Cell type specificity of glucocorticoid signaling in the adult mouse hippocampus

Abstract

Glucocorticoid stress hormones are powerful modulators of brain function and can affect mood and cognitive processes. The hippocampus is a prominent glucocorticoid target and expresses both the glucocorticoid receptor (GR: Nr3c1) and the mineralocorticoid receptor (MR: Nr3c2). These nuclear steroid receptors act as ligand‐dependent transcription factors. Transcriptional effects of glucocorticoids have often been deduced from bulk mRNA measurements or spatially informed individual gene expression. However, only sparse data exists allowing insights on glucocorticoid‐driven gene transcription at the cell type level. Here, we used publicly available single‐cell RNA sequencing data to assess the cell‐type specificity of GR and MR signaling in the adult mouse hippocampus. The data confirmed that Nr3c1 and Nr3c2 expression differs across neuronal and non‐neuronal cell populations. We analyzed co‐expression with sex hormones receptors, transcriptional coregulators, and receptors for neurotransmitters and neuropeptides. Our results provide insights in the cellular basis of previous bulk mRNA results and allow the formulation of more defined hypotheses on the effects of glucocorticoids on hippocampal function.

Mineralocorticoid receptor and glucocorticoid receptor work alone and together in cell-type-specific manner: Implications for resilience prediction and targeted therapy

“…This implies that they may become limiting for receptor function and provide a mechanism for cross talk between these types of receptors ( Lonard and O'Malley, 2012 ). Second, coregulators show substantial differences in neuroanatomical distribution ( Mahfouz et al, 2016 ; Viho et al, 2022 ). This may explain why in the PVN glucocorticoids can suppress the expression of the Crh gene, while in other brain regions such as the amygdala GR potently stimulates its expression ( Zalachoras et al, 2016 ).…”

Gene expression changes in the brain of a Cushing's syndrome mouse model

“…Most of these effects locate in PVN and hippocampus, where there is substantial coexpression of MR/GR with sex steroid receptors. 29 These differences were generally modest and restricted to single areas for each gene, with neuronal activation markers as the most consistently different between sexes. It has been shown that there are sexual differences in oligodendrocyte precursor proliferation and metabolism; microglial cell density, membrane properties and antigen presenting potential; and in both types of cells, gene expression profile.…”

“…We obtained significant intrinsic sex effects as well as interactions between genotype and sex in genes related to oligodendrocytes, microglia, neuronal activity and oxidative stress. Most of these effects locate in PVN and hippocampus, where there is substantial coexpression of MR/GR with sex steroid receptors 29 . These differences were generally modest and restricted to single areas for each gene, with neuronal activation markers as the most consistently different between sexes.…”

“…The metadata was used to subset cells of the hippocampus region from the gene expression matrix. The newly obtained matrix was processed and analysed in R v3.6.1 according to the Seurat v3.1.5 pipeline for quality control, analysis, and exploration of scRNA‐seq data 28 as described elsewhere 29 …”

“…The newly obtained matrix was processed and analysed in R v3.6.1 according to the Seurat v3.1.5 pipeline for quality control, analysis, and exploration of scRNA-seq data 28 as described elsewhere. 29 females, respectively. A significant genotype effect was found (p < .01), indicating higher levels in AdKO 2.0 mice compared to wildtype (Figure 1).…”