Alterations of microRNAs across human and mouse limbic brain areas: molecular mechanisms and biological processes involved in major depressive disorder

The etiology of major depressive disorder (MDD) is multifactorial with both genetic and environmental factors, such as adverse/stressful life events, contributing to risk. There is some evidence suggesting that microRNAs (miRNAs) mediate environmental-genetic interaction leading to the brain dysfunctions that underlie MDD. However, changes in miRNAs expression in human brain regions due to stress and associated with MDD are unclear. To increase the evidence in this regard, miRNA sequencing was performed on tissue samples of subgenual anterior cingulate cortex (sgACC) obtained from depressed patients and control subjects, as well on tissue samples of medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) from mice exposed to chronic social stress (CSS) and control animals. DESeq2 was applied to identify differentially expressed miRNAs (DEMs) and weighted co-expression network preservation analysis to uncover conserved molecular mechanisms between species. Finally, pathways obtained from DESeq2 and preservation analyses were overlapped to robustly identify MDD-related processes across bioinformatic approaches.Eighteen DEMs were identified in the human sgACC, 11 in the mPFC and 9 in the BLA of mice. The human sgACC DEMs were involved mainly in intracellular signaling and immune system-related pathways. The mouse mPFC and BLA DEMs were mainly involved in, respectively, intracellular signaling and nervous system functions. Preservation patterns between humans and mice indicated an over-representation of processes related to cellular signaling. Transcriptional regulation by MECP2 and Protein Kinase A signaling were the two pathways consistently altered across species, brain regions, and bioinformatic approaches. Although further studies are needed, they could represent a novel target for intervention strategies and confirm the dysregulation of intracellular signaling, immune, neuronal and synaptic functions in MDD.