Cited by 1,836Memory and Neural MechanismsMemory Processes and InfluencesNeuroscience and Neuropharmacology Research

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

Neurons in medial prefrontal cortex signal memory for fear extinction

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/nature01138

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Emotion circuits in the brain
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444
The endogenous cannabinoid system controls extinction of aversive memories
Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascio, M. G., Hermann, H., Tang, J., Hofmann, C., Zieglgänsberger, W., et al. (2002) · Nature · doi:10.1038/nature00839 · Cited by 1,728
Integrative activity of the brain
Konorski, J. (1967) · Cited by 1,372
The neuroanatomical and neurochemical basis of conditioned fear
Fendt, M., & Fanselow, M. S. (1999) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(99)00016-0 · Cited by 1,092
The role of ventromedial prefrontal cortex in the recovery of extinguished fear
Quirk, G. J., Russo, G. K., Barron, J. L., & Lebron, K. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-16-06225.2000 · Cited by 957 · cited 2×
“ANOVA showed a highly significant main effect of group (F (2,29) 1⁄4 16.”
BackgroundMethodSelf-citation
Extinction of emotional learning: contribution of medial prefrontal cortex
Morgan, M. A., Romanski, L. M., & LeDoux, J. E. (1993) · Neuroscience Letters · doi:10.1016/0304-3940(93)90241-c · Cited by 897 · cited 1×
“Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinctio”
Background
Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: Parallel recordings in the freely behaving rat
Quirk, G. J., Repa, J. C., & LeDoux, J. E. (1995) · Neuron · doi:10.1016/0896-6273(95)90092-6 · Cited by 808
Self-citation
Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study
Bremner, J. D., Staib, L. H., Kaloupek, D. G., Southwick, S. M., Soufer, R., & Charney, D. S. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00297-2 · Cited by 727
Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats.
Morgan, M. A., & LeDoux, J. E. (1995) · Behavioral Neuroscience · doi:10.1037/0735-7044.109.4.681 · Cited by 717
Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat
McDonald, A. J., Mascagni, F., & Guo, L. (1996) · Neuroscience · doi:10.1016/0306-4522(95)00417-3 · Cited by 689

Flagged first, then by citations

Show all 30 references

Research works printed but not linked: 1

Pavlov, I. P. Conditioned Reflexes (Oxford Univ. Press, London, 1927)

