Serotonergic-dependent effects of exercise and elevated stress hormone on small non-coding RNA transcriptomics and proteomics in a mouse model of affective disorders.

Abstract

Environmental changes may alter gene expression in depression and anxiety disorders through epigenetic regulation, including small non-coding RNAs (sncRNAs) and their major subclass, microRNAs (miRNAs). However, underlying mechanisms mediating miRNA regulation in response to changing environmental stimuli are unclear. Using the serotonin transporter (5-HTT) knockout (KO) mouse model of depression/anxiety, this study aimed to compare the effects of voluntary exercise (EX) versus chronic treatment with the stress hormone (CT), corticosterone, on hippocampal miRNA transcriptome and proteome in five comparison groups: WT-SH vs. KO-SH; WT-SH vs. WT-EX; KO-SH vs. KO-EX; WT-SH vs. WT-CT; KO-SH vs. KO-CT. We hypothesized that treatment with stress hormone will result in miRNA and proteomics changes observed in genetic model of depression, while exercise will have beneficial effects similar to antidepressant treatment. Using high-throughput sequencing of miRNAs and mass spectrometry (MS)-based approaches for protein expression, we described 337 differentially expressed (DE) miRNAs and 67 proteins in 5-HTT KO mice compared to wild-type (WT) control mice in standard-housing conditions. After exercise, there were 200 DE miRNAs and 3 DE proteins in WT mice, and 20 DE miRNAs and 95 DE proteins in 5-HTT KO mice, while corticosterone treatment led to 168 DE miRNAs and 1 DE protein in WT, and 21 DE miRNAs and 21 DE proteins in 5-HTT KO mice. Serotonergic dysfunction (due to the 5-HTT KO gene mutation) induced altered expression of miRNAs and proteins involved in regulation of neurodevelopment, neurogenesis and neuroinflammatory responses. Elevation of the stress hormone corticosterone activated similar (to 5-HTT KO) molecules in WT mice, while exercise caused antidepressant-like effects. We suggest that these findings indicate that functional 5-HTT might be required for the beneficial effects of exercise on miRNA expression. Our study is the first to explore how gene-environment interactions affect miRNA/proteomics composition in a mouse model of depression/anxiety and extends our understanding of gene-environmental interactions underlying these affective disorders.