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

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^GABA neurons, concurrent with increased spontaneous firing activity of LH^GABA neurons during high estrogen exposure or pregnancy. LH^GABA neurons project to the hippocampal Cornu Ammonis 3 (CA3). Chemogenetic suppression of CA3-projecting LH^GABA neurons protects against high estrogen-induced cognitive dysfunction, while activation of CA3-projecting LH^GABA 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.