Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex
Abstract
What brain regions are involved in regulating behavior when the emotional consequence of a stimulus changes from harmful to harmless? One way to address this question is to study the neural mechanisms underlying extinction of Pavlovian fear conditioning, an important form of emotional regulation that has direct relevance to the treatment of human fear and anxiety disorders. In fear extinction, the capacity of a conditioned stimulus to elicit fear is gradually reduced by repeatedly presenting it in the absence of any aversive consequence. In recent years there has been a dramatic increase in research on the brain mechanisms of fear extinction. One region that has received considerable attention as a component of the brain's extinction circuitry is the medial prefrontal cortex (mPFC). In the present article, we review the historical foundations of the modern notion that the mPFC plays a critical role in emotional regulation, a literature that was largely responsible for studies that explored the role of the mPFC in fear extinction. We also consider the role of the mPFC in a broader neural circuit for extinction that includes the amygdala and hippocampus.
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CBT and exposure are thought to be effective by increasing inhibitory control over aversive salience-driven processing, and ABM training may augment their effects by further supporting these processes.
“Both CBT and exposure are thought to be effective by increasing inhibitory control over aversive salience-driven processing [77,78], and ABM training may therefore augment their effects by further supporting these processes.”
From Anxiety and Threat-Related Attention: Cognitive-Motivational Framework and Treatment (2018) · cites this paper as [78]
Fear extinction resulting from threat exposure is thought to depend on increasing the inhibitory effect of frontal brain regions on subcortical (amygdala) regions involved in fear learning and threat-salience evaluation.
“Fear extinction, which results from threat exposure, is thought to depend on increasing the inhibitory effect of frontal brain regions, which support top-down cognitive control, on subcortical (amygdala) regions involved in fear learning and threatsalience evaluation (e.g., Bishop, 2007;Sotres-Bayon, Cain, & LeDoux, 2006).”
From Anxiety and attention to threat: cognitive mechanisms and treatment with attention bias modification (2016) · cites this paper as Sotres-Bayon et al., 2006
The hippocampus has strong reciprocal connections with the mPFC and the amygdala; these three brain regions seem to interactively coordinate the encoding and expression of fear extinction.
“The hippocampus has strong reciprocal connections with the mPFC and the amygdala; these three brain regions seem to interactively coordinate the encoding and expression of fear extinction (Sotres-Bayon et al, 2006).”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Sotres-Bayon et al, 2006
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“Nonetheless, interest in the role of PFC in emotion re-emerged with the discovery that the medial PFC (mPFC) was necessary for extinction of conditioned fear [7,8].”
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- Authors
- Sotres-Bayon, F., Cain, C. K., & LeDoux, J. E.
- Affiliations
- New York University (US)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 60
- Issue
- 4
- Pages
- 329-336
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2085230334
- Cited by
- 433
- References
- 144
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 14 · 2023: 18 · 2022: 16 · 2021: 15 · 2020: 16 · 2019: 18 · 2018: 17 · 2017: 21 · 2016: 21 · 2015: 31 · 2014: 20 · 2013: 27 · 2012: 26
- FWCI
- 17.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f32mh077458-01)
- National Institute of Mental Health (R37MH038774, P50MH058911, R21MH072279, K05MH067048, R01MH046516, F32-MH077458)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- fear extinction, medial prefrontal cortex, fear conditioning, emotion regulation, amygdala, hippocampus, history of neuroscience, anxiety disorders
- MeSH terms
- Animals, Conditioning, Classical, Emotions, Extinction, Psychological, Fear, Humans, Neural Pathways, Prefrontal Cortex, Brain Injury, Chronic, Behavioral Research, History, 19th Century, History, 20th Century, History, 21st Century
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