Duan Chenchi, Ma Shuangshuang, Chen Min, Wang Junying, Jiang Yihao, Ye Mingliang, Tan Yi, Cheng Songxia, Yang Xuexuan, Hu Hailan, Yang Yan, Huang He-Feng
Obstetrics and Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai, China.
Nanhu Brain-Computer Interface Institute, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou, China.
Mol Psychiatry. 2025 Sep 5. doi: 10.1038/s41380-025-03215-6.
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.
从孕期到产后，生殖激素尤其是雌激素水平急剧下降，已知这会导致产后抑郁症（PPD），但雌激素受体（ERs）在此过程中的潜在机制和作用尚不清楚。在此，我们在雌性斯普拉格-道利大鼠中采用激素模拟妊娠（HSP）后的雌激素撤药诱导的PPD模型来诱导类似抑郁的行为。雌激素撤药后，我们观察到大脑抗奖赏中心外侧缰核（LHb）中星形胶质细胞特异性钾通道（Kir4.1）上调，同时LHb神经元的爆发性活动和兴奋性增强。在LHb中的所有3种ER亚型中，只有ERβ表现出与HSP相关的表达时间动态变化。全身给予选择性ERβ激动剂而非其他ER亚型的激动剂，可抑制神经元的爆发性活动，阻断LHb中Kir4.1的上调，并减少雌激素撤药诱导的类似抑郁的行为。重要的是，向LHb内注射ERβ激动剂足以挽救雌激素撤药诱导的类似抑郁的行为。相反，在LHb中局部敲低ERβ会抑制雌激素的抗抑郁样作用。我们的结果揭示了LHb在激素敏感性PPD发病机制中的关键作用，以及ERβ作为雌激素对PPD抗抑郁作用的关键介质的作用。
