Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders.

Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.

MicroRNAs as critical regulators of gene expression important for functions including neuronal development, synapse formation, and synaptic plasticity have been linked with the regulation of neurobiological systems that underlie anxiety processing in the brain. In this chapter, we give an update on associative evidence linking regulation of microRNAs with anxiety-and trauma-related

Background:Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear.Methods:The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse.Results:Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice.Conclusions:By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term.

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.

The chapter 'Role of MicroRNAs in Anxiety and Anxiety-Related Disorders' has now been made available open access under a CC BY 4.0 license.

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