Disrupted Estrogen Homeostasis Drives Female-Specific Depressive-Like and Anxiety-Like Behaviors via Convergent ERα Downregulation in the Ventral Hippocampus.

Although depression exhibits prominent sex differences, mechanisms linking estrogen fluctuations to this vulnerability remain unclear. Here, we reveal that disrupted estrogen homeostasis induces depressive- and anxiety-like behaviors via convergent downregulation of estrogen receptor alpha (ERα) and subsequent neuroinflammation in the female ventral hippocampus (vHPC). In humans (n=6,481), serum estradiol (E2) showed a U-shaped association with depression, increasing risk at both extremes. In mice, while chronic restraint stress (CRS) induced depressive-like behaviors across sexes, it selectively triggered E2 deficiency, anxiety-like behaviors, and decreased vHPC ERα (but not ERβ) in females. Therefore, focusing on females, both supraphysiological E2 (sE2)-induced elevation and CRS-induced E2 deficiency produced depressive- and anxiety-like behaviors converging on vHPC ERα downregulation. Cross-species transcriptomics and multi-omics revealed global concordance between female major depressive disorder (MDD) and both mouse models, identifying ERα as a top upstream regulator associated with neuroinflammation, lipid dysregulation, and synaptic dysfunction. Pharmacological inhibition of ERα exacerbated depressive- and anxiety-like behaviors and neuroinflammation under subthreshold CRS, whereas vHPC ERα overexpression rescued CRS-induced behavioral deficits and neuroinflammatory responses. Integrating human MDD GWAS and PsyGeNET datasets supported this pathway's genetic and clinical relevance. Collectively, we identify vHPC ERα as a unifying therapeutic target for female depression.