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.

Regulation of emotions is generally associated exclusively with the brain. However, there is evidence that peripheral systems are also involved in mood, stress vulnerability vs. resilience, and emotion‐related memory encoding. Prevalence of stress and mood disorders such as major depression, bipolar disorder, and post‐traumatic stress disorder is increasing in our modern societies. Unfortunately, 30%–50% of individuals respond poorly to currently available treatments highlighting the need to further investigate emotion‐related biology to gain mechanistic insights that could lead to innovative therapies. Here, we provide an overview of inflammation‐related mechanisms involved in mood regulation and stress responses discovered using animal models. If clinical studies are available, we discuss translational value of these findings including limitations. Neuroimmune mechanisms of depression and maladaptive stress responses have been receiving increasing attention, and thus, the first part is centered on inflammation and dysregulation of brain and circulating cytokines in stress and mood disorders. Next, recent studies supporting a role for inflammation‐driven leakiness of the blood–brain and gut barriers in emotion regulation and mood are highlighted. Stress‐induced exacerbated inflammation fragilizes these barriers which become hyperpermeable through loss of integrity and altered biology. At the gut level, this could be associated with dysbiosis, an imbalance in microbial communities, and alteration of the gut–brain axis which is central to production of mood‐related neurotransmitter serotonin. Novel therapeutic approaches such as anti‐inflammatory drugs, the fast‐acting antidepressant ketamine, and probiotics could directly act on the mechanisms described here improving mood disorder‐associated symptomatology. Discovery of biomarkers has been a challenging quest in psychiatry, and we end by listing promising targets worth further investigation.

Summary: Chronic stress can promote loss of blood-brain barrier (BBB) integrity leading to passage of circulating inflammatory mediators in mood-regulating brain areas and establishment of depressive behaviors. Conversely, neurovascular adaptations favoring resilience to stress exposure remain undetermined. Here, we report that environmental enrichment dampens stress-induced loss of endothelial tight junction protein Claudin-5 (Cldn5) along with anxiety- and depression-like behaviors in mice via an increase in fibroblast growth factor 2 (Fgf2). Treatment of mouse and human endothelial cells with Fgf2 preceding an immune challenge with the proinflammatory cytokine TNFα, elevated after chronic stress and in depression, reduces BBB dysfunction, and altered cell signaling. Coping with voluntary physical exercise also protects the BBB from stress deleterious effects by increasing Fgf2 preventing Cldn5 loss, exacerbated inflammation, and social avoidance. Circulating FGF2 level is linked with depression severity and symptomatology in humans supporting involvement of this growth factor in mood disorders and stress-induced BBB changes.

Experiences are linked to emotions impacting memory consolidation and associated brain neuronal circuits. Posttraumatic stress disorder is an example of strong negative emotions affecting memory processes by flashbacks of past traumas. Stress-related memory deficits are also observed in major depressive disorder (MDD). We recently highlighted that sex-specific blood-brain barrier (BBB) alterations underlie stress responses in mice and human depression. However, little is known about the relationship between emotional valence, memory encoding and BBB function. Here, we investigated the effects of novel object recognition (NOR) test, an experience considered of neutral emotional valence, on BBB properties in dorsal vs ventral hippocampus in the context of various environmental conditions (arena size, handling, age). The hippocampus is a brain area central for learning and memory processes with the dorsal and ventral subregions being associated with working memory vs reference memory retrieval, respectively. Expression of genes related to BBB integrity are altered in line with learning and memory processes in a region- and sex-specific manner. We observed correlations between poor learning, anxiety, stress-induced corticosterone release and changes in BBB-associated gene expression. Comparison of BBB transcriptomes between sexes also revealed profound differences at baseline in both ventral and dorsal hippocampus. Finally, we identified circulating vascular biomarkers, such as sE-selectin and Mmp-9, altered following NOR exposure supporting that recognition memory formation has an impact on the neurovasculature. Although deemed as a neutral valence test, NOR experimental conditions impact performance, highlighting the need to minimize anxiety when performing this commonly used test in mice. Significance Statement With this study, we aim to investigate the blood-brain barrier’s (BBB) role in memory acquisition and consolidation to unravel new mechanisms and decipher the involvement of non-neuronal cell types in these processes. For this purpose, male and female mice were subjected to a recognition memory test associated with a neutral emotional experience and impact on the transcriptomic profile of the BBB along with blood vascular biomarkers were evaluated under various experimental conditions. Crossing the BBB remains an important challenge to develop therapeutic drugs including in the context of memory deficits driven by psychiatric disorders or neurodegenerative diseases and thus, the possibility to directly target this barrier by better understanding its biology is attractive and innovating.