Potential of microRNAs as novel targets in the alleviation of pathological fear

The current treatment of post-traumatic stress disorder (PTSD), phobias and other anxiety disorders, remains insufficient particularly in producing long-lasting full symptom control. Dysfunctional fear processing is common in these disorders, including a deficiency in fear-inhibitory mechanisms and impairment in the ability to discriminate between safety and danger cues. Research has aimed to elucidate brain circuitries, neurotransmitters and downstream signaling pathways important in the alleviation of aberrant fear, with a specific focus on mechanisms modulating fear memory and its behavioral expression. MicroRNAs (miRNA) as "fine tuners" of gene expression at the post-transcriptional level have emerged as critical regulators of such mechanisms important in both, the generation and the inhibition of fear memories. Along these lines, abnormal expression of miRNAs has been associated with different fear-related disorders. After providing an updated overview on the involvement of miRNAs in fear learning mechanisms, we summarize and discuss in particular those studies in which the implication of miRNAs in successful inhibition of fear has been explored. For a better overview, we dissociate the different modes of fear alleviation investigated in this regard and present studies in rodents demonstrating that specific miRNAs are involved in the destabilization of fear by interfering with consolidation/reconsolidation mechanisms or that they are associated with the generation of fear extinction or safety learning. Finally, we discuss the potential of miRNAs as biomarkers and novel therapeutic targets, as well as the challenges involved in applying the discovered mechanisms in the development of improved treatments of fear- and trauma-related disorders.