Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits

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Abstract

Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression and fear reinstatement. These findings demonstrate that a dopamine-dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders.

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Natsuko Hitora-Imamura

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Yuki Miura

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Chie Teshirogi

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Yuji Ikegaya

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Norio Matsuki

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Hiroshi Nomura

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States

For correspondence
h-nomu@umin.ac.jp

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments were approved by the animal experiment ethics committee at The University of Tokyo (approval number 24-10) and were in accordance with The University of Tokyo guidelines for the care and use of laboratory animals. All surgery was performed under xylazine and pentobarbital anesthesia, and every effort was made to minimize suffering.

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