MicroRNA Regulates Early-Life Stress-Induced Depressive Behavior via Serotonin Signaling in a Sex-Dependent Manner in the Prefrontal Cortex of Rats.

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. and were upregulated in the frontal cortex following MS. In male MS rats, enrichment slightly reversed expression to levels similar to control rats. miR-200a-3p and miR-322-5p, which target , were decreased by MS, but not significantly. An -targeting miRNA, miR-320-5p, was also downregulated by MS and showed slight reversal by enrichment in male animals. miR-320-5p targeting of 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.