Chronic social stress alters blood-brain barrier (BBB) integrity through downregulation of the tight junction protein claudin-5. This drives the development of depression-like behaviors. Specifically, chronic social defeat stress reduces claudin-5 mRNA and protein levels in the nucleus accumbens, causing ultrastructural abnormalities in blood vessels and increased BBB permeability. Antidepressant treatment can reverse these effects by normalizing claudin-5 expression. Knockdown of claudin-5 also produces depression-like behaviors in stressed mice, confirming its role in mediating stress responses.