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High-level estrogen impairs memory via estrogen receptor signaling in a hypothalamic-hippocampal neural circuit.

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Title: High-level estrogen impairs memory via estrogen receptor signaling in a hypothalamic-hippocampal neural circuit.
Authors: Li X; Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA., Zang N; Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, China., Zhao Q; Pennington Biomedical Research Center, Brain Glycemic and Metabolism Control Department, Louisiana State University, Baton Rouge, LA 70808, USA., Sun Y; Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA., Siva Kumar UK; Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA., Hua M; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan 250012, China., Zhou W; Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA., Qi Y; Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Chen H; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Xia L; Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, China., Qin J; Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, China., Sun L; Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, China., Rai C; Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA., Cheng C; Department of Medicine, Epidemiology and Population Science, Baylor College of Medicine, Houston, TX 77030, USA., Liu Z; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Chen L; Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, China., Xu Y; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Hu Z; Department of Medicine, Division of Nephrology, Baylor College of Medicine, Houston, TX 77030, USA., Li H; Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Hou X; Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: houxinguo@sdu.edu.cn., He Y; Pennington Biomedical Research Center, Brain Glycemic and Metabolism Control Department, Louisiana State University, Baton Rouge, LA 70808, USA. Electronic address: yanlin.he@pbrc.edu., Zhuang X; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: zhuangxianghua@email.sdu.edu.cn., Sun Z; Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: zheng.sun@bcm.edu.
Source: Science bulletin [Sci Bull (Beijing)] 2026 Sep 30; Vol. 71 (18), pp. 4762-4779. Date of Electronic Publication: 2026 Aug 25.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101655530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2095-9281 (Electronic) Linking ISSN: 20959273 NLM ISO Abbreviation: Sci Bull (Beijing) Subsets: MEDLINE
Imprint Name(s): Publication: 2017- : Amsterdam : Beijing : Elsevier B.V. ; Science China Press
Original Publication: Beijing : Berlin ; Heidelberg : Science China Press ; Springer-Verlag, 2015-
MeSH Terms: Estrogens*/metabolism , Estrogen Receptor alpha*/metabolism , Estrogen Receptor alpha*/genetics , Memory Disorders*/chemically induced , Memory Disorders*/metabolism , Memory*/drug effects , Hippocampus*/metabolism , Hypothalamus*/metabolism , Receptors, Estrogen*/metabolism, Estrogen Receptor beta/metabolism ; Estrogen Receptor beta/genetics ; GABAergic Neurons/metabolism ; Animals ; Female ; Signal Transduction ; Pregnancy ; Mice ; Mice, Inbred C57BL
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 the 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.
(Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
Contributed Indexing: Keywords: Estrogen; Hypothalamus; Memory; Momnesia; Pregnancy brain
Substance Nomenclature: 0 (Estrogens)
0 (Estrogen Receptor alpha)
0 (Estrogen Receptor beta)
0 (Receptors, Estrogen)
Entry Date(s): Date Created: 20260902 Date Completed: 20260926 Latest Revision: 20260926
Update Code: 20260927
DOI: 10.1016/j.scib.2026.08.057
PMID: 42686501
Database: MEDLINE
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  Data: <searchLink fieldCode="MM" term="%22Estrogens%22">Estrogens*</searchLink>/<searchLink fieldCode="MM" term="%22Estrogens+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Estrogen+Receptor+alpha%22">Estrogen Receptor alpha*</searchLink>/<searchLink fieldCode="MM" term="%22Estrogen+Receptor+alpha+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Estrogen+Receptor+alpha%22">Estrogen Receptor alpha*</searchLink>/<searchLink fieldCode="MM" term="%22Estrogen+Receptor+alpha+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+chemically+induced%22">chemically induced</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory%22">Memory*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Hippocampus%22">Hippocampus*</searchLink>/<searchLink fieldCode="MM" term="%22Hippocampus+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Hypothalamus%22">Hypothalamus*</searchLink>/<searchLink fieldCode="MM" term="%22Hypothalamus+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Receptors%2C+Estrogen%22">Receptors, Estrogen*</searchLink>/<searchLink fieldCode="MM" term="%22Receptors%2C+Estrogen+metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Estrogen+Receptor+beta%22">Estrogen Receptor beta</searchLink>/<searchLink fieldCode="MH" term="%22Estrogen+Receptor+beta+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Estrogen+Receptor+beta%22">Estrogen Receptor beta</searchLink>/<searchLink fieldCode="MH" term="%22Estrogen+Receptor+beta+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22GABAergic+Neurons%22">GABAergic Neurons</searchLink>/<searchLink fieldCode="MH" term="%22GABAergic+Neurons+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Signal+Transduction%22">Signal Transduction</searchLink> ; <searchLink fieldCode="MH" term="%22Pregnancy%22">Pregnancy</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink>
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  Data: 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 the LH, is enriched in Gamma-Aminobutyric Acid-releasing (GABAergic) neurons and that high-level estrogen downregulates GABA-A receptor signaling within LH<superscript>GABA</superscript> neurons, concurrent with increased spontaneous firing activity of LH<superscript>GABA</superscript> neurons during high estrogen exposure or pregnancy. LH<superscript>GABA</superscript> neurons project to the hippocampal Cornu Ammonis 3 (CA3). Chemogenetic suppression of CA3-projecting LH<superscript>GABA</superscript> neurons protects against high estrogen-induced cognitive dysfunction, while activation of CA3-projecting LH<superscript>GABA</superscript> 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.<br /> (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
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      – SubjectFull: Estrogen Receptor beta metabolism
        Type: general
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