高水平雌激素通过下丘脑-海马神经回路中的雌激素受体信号传导损害记忆
高水平雌激素通过下丘脑-海马神经回路中的雌激素受体信号传导损害记忆
作者： 小柯机器人 发布时间：2026/8/26 15:45:49
本期文章：《科学通报》：Online/在线发表
2026年8月25日，山东大学齐鲁医院侯新国 等合作 在《科学通报》发表研究，揭示了高水平雌激素通过下丘脑-海马神经回路中的雌激素受体信号传导损害记忆的机制。
正常的雌激素暴露——如在有生育能力的月经规律女性中所观察到的那样——对神经认知很重要，这一点已由绝经后激素替代疗法所证实。然而，在口服避孕药或妊娠背景下，持续高水平雌激素对认知的影响尚不清楚。在此，研究人员表明，高水平雌激素在小鼠中诱导暂时性记忆功能障碍，但不影响情绪相关行为或探索动机，这与外侧下丘脑（LH）中基因表达的改变相关。外侧下丘脑中神经元雌激素受体α/β（ERα/β）的耗竭可挽救雌激素或妊娠诱导的认知功能障碍。单核RNA测序显示，ERα（LH中主要的ER）富集于释放γ-氨基丁酸（GABA能）神经元中，且高水平雌激素下调LHGABA神经元内的GABA-A受体信号传导，同时在高水平雌激素暴露或妊娠期间伴随LHGABA神经元自发放电活动的增加。LHGABA神经元投射至海马角氨区3（CA3）。对CA3投射的LHGABA神经元进行化学遗传学抑制可防止高水平雌激素诱导的认知功能障碍，而激活CA3投射的LHGABA神经元则导致认知功能障碍。最后，研究人员观察到女性在妊娠晚期的任务特异性记忆损伤，即使在校正其他协变量后，这种损伤仍与循环雌激素水平升高相关。这些发现描绘了高水平雌激素对认知影响的分子和神经机制，对于理解与妊娠或口服避孕药相关的“脑雾”具有启示意义。
Title: High-level estrogen impairs memory via estrogen receptor signaling in a hypothalamic–hippocampal neural circuit
Author: anonymous
Issue&Volume: 2026/08/25
Abstract: Normal estrogen exposure, as observed in eumenorrheic women of reproductive age, is important for neurocognition, as demonstrated by postmenopausal hormone replacement. However, the cognitive effects of sustained high-level estrogen in the context of oral contraceptives or pregnancy are unclear. Here, we show that high estrogen induces temporary memory dysfunction in mice without affecting mood-related behaviors or exploratory motivation, which is associated with altered gene expression in the lateral hypothalamus (LH). Depletion of neuronal estrogen receptor α/β (ERα/β) in the LH rescues estrogen- or pregnancy-induced cognitive dysfunction. Single-nucleus RNA-seq revealed that ERα, the predominant ER in LH, is enriched in Gamma-Aminobutyric Acid-releasing (GABAergic) neurons and that high-level estrogen downregulates GABA-A receptor signaling within LHGABA neurons, concurrent with increased spontaneous firing activity of LHGABA neurons during high estrogen exposure or pregnancy. LHGABA neurons project to the hippocampal Cornu Ammonis 3 (CA3). Chemogenetic suppression of CA3-projecting LHGABA neurons protects against high estrogen-induced cognitive dysfunction, while activation of CA3-projecting LHGABA neurons causes cognitive dysfunction. Lastly, we observed task-specific memory impairment in women during late pregnancy, which was associated with elevated circulating estrogen levels even after correcting for other covariates. These findings delineate a molecular and neural mechanism underlying the cognitive effects of high-level estrogen, with implications for understanding the brain fog associated with pregnancy or oral contraceptives.
DOI: 10.1016/j.scib.2026.08.057
Source:https://www.sciencedirect.com/science/article/pii/S2095927326009758