Early life and adult stress promote sex dependent changes in hypothalamic miRNAs and environmental enrichment prevents stress-induced miRNA and gene expression changes in rats

Lauren Allen Mckibben,Yogesh Dwivedi

doi:10.1186/s12864-021-08003-4

Abstract

BackgroundThe hypothalamus plays a key role in the stress response. While early life stress (ELS) increases susceptibility to psychiatric disorders including major depressive disorder (MDD), acute stress during adulthood can also precipitate MDD after ELS.AimHere, we tested the expression of miRNAs following ELS and susceptibility to depression-like behavior and whether sex or acute stress exacerbates this response. We also tested whether environmental enrichment (Enr) promotes early life and adult behavioral stress resilience and its effect on hypothalamic miRNA and gene expression. Following rat maternal separation (MS) as an ELS model, Enr from weaning through adulthood, and restraint (RS) as acute adult stress, we tested both animal behavior and miRNA expression in the hypothalamus. Target genes and their enrichment and ontology were analyzed using bioinformatic tools. Target gene expression changes were tested using qPCR, and miRNA promoter methylation was studied using methylated-DNA immunoprecipitation qPCR.ResultsMS, Enr, RS, and sex altered hypothalamic miRNAs, including several previously reported in MS literature: miRs-29, − 124, − 132, − 144, − 504. Sex had a significant effect on the greatest number of miRNAs. Also, Enr reversed downregulation of miR-29b-1-5p and -301b-3p in MS. qPCR showed that MAPK6 and MMP19, targets of miR-301b-3p, were upregulated in MS and reversed by Enr. Additionally, miR-219a was hypermethylated in MS coinciding with decreased miR-219a expression.ConclusionsThis study found that sex plays a critical role in the hypothalamic miRNA response to both ELS and acute stress, with males expressing greater changes following postnatal stress. Moreover, enrichment significantly altered behavior as well as hypothalamic miRNA expression and their gene targets. Because of its role as the initiator of the autonomic stress response and connection to hedonic and motivational behavior, the hypothalamic miRNA landscape may significantly alter both the short and long-term behavioral response to stress.

Highlights

The hypothalamus plays a key role in the stress response
This study found that sex plays a critical role in the hypothalamic miRNA response to both early life stress (ELS) and acute stress, with males expressing greater changes following postnatal stress
The purpose of the study was: 1) to show whether ELS-induced depressive behavior is associated with miRNA expression changes in the hypothalamus and whether there is an interaction between maternal separation (MS), RS, and sex on miRNA expression; 2) to examine the effect of the interaction between RS, sex and Enr in MS animals on hypothalamic miRNA expression; 3) explore if these MS-induced miRNAs changes in the hypothalamus relate to gene expression changes and whether these miRNAs themselves might be regulated via methylation

Summary

Introduction

While early life stress (ELS) increases susceptibility to psychiatric disorders including major depressive disorder (MDD), acute stress during adulthood can precipitate MDD after ELS. Life stress (ELS), namely abuse, neglect, and household dysfunction, is estimated to affect 64% of the US population [1]. This poses a major public health risk as ELS increases susceptibility to psychiatric disorders, including major depressive disorder (MDD). ELS and stress during adulthood can interact producing more severe or long-lasting symptoms than individually [4], described as the two/three-hit hypothesis of stress susceptibility [5]. There are only a limited number of studies that have examined sex-mediated depressive response to ELS [9]

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