Sorted by citations

Items 801–900 of 1,010

Emotional learning, stress, and development: An ever-changing landscape shaped by early-life experience
Pattwell, S. S., & Bath, K. G. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.04.014 · Cited by 51
“…cortex (vmPFC), in particular, has been shown to be important for making the switch from fear expression to fear inhibition during fear extinction learning and retention of extinction memory (Milad & Quirk, 2002; Pare, Quirk, & Ledoux, 2004; Santini, Ge, Ren, Pena de Ortiz, & Quirk, 2004).”
Background
Involvement of microglia in disturbed fear memory regulation: Possible microglial contribution to the pathophysiology of posttraumatic stress disorder
Enomoto, S., & Kato, T. A. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104921 · Cited by 43
A arte de esquecer
Izquierdo, I., Bevilaqua, L. R., & Cammarota, M. (2006) · Estudos Avançados · doi:10.1590/s0103-40142006000300024 · Cited by 43
Dopamine D1 sensitivity in the prefrontal cortex predicts general cognitive abilities and is modulated by working memory trainingPreprint
Wass, C., Pizzo, A., Sauce, B., Kawasumi, Y., Sturzoiu, T., Ree, F., Otto, T., & Matzel, L. D. (2013) · Learning & Memory · doi:10.1101/lm.031971.113 · Cited by 43
Development switch in neural circuitry underlying odor-malaise learningPreprint
Shionoya, K., Moriceau, S., Lunday, L., Miner, C. A., Roth, T. L., & Sullivan, R. M. (2006) · Learning & Memory · doi:10.1101/lm.316006 · Cited by 43
Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits
HitoraーImamura, N., Miura, Y., Teshirogi, C., Ikegaya, Y., Matsuki, N., & Nomura, H. (2015) · eLife · doi:10.7554/elife.08274 · Cited by 43
The stressed female brain: neuronal activity in the prelimbic but not infralimbic region of the medial prefrontal cortex suppresses learning after acute stress
Maeng, L. Y., & Shors, T. J. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00198 · Cited by 45
“In contrast, neuronal activity within the IL is critical for inhibiting conditioned fear after the animal has undergone extinction (Milad and Quirk, 2002; Lebrón et al., 2004; Vidal-Gonzalez et al., 2006; Sierra-Mercado et al., 2011).”
Background
Behavioural and neuroplastic properties of chronic lurasidone treatment in serotonin transporter knockout rats
Luoni, A., Hulsken, S., Cazzaniga, G., Racagni, G., Homberg, J. R., & Riva, M. A. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712001332 · Cited by 42
“Moreover, based on the role of the PFC and BDNF in fear extinction (Milad and Quirk, 2002) and considering the impaired expression of the neurotrophin in the PFC of SERTx/x rats (Molteni et al.”
Low-Frequency Stimulation Depresses the Primate Anterior-Cingulate-Cortex and Prevents Spontaneous Recovery of Aversive Memories
Klavir, O., Genud-Gabai, R., & Paz, R. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6481-11.2012 · Cited by 43
“In principle, attenuation of spontaneous recovery could be achieved by affecting the strength of extinction (Milad and Quirk, 2002; Sierra-Mercado et al., 2011), or of the original memory.”
BackgroundInfluential
Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear
Chai, N., Liu, J., Xue, Y.-X., Yang, C., Yan, W., Wang, H.-M., Luo, Y., Shi, H., Wang, J.-S., Bao, Y., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.42 · Cited by 41
“It has been suggested to encode contextual specificity to regulate extinction memory (Ji and Maren, 2007; SotresBayon et al, 2012), whereas extinction memory might be encoded in the prefrontal cortex (Milad and Quirk, 2002; Morgan and LeDoux, 1999; Quirk, 2002; Quirk et al, 2006; Quirk et al, 2000).”
Background
Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD
Girgenti, M. J., Hare, B. D., Ghosal, S., & Duman, R. S. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0841-3 · Cited by 45
A Rodent Model of Exposure Therapy: The Use of Fear Extinction as a Therapeutic Intervention for PTSD
Paredes, D., & Morilak, D. A. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00046 · Cited by 44
“Fear extinction is a form of safety learning that consists of the formation of a new memory in the ventromedial PFC (vmPFC; Milad and Quirk, 2002).”
Background
Diminished Fear Extinction in Adolescents Is Associated With an Altered Somatostatin Interneuron–Mediated Inhibition in the Infralimbic Cortex
Koppensteiner, P., Itter, R. V., Melani, R., Galvin, C., Lee, F. S., & Ninan, I. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.04.035 · Cited by 44
Functional and Optogenetic Approaches to Discovering Stable Subtype-Specific Circuit Mechanisms in Depression
Grosenick, L., Shi, T. C., Gunning, F. M., Dubin, M. J., Downar, J. H., & Liston, C. M. (2018) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2019.04.013 · Cited by 43
Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitability and Seizure Susceptibility
Yoo, Y.-E., Yoo, T., Lee, S., Lee, J., Kim, D., Han, H.-M., Bae, Y.-C., & Kim, E. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00155 · Cited by 41
Infralimbic cortex controls fear memory generalization and susceptibility to extinction during consolidation
Bayer, H., & Bertoglio, L. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-72856-0 · Cited by 42
Predicting clinical outcomes via human fear conditioning: A narrative review.
Scheveneels, S., Boddez, Y., & Hermans, D. (2021) · Behaviour Research and Therapy · doi:10.1016/j.brat.2021.103870 · Cited by 38
Neural reinstatement reveals divided organization of fear and extinction memories in the human brain
Hennings, A. C., McClay, M., Drew, M. R., Lewis‐Peacock, J. A., & Dunsmoor, J. E. (2021) · Current Biology · doi:10.1016/j.cub.2021.11.004 · Cited by 48
Dissociation of Extinction and Behavioral Disinhibition: The Role of NMDA Receptors in the Pigeon Associative Forebrain during Extinction
Lissek, S., & Güntürkün, O. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-22-08119.2003 · Cited by 42
“A recent study demonstrated that the constitution of extinction memory results in cellular prefrontal activations correlated with the recall of extinction (Milad and Quirk, 2002).”
Background
Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: Implications for mood disorders
Stan, A. D., Schirda, C. V., Bertocci, M. A., Bebko, G. M., Kronhaus, D. M., Aslam, H. A., LaBarbara, E. J., Tanase, C., Lockovich, J. C., Pollock, M. H., et al. (2014) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2014.05.016 · Cited by 35
“…the main inhibitory brain neurotransmitter, critically influence prefrontal cortical and ACC function (Buzsaki et al., 2007; Markram et al., 2004; Milad and Quirk, 2002; Milad et al., 2007; Northoff et al., 2002; Palomero-Gallagher et al., 2008), in the present study we chose to focus on roles…”
Background
Neural response to reward anticipation in those with depression with and without panic disorder
Gorka, S. M., Huggins, A. A., Fitzgerald, D. A., Nelson, B. D., Phan, K. L., & Shankman, S. A. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.04.019 · Cited by 48
“Although the mechanisms underlying these findings are still unclear, evidence indicates that the dACC is involved in the expression of fear, which is why damage/abnormalities in this region may cause or maintain PD (Milad and Quirk, 2002; Phelps et al., 2004).”
Background
Impact of infralimbic inputs on intercalated amygdala neurons: A biophysical modeling studyPreprint
Li, G., Amano, T., Paré, D., & Nair, S. S. (2011) · Learning & Memory · doi:10.1101/lm.1938011 · Cited by 47
Behavioral and paired-pulse facilitation analyses of long-lasting depression at excitatory synapses in the medial prefrontal cortex in mice
Herry, C., & Garcia, R. (2003) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.09.017 · Cited by 41
Activated Tryptophan-Kynurenine metabolic system in the human brain is associated with learned fear
Battaglia, M. R., Fazio, C. D., & Battaglia, S. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1217090 · Cited by 40
“In an experimental context, fear learning involves a type of learning where a previously neutral stimulus is repeatedly paired with an aversive stimulus, eliciting a fear response (Maren, 2001; Bouton, 2002; Milad and Quirk, 2002; Schiller et al., 2008; Lonsdorf et al., 2017).”
Background
The downside of strong emotional memories: How human memory-related genes influence the risk for posttraumatic stress disorder – A selective review
Wilker, S., Elbert, T. R., & Kolassa, I. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.08.015 · Cited by 44
“Extinction learning, and particularly extinction memory retention, depends on the medial prefrontal cortex, which regulates fear expression via inhibitory projections to the amygdala (Milad & Quirk, 2002; Quirk, Garcia, & Gonzalez Lima, 2006).”
Layer- and subregion-specific differences in the neurophysiological properties of rat medial prefrontal cortex pyramidal neurons
Song, C., & Moyer, J. R. (2017) · Journal of Neurophysiology · doi:10.1152/jn.00146.2017 · Cited by 44
The role of prefrontal–subcortical circuitry in negative bias in anxiety: Translational, developmental and treatment perspectives
Carlisi, C. O., & Robinson, O. J. (2018) · Brain and Neuroscience Advances · doi:10.1177/2398212818774223 · Cited by 48
“, 2014), while fear extinction also enhances activity in BLA projections up to the IL (Milad and Quirk, 2002; Senn et al., 2014).”
Background
