Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: The role of miR-34a in stress-induced neurotransmission within Dorsal Raphe Nuclei

Mounting clinical and preclinical evidence support the involvement of non-coding RNAs such as microRNAs (miRs) in the adaptive (and maladaptive) brain responses to stressful stimuli. Among miRs, the miR-34 family has been involved in the neurobiological processes that underlie the regulation of stress response. Here we elucidate the mechanism through which miR-34 family modulates stress-induced neurotransmission and stress-coping behavior. First, we evaluated the expression of miR-34 family in stress-related brain areas and their role in behavioral and neurochemical stress-response. Then, using histological, molecular, and genetic approaches we examined miR-34a cellular localization in the Dorsal Raphe Nuclei (DRN), and we investigated its specific functions on neurotransmission. Finally, we evaluated a potential involvement of miR-34 family in physiological adaptations to chronic stress exposure. We found that, within brain, miR-34 (especially the isoform a) is highly expressed in DRN. Here it plays a modulatory role on Serotoninergic release to projection areas, through a fine inhibitory tuning of GABA release, thus determining the adopted coping response to acute and chronic stressors. Finally, we identified through next-gen RISC-RNA sequencing several miR-34s’ target, that are possibly involved in physiological adaptations to chronic stress. This study points out that miR-34a could be a selective GABAergic regulator of the DRN activity. This factor seems to exert an inhibitory control on GABA neurons within the DRN, that in turn regulates the serotonergic activity and determines the adopted coping response to stressful stimuli.