MicroRNA-34a regulates the depression-like behavior in mice by modulating the expression of target genes in the Dorsal Raphè

Chronic or cumulative stress sustained over a long period of time increases the risk of affective illness. Mounting clinical and preclinical evidences support the involvement of the miR-34 family of microRNAs in stress-related psychiatric conditions and in the neurobiological mechanisms that underlie the regulation of stress response. In this study, by molecular and behavioral approaches, we investigate the role of miR-34 in the behavioral and functional modifications induced in the mouse brain by a chronic stress exposure (repeated restraint) and try to elucidate the underlying mechanism by the identification of miR-34 “in vivo” multiple downstream targets, under the context of a stressful challenge. We show that the miR-34a, under chronic stress, is highly induced in the mouse Dorsal Raphe Nuclei, where its recruitment is necessary to produce the behavioral modifications and impact the serotonergic system functionality. Moreover, through next generation RNA-seq in Ago-2 -bound mRNAs (RISC-Seq), we identified genes that are targeted by miR-34 in response to the chronic stress, and that are likely to mediate its effect.