Involvement of miRNAs and metabolites in inducing vulnerability to traumatic stress in an animal model

Psychological stress associated with severe trauma leads to PTSD in vulnerable individuals, however, the majority of individuals, around 60%-70%, appear resilient despite experiencing qualitatively and quantitatively similar trauma. Understanding the molecular determinants of resilience/ vulnerability to traumatic stress could offer the opportunity to devise novel therapeutic targets for treatment or prevention of PTSD and other stress-related disorders. Using the predator exposure model of traumatic stress, we identified in the ventromedial prefrontal cortex (vmPFC) two strong miRNA candidates, miRK451a and miRK144K3p, that emerged as prominent regulators of trauma-induced extremely anxious behavior. We then focally inhibited these two miRNAs in the prelimbic and infralimbic sub-cortices of vmPFC in naïve animals, 24hrs before behavioral evaluation of anxiety in the elevated plus maze (EPM). This experiment led to very interesting results, demonstrating that miR-144/451a downregulation in the prelimbic and infralimbic cortices of vmPFC produce opposing results on anxiety behaviors. Finally, we verified if inhibition of miR-144/451a in the prefrontal cortex, which significantly reduced anxiety in naive mice, was also able to reverse the long-lasting extremely anxious phenotype observed after trauma exposure. We demonstrated that injection of miR-144/451a inhibitor in the prelimbic cortex immediately post-exposure remarkably reversed extreme anxious behavior measured 13 days after stress, compared to scramble treated animals. As part of this project, we recently also focused on the identification of differences in circulating metabolites between trauma resilient and susceptible mice, using a metabolomics approach.