Estrogen receptor beta in lateral habenula mediates antidepressant effects of estrogen in postpartum-hormone-withdrawal-induced depression

Dramatic drop in reproductive hormone, especially estrogen level, from pregnancy to postpartum period is known to contribute to postpartum depression (PPD), but the underlying mechanism and the role of the estrogen receptors (ERs) in this process were unclear. Here, we used an estrogen-withdrawal-induced PPD model following hormone simulated pregnancy (HSP) in female Sprague-Dawley rats to induce depressive-like behaviors. After estrogen withdrawal, we observe an up-regulation of astrocyte-specific potassium channel (Kir4.1) in the brain's anti-reward center lateral habenula (LHb), along with enhanced bursting and excitability of LHb neurons. Among all 3 subtypes of ERs in the LHb, only ERβ shows an HSP-correlated expression temporal dynamics. Systemic administration of selective ERβ agonist, but not agonists of other subtypes of ERs, inhibits neuronal bursting activities and blocks up-regulation of Kir4.1 in the LHb, as well as decreases estrogen-withdrawal-induced depressive-like behavior. Importantly, intra-LHb injection of ERβ agonist is sufficient to rescue depressive-like behaviors induced by estrogen withdrawal. Conversely, local knock-down of ERβ in the LHb suppresses the antidepressant-like effect of estrogen. Our results reveal a critical role of LHb in the pathogenesis of hormone-sensitive PPD and ERβ as a critical mediator of estrogen's antidepressant effects on PPD.