Project description:Background: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena. Methods: Spontaneous recovery and fear renewal tests, assessed persistence and context-independence of treatments rescuing deficient fear extinction in 129S1/SvImJ mice. To reveal neurobiological mechanisms supporting long-lasting extinction rescue, whole-genome expression profiling, qRT-PCR, immunohistochemistry and chromatin immunoprecipitation were used. Results: Persistent and context-independent rescue of deficient fear extinction induced by dietary zinc-restriction was associated with enhanced expression of dopamine-related genes, such as genes encoding the dopamine- D1 (Drd1a) and -D2 (Drd2) receptor in the medial prefrontal cortex (mPFC) and amygdala. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a possibly involved gene regulatory mechanism. While enhancing histone acetylation, via administering the HDAC inhibitor MS275, does not induce successful fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated. This was associated with enhanced neuronal histone acetylation in 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. Conclusion: 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.

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