Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

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,...

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Bibliographic Details
Published in:	Translational psychiatry Vol. 6; no. 12; p. e974
Main Authors:	Whittle, N, Maurer, V, Murphy, C, Rainer, J, Bindreither, D, Hauschild, M, Scharinger, A, Oberhauser, M, Keil, T, Brehm, C, Valovka, T, Striessnig, J, Singewald, N
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 06-12-2016 Nature Publishing Group
Subjects:	631/154/436 631/378/2584/2585 Amygdala - physiology Animals Behavioral Sciences Benzamides - pharmacology Biological Psychology Combined Modality Therapy Conditioning, Classical - drug effects Conditioning, Classical - physiology Dopamine - physiology Extinction, Psychological - drug effects Extinction, Psychological - physiology Fear - drug effects Fear - physiology Histone Acetyltransferases - physiology Implosive Therapy Levodopa - pharmacology Male Medicine Medicine & Public Health Mice Neurosciences Original original-article Pharmacotherapy Prefrontal Cortex - physiology Psychiatry Pyridines - pharmacology Signal Transduction - drug effects Signal Transduction - physiology
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Summary:	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.
Bibliography:	These authors contributed equally to this work. Present address: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
ISSN:	2158-3188 2158-3188
DOI:	10.1038/tp.2016.231