Social stress induces neurovascular pathology promoting depression

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 f...

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Veröffentlicht in:	Nature neuroscience Jg. 20; H. 12; S. 1752 - 1760
Hauptverfasser:	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.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.12.2017 Nature Publishing Group
Schlagworte:	631/250/127 631/250/256 631/378/1341 631/378/1831 692/699/476/1414 Adrenergic Uptake Inhibitors - pharmacology Animal Genetics and Genomics Animals Antidepressants Anxiety - psychology Behavior, Animal Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Blood vessels Blood-brain barrier Blood-Brain Barrier - pathology Brain Cardiovascular diseases Claudin-5 - biosynthesis Claudin-5 - genetics Complications and side effects Cytokines Cytology Depression (Mood disorder) Depression - pathology Depression - psychology Endothelial cells Endothelium Feeding Behavior Food Preferences Imipramine - pharmacology Infiltration Inflammation Integrity Interleukin 6 Interleukin-6 - biosynthesis Interleukins Major depressive disorder Male Medical research Medical schools Membrane permeability Mental depression Mice Mice, Inbred C57BL Neurobiology Neurosciences Nucleus accumbens Nucleus Accumbens - pathology Parenchyma Pathogenesis Patient outcomes Permeability Risk factors Rodents Social Environment Social interactions Stress Stress, Psychological - pathology Stress, Psychological - psychology Stresses Swimming - psychology Tight Junction Proteins - metabolism Viruses
ISSN:	1097-6256, 1546-1726, 1546-1726
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Zusammenfassung:	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. Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Present address: Département de psychiatrie et neurosciences, Faculté de médecine and CERVO Brain Research Center, Université Laval, Quebec City, Canada
ISSN:	1097-6256 1546-1726 1546-1726
DOI:	10.1038/s41593-017-0010-3