Abstract
Background
The underlying neurobiology of early-life stress (ELS)-induced major depressive disorder is not clearly understood.Methods
In this study, we used maternal separation (MS) as a rodent model of ELS and tested whether microRNAs (miRNAs) target serotonin genes to regulate ELS-induced depression-like behavior and whether this effect is sex dependent. We also examined whether environmental enrichment prevents susceptibility to depression- and anxiety-like behavior following MS and whether enrichment effects are mediated through serotonin genes and their corresponding miRNAs.Results
MS decreased sucrose preference, which was reversed by enrichment. Males also exhibited greater changes in forced swim climbing and escape latency tests only following enrichment. S lc6a4 and H tr1a were upregulated in the frontal cortex following MS. In male MS rats, enrichment slightly reversed H tr1a expression to levels similar to control rats. miR-200a-3p and miR-322-5p, which target SLC6A4, were decreased by MS, but not significantly. An HTR1A-targeting miRNA, miR-320-5p, was also downregulated by MS and showed slight reversal by enrichment in male animals. miR-320-5p targeting of H tr1a was validated in vitro using SHSY neuroblastoma cell lines.Conclusions
Altogether, this study implicates miRNA interaction with the serotonin pathway in ELS-induced susceptibility to depression-related reward deficits. Furthermore, because of its recovery by enrichment in males, miR-320 may represent a viable sex-specific target for reward-related deficits in major depressive disorder.