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Neurons in medial prefrontal cortex signal memory for fear extinction

Milad, Mohammed R., Quirk, Gregory J.·2002·Nature

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Abstract

Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.

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Background
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Influential
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“…recordings performed in the PL and IL identified neurons whose activity correlated with fear expression and inhibition, respectively (Herry and Garcia, 2002; Milad and Quirk, 2002; Milad et al., 2004; Vidal-Gonzalez et al., 2006; Burgos-Robles et al., 2007, 2009; Courtin et al., 2014).”
Background
Differential effects of infralimbic vs. ventromedial orbital PFC lidocaine infusions in CD-1 mice on defensive responding in the mouse defense test battery and rat exposure test
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“Growing evidence supports the idea that the medial prefrontal cortex, and particularly the infralimbic area (IL), is a key structure in controlling the behavioral and neural responses to aversive or stressful stimuli (Milad & Quirk, 2002; Morgan et al., 2003; Amat et al., 2005).”
Background
Serotonergic neuromodulation of synaptic plasticity
Higa, G. S. V., Viana, F. J. C., Francis-Oliveira, J., Cruvinel, E., Franchin, T. S., Marcourakis, T., Ulrich, H., & De Pasquale, R. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110036 · Cited by 29
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Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic Pathway
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“The lack of a freezing behavior has been reported in sheep and in deer infected with scrapie (38), presumably reflecting a malfunction of the prefrontal cortex (25).”
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“The observation of imbalanced activity in the amygdala–vmPFC network in anxious individuals is consistent with a variety of work in animals (28, 29), in humans (30–34), and in childhood and adolescent mood and anxiety disorders (35, 36), implicating an inverse relationship between these structures that governs affecti…”
Extinction Generates Outcome-Specific Conditioned Inhibition.
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Predictable Chronic Mild Stress during Adolescence Promotes Fear Memory Extinction in Adulthood
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Neural activity in functional movement disorders after inpatient rehabilitation
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Dorsal Hippocampus to Infralimbic Cortex Circuit is Essential for the Recall of Extinction Memory
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Inhibitory circuits in fear memory and fear-related disorders
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“Furthermore, the IL-PFC was involved in the suppression of fear memory via their excitatory projection to the BLA and GABAergic ITC clusters, which can limit the activation of the CeM output (Milad and Quirk, 2002).”
BackgroundResult
The effect of repetitive transcranial magnetic stimulation on fear extinction in rats.
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“We also modified the commercial TMS apparatus for use on smaller rats, but the coil size was still too large to focus on the vmPFC, which is possibly implicated in consolidation, retention, and expression of extinction memory (Quirk et al., 2000; Milad and Quirk, 2002; Morgan et al., 2003; Milad et al., 2004; Santini…”
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Enhance, delete, incept: Manipulating hippocampus-dependent memories
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“Rather, extinction likely involves the active suppression of a still intact fear memory by regions of the brain distinct from where the original fear memory is stored (Milad and Quirk, 2002).”
Neural correlates of and processes underlying generalized and differential return of fear
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“…for its role in fear inhibition during extinction recall (Kalisch et al., 2006; Milad et al., 2007; Lonsdorf et al., 2014) and safety processing (Milad and Quirk, 2002), a reduction of vmPFC activation in our study might be indicative of RI-induced ‘release from inhibition’ specifically for the…”
Background
Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fearPreprint
Criado‐Marrero, M., Silva, R. J. M., Velázquez, B., Hernández, A., Colon, M., Cruz, E., Soler‐Cedeño, O., & Porter, J. T. (2017) · Learning & Memory · doi:10.1101/lm.043000.116 · Cited by 32
“In this study, we focused on the infralimbic (IL) and the prelimbic cortexes (PL) since these regions of the mPFC play a prominent role in the control of fear conditioning and extinction (Milad and Quirk 2002, 2012; Sierra-Mercado et al. 2011; Giustino and Maren 2015).”
BackgroundMethod
Prelimbic and infralimbic medial prefrontal cortex neuron activity signals cocaine seeking variables across multiple timescales
Moorman, D. E., & Aston‐Jones, G. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06287-2 · Cited by 31
“2008) and in extinction of fear conditioning (Milad and Quirk 2002), we expected to see enhanced IL activity during extinction.”
Background
Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study
Tose, K., Takamura, T., Isobe, M., Hirano, Y., Sato, Y., Kodama, N., Yoshihara, K., Maikusa, N., Moriguchi, Y., Noda, T., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02378-4 · Cited by 34
