Mind the Gap: Estrogen Receptor-β in Astrocytes Is a Therapeutic Target to Prevent Cognitive Problems at Menopause [ID 2683385]

INTRODUCTION: Menopause entails cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms remain unclear. METHODS: Aging female mice were examined for cognitive deficits, hippocampal atrophy by MRI, and neuropathology. RESULTS: A sex hormone by age interaction was discovered. Loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and glial activation with synaptic loss. Deletion of estrogen receptor-β (ERβ) in astrocytes, but not neurons, in gonadally intact females recapitulated these effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERβ conditional knockout (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from astrocyte-ERβ cKO at midlife and postmenopausal women. ERβ ligand treatment at midlife reversed dorsal hippocampal neuropathology. CONCLUSION: Estrogen receptor-β in hippocampal astrocytes modulates cognitive function in mid-age female mice.