期刊
TRANSLATIONAL PSYCHIATRY
卷 12, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41398-022-01864-7
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类别
资金
- Hope for Depression Research Foundation
- Rockefeller Gary Helman Fellowship
- NIH-NIAAA [K99AA028817, P50AA022538]
In this study, the genomic effects of glucocorticoids on the dorsal and ventral hippocampus were investigated in male and female mice. The results showed that there were significant differences in gene expression and methylation patterns between males and females, as well as between different subregions of the hippocampus.
The genomic effects of circulating glucocorticoids are particularly relevant in cortico-limbic structures, which express a high concentration of steroid hormone receptors. To date, no studies have investigated genomic differences in hippocampal subregions, namely the dorsal (dHPC) and ventral (vHPC) hippocampus, in preclinical models treated with exogenous glucocorticoids. Chronic oral corticosterone (CORT) in mouse is a pharmacological approach that disrupts the activity of the hypothalamic-pituitary-adrenal axis, increases affective behavior, and induces genomic changes after stress in the HPC of wildtype (WT) mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor Va166Met (hMet), a variant associated with genetic susceptibility to stress. Using RNA-sequencing, we investigated the genomic signatures of oral CORT in the dHPC and vHPC of WT and hMet male and female mice, and examined sex and genotype differences in response to oral CORT. Males under CORT showed lower glycemia and increased anxiety- and depression-like behavior compared to females that showed instead opposite affective behavior in response to CORT. Rank-rank-hypergeometric overlap (RRHO) was used to identify genes from a continuous gradient of significancy that were concordant across groups. RRHO showed that CORT-induced differentially expressed genes (DEGs) in WT mice and hMet mice converged in the dHPC of males and females, while in the vHPC, DEGs converged in males and diverged in females. The vHPC showed a higher number of DEGs compared to the dHPC and exhibited sex differences related to glucocorticoid receptor (GR)-binding genes and epigenetic modifiers. Methyl-DNA-immunoprecipitation in the vHPC revealed differential methylation of the exons 1(C) and 1(F) of the GR gene (Nr3c1) in hMet females. Together, we report behavioral and endocrinological sex differences in response to CORT, as well as epigenetic signatures that i) differ in the dHPC and vHPC,ii) are distinct in males and females, and iii) implicate differential methylation of Nr3c1 selectively in hMet females.
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