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.

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This study evaluated an inference-based approach (IBA) to the treatment of obsessive-compulsive disorder (OCD) by comparing its efficacy with a treatment based on the cognitive appraisal model (CAM) and exposure and response prevention (ERP). IBA considers initial intrusions in OCD (e.g. "Maybe the door is open", "My hands could be dirty") as idiosyncratic inferences about possible states of affairs arrived at through inductive reasoning. In IBA such primary inferences represent the starting point of obsessional doubt, and the reasoning maintaining the doubt forms the focus for therapy. This is unlike CAM, which regards appraisals of intrusions as the maintaining factors in OCD. Fifty-four OCD participants, of whom 44 completed, were randomly allocated to CAM, ERP or IBA. After 20 weeks of treatment all groups showed a significant reduction in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Padua Inventory. Participants with high levels of obsessional conviction showed greater benefit from IBA than CAM. Appraisals of intrusions changed in all treatment conditions. Strength of primary inference was not correlated with symptom measures except in the case of strong obsessional conviction. Strength of primary inference correlated significantly with the Y-BOCS insight item. Treatment matching for high and low conviction levels to IBA and CAM, respectively, may optimize therapy outcome.

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Both treatments resulted in reduced anxiety, avoidance, general psychopathology and better social functioning that maintained over follow-up. Continuing improvement in remission rates was noted; fully 60% of the patients no longer fulfilled criteria for social phobia at the end of 1-year follow-up.