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

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 versus chronic treatment with the stress hormone, corticosterone, on miRNA transcriptome and proteome. 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.