. and S.J.R. designed the study and wrote the manuscript. C.M., M.L.P., G.E.H., A.T., M.E.F., H.A., K.B.L., Z.S.L., S.A.G. and M.H. performed stereotaxic surgeries, tissue collection and behavioral manipulations and analyzed data. V.K. performed and analyzed flow experiments and Ccr2RFP::Cx3cr1GFP mouse immunostaining. V.K. and M.M. provided Ccr2RFP::Cx3cr1GFP mice and provided advice on BBB- and immune-related studies. V.X.W., Z.A.F. and C.Y.T. designed, performed and analyzed magnetic resonance imaging scans. S.B. advised on analysis approaches and analyzed data. W.G.J. prepared and imaged transmission electron microscopy samples. B.L., E.M.P., C.T. and G.T. provided post-mortem human tissue samples. M.C. provided viral vectors and advised on viral studies. All the authors read and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Scott J. Russo.

Integrated Supplementary Information

  1. Supplementary Figure 1: Behavioral phenotype of quantitative PCR (qPCR) experiments and Cldn5 expression in other brain regions or animal model of stress

  2. Supplementary Figure 2: Behavioral phenotype of immunohistochemistry (IHC) experiments and assessment of Cldn5 endothelial cell specificity and stress-induced loss

  3. Supplementary Figure 3: Tight junction protein levels in the hippocampus (HIPP) and prefrontal cortex (PFC) following 10-d CSDS

  4. Supplementary Figure 4: Blood vessel and capillary morphology in the NAc and PFC of CTRL, SS and RES mice

  5. Supplementary Figure 5: Behavioral phenotype of SS mice treated chronically with vehicle or the antidepressant imipramine and CLDN5 expression in MDD patients and cocaine users

  6. Supplementary Figure 6: Gene expression in NAc of AAV-shRNA-Cldn5-injected mice, supplementary SI behaviors and anxiety test results

  7. Supplementary Figure 7: Experimental timeline for virally mediated HIPP injections and rescue experiment, virus validation and behaviors

  8. Supplementary Figure 8: Gd-DTPA and cadaverine Alexa Fluor-555 experiments

  9. Supplementary Figure 9: Supplementary behavioral data for Evans blue (EB) extravasation and Ccr2 RFP::Cx3cr1 GFP mice after CSDS

  10. Supplementary Figure 10: Behavioral data for IL-6 ELISA, IL-6–biotin passage into the parenchyma and NAc IL-6 versus saline infusion

  11. Supplementary Figure 11: Social stress induces neurovascular pathology and BBB leakiness promoting depression-like behaviors

  12. Supplementary Figure 12: Full-length blots of cropped blots in Supplementary Fig. 7

Supplementary material