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Dulka, B. N., Bress, K. S., Grizzell, J. A., & Cooper, M. A. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.07.042 · Cited by 27
“It is also well established that neural activity specifically within the IL is required for the formation of an extinction memory (Milad and Quirk, 2002; Milad et al., 2004).”
Background
Altered functional connectivity in the fear network of firefighters with repeated traumatic stress
Jeong, H. S., Park, S., Dager, S. R., Lim, S. M., Lee, S. L., Hong, H., Ma, J., Ha, E., Hong, Y. S., Kang, I., et al. (2018) · The British Journal of Psychiatry · doi:10.1192/bjp.2018.260 · Cited by 28
Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive Onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Male Rats
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Individual Differences in Conditioned Fear and Extinction in Female Rats
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NMDA Receptor Blockade in the Prelimbic Cortex Activates the Mesolimbic System and Dopamine-Dependent Opiate Reward Signaling
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“associative memories (Peters et al. 2008; Milad and Quirk 2002), we have reported previously that sub-populations of neurons within the PLC are involved in the acquisition and recall phases of morphine-related associative learning, and show strongly increased activity specifically during the acquisition and recall of…”
Background
Dissociating Value Representation and Inhibition of Inappropriate Affective Response during Reversal Learning in the Ventromedial Prefrontal Cortex
Zhang, Z., Mendelsohn, A., Manson, K. F., Schiller, D., & Levy, I. (2015) · eNeuro · doi:10.1523/eneuro.0072-15.2015 · Cited by 29
“, 2000), and vmPFC neurons only responded to a conditioned stimulus during a delayed test of extinction (Milad and Quirk, 2002).”
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Contextual fear conditioning depresses infralimbic excitability
Soler‐Cedeño, O., Cruz, E., Criado‐Marrero, M., & Porter, J. T. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.01.015 · Cited by 29
“Although IL is more known for its role in the extinction of fear memory (Milad and Quirk, 2002; Vidal-Gonzalez et al., 2006; Burgos-Robles et al., 2007), a recent study suggests that IL contributes to the contextual discrimination of fear conditioning memory (Zelikowsky et al., 2013).”
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The role of human orbitofrontal cortex in reward prediction and behavioral choice: insights from neuroimaging
O’Doherty, J. P., & Dolan, R. J. (2006) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780198565741.003.0010 · Cited by 28
Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine
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“However, exposure therapy is effective in the short term and does not modify the original memory trace (Bouton 1993; Milad and Quirk 2002).”
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Switching From Fear to No Fear by Different Neural Ensembles in Mouse Retrosplenial Cortex
Wang, G., Xie, H. B., Wang, L., Luo, W., Wang, Y., Jiang, J., Xiao, C. L., Feng, X., & Guan, J. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz050 · Cited by 29
Possible relationship between the stress‐induced synaptic response and metaplasticity in the hippocampal CA1 field of freely moving rats
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Exposure Therapy for Post-Traumatic Stress Disorder: Factors of Limited Success and Possible Alternative Treatment
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Competing Visions of the Implications of Neuroscience for Psychotherapy
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“Whereas the long-term memory of a learned fear is stored in the amygdala itself ( Maren, 1999a , 1999b ), a subsequent, counteractive learning is stored elsewhere, in a particular region of the cortex ( Milad & Quirk, 2002 ; Phelps, Delgado, Nearing and LeDoux 2004 ; Quirk, Likhtik, Pelletier & Pare, 2003 ).”
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Altered resting-state brain activity at functional MRI during automatic memory consolidation of fear conditioning
Feng, T., Feng, P., & Chen, Z. (2013) · Brain Research · doi:10.1016/j.brainres.2013.05.039 · Cited by 27
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Authors: Milad, M. R., & Quirk, G. J.
Affiliations: Ponce Health Sciences University (PR)
Corresponding author: Quirk, Gregory J.
ORCID: Milad, Mohammed R.
Quirk, Gregory J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2002-11
Volume: 420
Issue: 6911
Pages: 70-74
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature01138
OpenAlex: W1989045560
Cited by: 1,836
References: 30
Citations by year: 2026: 40 · 2025: 55 · 2024: 73 · 2023: 59 · 2022: 58 · 2021: 82 · 2020: 75 · 2019: 88 · 2018: 90 · 2017: 80 · 2016: 102 · 2015: 95 · 2014: 95 · 2013: 121 · 2012: 88
FWCI: 23.32
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Science Foundation
National Institute of Mental Health
National Institute of General Medical Sciences
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: fear extinction, medial prefrontal cortex, infralimbic cortex, prelimbic cortex, memory extinction, fear conditioning, memory consolidation, neuronal firing, electrical stimulation, freezing behavior, rats
MeSH terms: Acoustic Stimulation, Animals, Conditioning, Classical, Electroshock, Extinction, Psychological, Fear, Male, Memory, Neurons, Sound, Rats, Sprague-Dawley, Prefrontal Cortex, Rats

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Neurons in medial prefrontal cortex signal memory for fear extinction

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