Abstract
Three strains of mice with various susceptibilities to restraint stress (RS), i.e., mice with a knocked out norepinephrine transporter gene (NET-KO), SWR/J and C57BL/6J (WT) mice were shown to serve as a good model to study the molecular mechanisms underlying different stress-coping strategies. We identified 14 miRNAs that were altered by RS in the PFC of these mice in a genotype-dependent manner, where the most interesting was let-7e. Further in silico analysis of its potential targets allowed us to identify five mRNAs (Bcl2l11, Foxo1, Pik3r1, Gab1 and Map2k4), and their level alterations were experimentally confirmed. A next-generation sequencing (NGS) approach, which was employed to find transcripts differentially expressed in the PFC of NET-KO and WT mice, showed that, among others, two additional mRNAs were regulated by mmu-let-7e, i.e., mRNAs that encode Kmt2d and Inf2. Since an increase in Bcl2l11 and Pik3r1 mRNAs upon RS in the PFC of WT mice resulted from the decrease in mmu-let-7e and mmu-miR-484 regulations, we postulated that MAPK, FoxO and PI3K-Akt signaling pathways were associated with stress resilience, although via different, genotype-dependent regulation of various mRNAs by let-7e and miR-484. However, a higher level of Kmt2d mRNA (regulated by let-7e) that was found with NGS analysis in the PFC of NET-KO mice indicated that histone methylation was also important for stress resilience.
Highlights
Mood disorders, including major depressive disorder (MDD), are still a considerable burden for modern society
Wewe were able totoidentify study, were able identifynumerous numerousmiRNAs miRNAsthat thatare arepresent present in in the mouse serum, which differentiated three strains of mice depending on their rethe which differentiated three strains of mice depending on their response sponse to restraint stress (RS)
These miRNAs might be regarded as biomarkers of stress stress resilience
Summary
Mood disorders, including major depressive disorder (MDD), are still a considerable burden for modern society. We were able to show alterations at the level of microRNAs (miRNAs) in the serum of these three genotypes, both between strains and regarding their response to RS [4,5]. The molecular mechanisms underlying these alterations, especially mechanisms that differentiate stress responses, namely, resilience and susceptibility, are not fully understood, but the increasing number of experimental data indicates that phenomena of epigenetic regulation of gene expression by microRNA have gained great interest. We identified miRNAs that were differentially expressed in the PFC of three strains of mice, which were characterized earlier as displaying different stresscoping strategies. We employed a next-generation sequencing (NGS) approach to find additional transcripts that were differentially expressed in the PFC of NET KO and WT mice
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