Abstract
Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.
Highlights
Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences
Transcriptional profiling of genes associated with vascular integrity, permeability, angiogenesis, tight junctions, and blood-brain barrier (BBB) formation was performed in the nucleus accumbens (NAc) of unstressed control (CTRL), SS and RES mice after 10-day chronic social defeat stress (CSDS) (Fig. 1c; quantitative PCR primers are listed in Supplementary Table 1)
The NAc plays crucial roles in reward processing, stress responses and mood disorders, including MDD20, and we reported in a previous study[7] that the vasculature of this brain region is altered in SS males
Summary
Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. The NAc plays crucial roles in reward processing, stress responses and mood disorders, including MDD20, and we reported in a previous study[7] that the vasculature of this brain region is altered in SS males In contrast to their male counterparts, we did not observe significant changes for BBB-related gene expression in the NAc of females (Fig. 1c and Supplementary Fig. 1c), including for the tight junction Claudin-5 (Cldn5) (Fig. 1d), a gatekeeper of BBB permeability associated with depression-like behaviours in male mice[7]. Stress susceptibility was again associated with a loss of Cldn[5] in mood-related brain regions, including the PFC (Supplementary Fig. 2c, p = 0.0122), with no difference for RES females when compared to unstressed CTRL, confirming that vulnerability to chronic social stress is linked to alterations in the female brain vasculature. Together these findings suggest that chronic stress induces region-specific BBB alterations that may be involved in sex differences in MDD symptomatology
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