Chronic stress exposure is known to increase vulnerability to the expression of psychiatric disorders, such as depression. Clinical and preclinical evidences support the involvement of the microRNA-34 family in stress-related psychiatric conditions and in the regulation of stress responses. However, the mechanism and the multiple targets by which the microRNA-34 family can affect the stress response and stress-related behavioral alteration are not fully known. Here, with the aid of constitutive and conditional genetic strategy, we examined the role of microRNA-34 family in the expression of depression-like phenotype in mice induced by chronic stress exposure, and we identified their "in vivo" targets during the stressful challenge. We found that microRNA-34a, under chronic stress, is significantly up-regulated in the mouse raphe nuclei, where its recruitment is necessary to induce depression-like behavioral alterations and impact the function of the serotonergic system. Moreover, by next-generation RNA-seq of Ago-2-bound mRNAs, we identified genes that are targeted by microRNA-34a in response to chronic stress and that are likely to mediate its effects.
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