MiRNA-34 and stress response

Psychiatric disorders are known to result from a strong interaction between genetic predisposition and environmental factors, mainly exposure to stressful events. Environmental events can modulate genes expression, possibly via epigenetic mechanisms, and affect onset/ expression of a disease [1]. Epigenetic mechanisms include, among others, post-transcriptional regulation by non-coding RNAs such as microRNAs (miRNAs). MiRNAs are small non-coding RNAs predicted to regulate hundreds of targets and to be engaged in every biological process [2]. Thanks to their ability to fine-tune gene expression, miRNAs can control gene expression patterns favoring organism's adaptation to internal and environmental (external) factors [3], such as stressful events. Studies in humans and in animal models have provided important insights into the role of miRNAs in different psychiatric disorders, showing that miRNAs are involved in neuroplasticity, neuronal adaptation to stress, and stress-related disorders including anxiety, depression, and bipolar disorder [1, 3-5]. In particular, animal models offer the opportunity to correlate miRNA expression in specific brain structures with different behavioral phenotypes [1, 3-5]. Recent evidence point to members of the miRNA-34 family of miRNAs as a critical modulators of stress response, showing their role in the manifestation of fear and anxiety-related behaviors [6, 7]. Although different brain areas are involved in stress response modulation, the medial preFrontal Cortex (mpFC) and the amygdala are crucially affected by stressful stimuli, and multiple lines evidence indicate that dysfunction of the neural circuit connecting these two structures underlies stress-related anxiety-like disorders [7]. Interestingly, miRNA-34c (a member of the miR-34 family) has been reported to be up-regulated in the central nucleus of the Amygdala following acute and chronic stress in mice [6]. Moreover, local inhibition of miRNA-34c increased anxiety-like behavior, while its ectopic expression partially reverted this phenotype [6]. We have recently demonstrated that serotonergic prefrontal transmission modulates the stress response acting on GABAergic transmission within the basolateral amygdala (BLA) in mice [8]. Using mice carrying a targeted deletion of miR-34a, miR-34b, and miR-34c (TKO), we have shown that miRNA-34 expression within the prefrontal-amygdala brain circuit regulates stress response. We evaluated the role of miRNA-34 in stress response by subjecting wild type (WT) and TKO mice to different anxiety-related tests (elevated plus maze, dark-light and open field tests). We also investigated prefrontal serotonergic-amygdalar GABAergic release induced by acute restraint stress exposure as well as dendritic remodeling induced by stress in the BLA of WT and TKO mice. We found that TKO mice had a …