Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits.

Natsuko Hitora-Imamura,Yuji Ikegaya,Chie Teshirogi,Norio Matsuki,Hiroshi Nomura,Yuki Miura

doi:10.7554/elife.08274

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.

Highlights

Anxiety disorders are often treated with cognitive-behavioural interventions such as exposure therapy (McNally, 2007; Vervliet et al, 2013)
We found that a reminder shock decreased infralimbic cortex (IL) and ventral intercalated amygdala neurons (ITCs) activity and increased central nucleus of the amygdala (CeM) activity as indexed by c-Fos expression
We found that a reminder shock activated IL-projecting dopaminergic neurons in the ventral tegmental area (VTA), and the blocking of IL D1 receptors (D1Rs) signalling prevented reduction of synaptic inputs, activity changes of ventral ITC and CeM, as well as fear reinstatement

Summary

Introduction

Anxiety disorders are often treated with cognitive-behavioural interventions such as exposure therapy (McNally, 2007; Vervliet et al, 2013). Fear conditioning and extinction are used in animal models of anxiety disorders and their treatment (Davis, 2002). Many studies have shown that the infralimbic cortex (IL) is a critical brain region for extinction (Herry et al, 2010; Sotres-Bayon and Quirk, 2010). The IL inhibits the medial subdivision of the central nucleus of the amygdala (CeM), a key region for fear expression (Wilensky et al, 2006; Ciocchi et al, 2010), partly through intercalated amygdala neurons (ITCs) (Likhtik et al, 2008; Amano et al, 2010), which are necessary for extinction

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Conclusion