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.

Environmental enrichment and physical exercise prevent stress-induced behavioral and blood-brain barrier alterations via Fgf2