title: Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits.
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.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hitora-Imamura
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Teshirogi
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuki
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0002-6172-4788
authors.initials: H
authors.lastname: Nomura
mesh_terms: D000679:Amygdala / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology; D012054:Reinforcement, Psychology; D017557:Ventral Tegmental Area
chemical_list: D004298:Dopamine
keywords: dopamine; fear conditioning; fear extinction; infralimbic cortex; mouse; neuroscience; reinstatement