Academic Journal
High-level estrogen impairs memory via estrogen receptor signaling in a hypothalamic-hippocampal neural circuit.
| Τίτλος: | High-level estrogen impairs memory via estrogen receptor signaling in a hypothalamic-hippocampal neural circuit. |
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| Συγγραφείς: | 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. |
| Πηγή: | Science bulletin [Sci Bull (Beijing)] 2026 Sep 30; Vol. 71 (18), pp. 4762-4779. Date of Electronic Publication: 2026 Aug 25. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | 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- |
| Ιατρικοί όροι (MeSH): | 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 |
| Περίληψη: | 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 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2095-9281 |
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| DOI: | 10.1016/j.scib.2026.08.057 |