MicroRNA-34 Contributes to the Stress-related Behavior and Affects 5-HT Prefrontal/GABA Amygdalar System through Regulation of Corticotropin-releasing Factor Receptor 1

• DOI: 10.1007/s12035-018-0925-z
• Publication Date: 2018-02-07T06:44:08Z
• Authors: Diego Andolina; Matteo Di Segni; Alessandra Accoto; Luisa Lo Iacono; Antonella Borreca; Donald Ielpo; Nicola Berretta; Emerald Perlas; Stefano Puglisi-A...; Rossella Ventura
• Keywords: Dorsal Raphe Nucleus; Male; 0301 basic medicine; microRNA; stress; animal models; Serotonin; Corticotropin-Releasing Hormone; Prefrontal Cortex; Motor Activity; Stress; Prefrontal cortex; Receptors, Corticotropin-Releasing Hormone; Immobilization; Mice; 03 medical and health sciences; 0302 clinical medicine; Animals; microRNA-34; Corticotropin-releasing factor receptor type 1; Dorsal raphe nuclei; Swimming; gamma-Aminobutyric Acid; Mice, Knockout; Behavior, Animal; Acenaphthenes; Amygdala; MicroRNAs; Gene Deletion; Stress, Psychological

Recent studies show that microRNA-34 (miR-34) family is critical in the regulation of stress response also suggesting that it may contribute to the individual responsiveness to stress. We have recently demonstrated that mice carrying a genetic deletion of all miR-34 isoforms (triple knockout, TKO) lack the stress-induced serotonin (5-HT) and GABA release in the medial prefrontal cortex (mpFC) and basolateral amygdala (BLA), respectively. Here, we evaluated if the absence of miR-34 was also able to modify the stress-coping strategy in the forced swimming test. We found that the blunted neurochemical response to stress was associated with lower levels of immobility (index of active coping behavior) in TKO compared to WT mice. Interestingly, among the brain regions mostly involved in the stress-related behaviors, the miR-34 displayed the strongest expression in the dorsal raphe nuclei (DRN) of wild-type (WT) mice. In the DRN, the corticotropin-releasing factor receptors (CRFR) 1 and 2, contribute to determine the stress-coping style and the CRFR1 is a target of miR-34. Thus, we hypothesized that the miR-34-dependent modulation of CRFR1 expression may be involved in the DRN regulation of stress-coping strategies. In line with this hypothesis, we found increased CRFR1 levels in the DNR of TKO compared to WT mice. Moreover, infusion of CRFR1 antagonist in the DRN of TKO mice reverted their behavioral and neurochemical phenotype. We propose that miR-34 modulate the mpFC 5-HT/BLA GABA response to stress acting on CRFR1 in the DRN and that this mechanism could contribute to determine individual stress-coping strategy.