Sex-Dependent Changes in miRNA Expression in the Bed Nucleus of the Stria Terminalis Following Stress.

Maria Mavrikaki,David Potter,Sami S Amr,Lorena Pantano,Nikolaos P Daskalakis,Kerry J Ressler,Maximilian A Rogers-Grazado,Frank J Slack,Eleni Anastasiadou,Elena Chartoff

doi:10.3389/fnmol.2019.00236

Abstract

Anxiety disorders disproportionately affect women compared to men, which may arise from sex differences in stress responses. MiRNAs are small non-coding RNAs known to regulate gene expression through actions on mRNAs. MiRNAs are regulated, in part, by factors such as stress and gonadal sex, and they have been implicated in the pathophysiology of multiple psychiatric disorders. Here, we assessed putative sex differences in miRNA expression in the bed nucleus of the stria terminalis (BNST) – a sexually dimorphic brain region implicated in anxiety – of adult male and female rats that had been exposed to social isolation (SI) stress throughout adolescence. To assess the translational utility of our results, we assessed if childhood trauma in humans resulted in changes in blood miRNA expression that are similar to those observed in rats. Male and female Sprague-Dawley rats underwent SI during adolescence or remained group housed (GH) and were tested for anxiety-like behavior in the elevated plus maze as adults. Small RNA sequencing was performed on tissue extracted from the BNST. Furthermore, we re-analyzed an already available small RNA sequencing data set from the Grady Trauma Project (GTP) from men and women to identify circulating miRNAs that are associated with childhood trauma exposure. Our results indicated that there were greater anxiogenic-like effects and changes in BNST miRNA expression in SI versus GH females compared to SI versus GH males. In addition, we found nine miRNAs that were regulated in both the BNST from SI compared to GH rats and in blood samples from humans exposed to childhood trauma. These studies emphasize the utility of rodent models in studying neurobiological mechanisms underlying psychiatric disorders and suggest that rodent models could be used to identify novel sex-specific pharmacotherapies for anxiety disorders.

Highlights

Life stressors, at vulnerable developmental periods such as adolescence or childhood, increase the risk for psychiatric disorders in adulthood (Chapman et al, 2004; Gillespie et al, 2009; Khoury et al, 2010; Mehta et al, 2013)
The present study focused on how stressful (SI) versus non-stressful housing conditions during adolescence impacted miRNA expression in the anterodorsal BNST (adBNST) in early adulthood
Focusing on miRNAs regulated by childhood trauma in the human samples, we found five miRNAs that are differential expression (DE) in social isolation (SI) compared to group housed (GH) female, and two miRNAs DE in SI compared to GH male, and two miRNAs that are DE in SI compared to GH male and female, rat adBNST (Table 1)

Summary

Introduction

At vulnerable developmental periods such as adolescence or childhood, increase the risk for psychiatric disorders in adulthood (Chapman et al, 2004; Gillespie et al, 2009; Khoury et al, 2010; Mehta et al, 2013). Stress-Regulated miRNAs in the BNST disorders are first evident in adolescence (Weintraub et al, 2010), raising the possibility that there are biologically and developmentally based sex differences underlying those disorders. Previous research demonstrated sex-specific effects of adolescent social isolation (SI) on adult stress reactivity, with adult female rats demonstrating more robust adrenal responses to acute and chronic stress compared to corresponding males (Weintraub et al, 2010). Adolescent SI is a translationally relevant stressor that can induce long-term and sex-specific changes in stress reactivity and behavior

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