Ricerc@Sapienza

MicroRNAs (miRNAs) are a growing class of therapeutic targets for many disorders as their function in regulating gene expression controls important processes like synaptic plasticity and behavior. Post-traumatic stress disorder (PTSD) is an anxiety disorder triggered by exposure to a trauma where only 20-30% of the individuals develop vulnerability towards the disorder. A majority of others cope or recover from stress and show no signs of long-term psychopathology. Though a few clinical and preclinical studies have shown miRNAs dysregulation in PTSD, no study ever explored the functioning of brain miRNAs in mediating stress resilience in PTSD. Understanding this molecular mechanism could offer the great opportunity to devise novel therapeutics to treat PTSD. Therefore, by utilizing the predator exposure murine model of PTSD, that has previously been shown to capture individual differences in stress response similar to human PTSD, we have identified two key miRNAs in the medial prefrontal cortex (mPFC), miR-451a and 144-3p that are significantly upregulated in vulnerable mice. Focal inhibition of the two miRNAs by anti-miR administration in the sub-regions of mPFC (i.e. prelimbic, PrL; infralimbic cortex, IL) of naïve mice produced a dichotomy in anxiety behavior: inhibition in the PrL elicited anxiolytic behavior, while inhibition in the IL increased anxiety. Coherently, miRNAs inhibition in the PrL of vulnerable mice reversed anxiety behavior. Here we propose to seek the top-down pathways of this resilience effect, which remains elusive. To this aim, brains of stressed and control mice injected with anti-miR in PrL and IL sub-regions will be stained for Fos, a neuronal activity marker in multiple brain regions. Fos expression changes will be mapped to identify the effect of miR-451 and 144 down-regulation on specific downstream brain structures. This study will help us unravel at a circuit level the role of mPFC miR-451a/144-3p in anxiety and PTSD-like symptoms.