Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice

Abstract

Menopause is associated with cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms are not fully understood. Here, we identify a sex hormone by age interaction whereby loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and astrocyte and microglia activation with synaptic loss. Selective deletion of estrogen receptor beta (ERβ) in astrocytes, but not neurons, in gonadally intact female mice induced the same brain effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERβ conditional knock out (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from both astrocyte-ERβ cKO female mice at midlife and from postmenopausal women. Gain of function studies showed that ERβ ligand treatment of midlife female mice reversed dorsal hippocampal neuropathology.

Circulating microRNAs are related to cognitive domains in the general population

“…Similarly, four microRNAs (miR-215-5p, miR-192-5p, miR-4732-3p, miR-340-5p) were associated with cognitive domain scores in a sex-dependent manner. This could be explained by an interaction of these microRNAs with sex hormone signaling, which is known to impact cognition [70]. In support of this, our functional enrichment results showed that miR-215-5p and miR-192-5p might regulate cellular responses to estradiol.…”

Lipopolysaccharide exacerbates depressive‐like behaviors in obese rats through complement C1q‐mediated synaptic elimination by microglia

“…Moreover, the exacerbated effect in obese rats with LPS exposure implies microglial priming resulting from chronic HFD exposure. Notably, male rats were used in the present study due to potential alterations in sex hormones, including estrogen, during menstrual cycles in female rats, which may impact glial function 45–47 . Further studies are needed to evaluate the sex differences in glial function in response to LPS, HFD, and the combined effects.…”

Linking alterations in estrogen receptor expression to memory deficits and depressive behavior in an ovariectomy mouse model

“…An ERβ-selective agonist suppressed the production and release of pro-inflammatory cytokines by microglia and astrocytes in an in vitro study 40 . In middle-aged female mice (12-14 months), selective deletion of ERβ in astrocytes presented hippocampal neuroinflammation and cognitive impairment 41 . In the present study, mice 12 weeks post-OVX presented reduced ERβ expressions in all brain regions, most prominently in three regions (hippocampus, PFC, and striatum), but ERα expression remained unchanged (Fig.…”