Fig. 6: Chronic stress induces BBB leakiness in the female PFC and release of vascular biomarkers in the blood of mice also observed in individuals with MDD.

a Experimental timeline of 10-d chronic social defeat stress (CSDS), social interaction (SI) test and retro-orbital injection of fluorescent-labelled dextran (10 kDa). Following behavioural phenotyping (SI ratio, *p = 0.0273), assessment of blood-brain barrier (BBB) permeability with dextran Alexa Fluor-488 dye revealed significant BBB leakiness in the prefrontal cortex (PFC) of stress-susceptible (SS) female mice (fluorescence, *p = 0.0144; frequency, ***p = 0.0005). Scale bars, 20 μm (b). c, d Experimental timeline of CSDS and subchronic variable stress (SCVS) paradigms and blood collection for multiplex assays. e, f Cardiovascular multiplex assays reveals significant upregulation of circulating soluble E-selectin (sE-selectin) when compared to baseline (pre-CSDS) serum levels (*p = 0.0267 for SOCIAL STRESS) in SS, but not RES mice (*p = 0.0131), and post-CSDS levels correlated with social avoidance (f). g, h Circulating sE-selectin levels were increased in female mice following 6-d SCVS without reaching significance and remained unchanged in male mice following 10-d CSDS, and no correlation was found with SI ratio. i, Baseline serum levels of sE-selectin was ~40% lower in female vs male mice (****p < 0.0001). j, k Circulating sE-selectin levels were significantly upregulated in women (*p = 0.0494) but not men with major depressive disorder (MDD), and levels in healthy controls were ~25% lower in women when compared to men (*p = 0.0499) (k). Data represent mean ± s.e.m; the number of animals or subjects (n) is indicated on graphs. Correlations were evaluated with Pearson’s correlation coefficient; 2-group comparisons were evaluated with unpaired t-tests and one-way ANOVA followed by Bonferroni’s multiple comparison test for other graphs. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Source data are provided as a Source Data file.