Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits

Elife. 2015 Jul 30;4:e08274. doi: 10.7554/eLife.08274.


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.

Keywords: dopamine; fear conditioning; fear extinction; infralimbic cortex; mouse; neuroscience; reinstatement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / physiology
  • Animals
  • Dopamine / metabolism*
  • Extinction, Psychological / drug effects*
  • Fear*
  • Male
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Prefrontal Cortex / physiology
  • Reinforcement, Psychology*
  • Ventral Tegmental Area


  • Dopamine

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.