Lateral, not medial, prefrontal cortex contributes to punishment and aversive instrumental learningPreprint
Jean-Richard-dit-Bressel, P., & McNally, G. P. (2016) · Learning & Memory · doi:10.1101/lm.042820.116 · Cited by 45
“…expression of Pavlovian fear responses (Corcoran and Quirk 2007; Courtin et al. 2013a,b; Senn et al. 2014; Do-monte et al. 2015) and IL suppresses these responses after inhibitory treatments such as extinction (Milad and Quirk 2002; Quirk et al. 2006; Santini et al. 2008; Senn et al. 2014).”
Background
Anxious to see you: Neuroendocrine mechanisms of social vigilance and anxiety during adolescence
Wright, E. C., Hostinar, C. E., & Trainor, B. C. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14628 · Cited by 55
“For example, increased activity in the infralimbic cortex is important for the extinction of conditioned fear responses (Chang, Berke, & Maren, 2010; Holmes et al., 2012; Milad & Quirk, 2002).”
Background
PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction
Chen, Y., Hu, N.-Y., Wu, D., Bi, L., Luo, Z.-Y., Huang, L., Wu, J., Wang, M., Li, J., Song, Y., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01355-z · Cited by 40
Early Interventions to Prevent Post-Traumatic Stress Disorder in Youth after Exposure to a Potentially Traumatic Event: A Scoping Review
Kerbage, H., Bazzi, O., El‐Hage, W., Corruble, E., & Purper‐Ouakil, D. (2022) · Healthcare · doi:10.3390/healthcare10050818 · Cited by 40
Chronic pain, chronic stress and substance use: overlapping mechanisms and implications
Schaffer, J., Fogelman, N., Seo, D., & Sinha, R. (2023) · Frontiers in Pain Research · doi:10.3389/fpain.2023.1145934 · Cited by 43
“Flexible and adaptive VmPFC function is necessary to “turn off” stress once fearful stimuli are gone (88, 89), and impaired VmPFC function is observed in patients with post-traumatic stress disorder (90).”
Background
A Flight Simulator Study of the Impairment Effects of Startle on Pilots During Unexpected Critical Events
Martin, W., Murray, P. S., Bates, P. R., & Lee, P. S. Y. (2016) · Aviation Psychology and Applied Human Factors · doi:10.1027/2192-0923/a000092 · Cited by 44
Chronic stress, cortical plasticity and neuroecology
Reser, J. E. (2016) · Behavioural Processes · doi:10.1016/j.beproc.2016.06.010 · Cited by 43
A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults
Zabik, N. L., Iadipaolo, A. S., Marusak, H. A., Peters, C., Burghardt, K. J., & Rabinak, C. A. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24860 · Cited by 44
“Previous animal work suggests that activation of fear- related brain regions is strongest during early phases of learning (i.e., early extinction learning and extinction recall (see Milad & Quirk, 2002; Milad, Wright, et al., 2007).”
Background
Ability of predator odour exposure to elicit conditioned versus sensitised post traumatic stress disorder-like behaviours, and forebrain ΔFosB expression, in rats
Mackenzie, L., Nalivaiko, E., Beig, M. I., Day, T. A., & Walker, F. R. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.05.005 · Cited by 44
The extinction of conditioned fear: structural and molecular basis and therapeutic use
Cammarota, M., Bevilaqua, L. R., Vianna, M. R. M. R., Medina, J. H., & Izquierdo, I. (2006) · Brazilian Journal of Psychiatry · doi:10.1590/s1516-44462006005000022 · Cited by 42
“The “center for extinction”? As mentioned, a number of studies indicate that the ventromedial prefrontal cortex may be crucial for extinction in several animal species [21,39,54].(24,35,38-40,53) The ventromedial”
Background
A magnetic resonance imaging study of cortical thickness in animal phobia
Rauch, S. L., Wright, C. I., Martis, B., Busa, E., McMullin, K. G., Shin, L. M., Dale, A. M., & Fischl, B. R. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2003.12.022 · Cited by 42
“Infralimbic prefrontal cortex plays a critical role in modulating the amygdala response to threatening stimuli (such as via extinction; Milad and Quirk 2002; Morgan and LeDoux 1995).”
Background
Impact of predatory threat on fear extinction in Lewis ratsPreprint
Goswami, S., Cascardi, M. A., Rodríguez-Sierra, O. E., Duvarci, S., & Paré, D. (2010) · Learning & Memory · doi:10.1101/lm.1948910 · Cited by 43
“In one study, for instance, the propensity of different strains of rats to develop extreme behavioral manifestations of anxiety (EBMAs) as a result of predatory threat has been characterized, revealing that a much higher proportion (50”
Background
Transitional and translational studies of risk for anxiety
Casey, B. J., Ruberry, E. J., Libby, V., Glatt, C. E., Hare, T. A., Soliman, F., Duhoux, S., Frielingsdorf, H., & Tottenham, N. (2011) · Depression and Anxiety · doi:10.1002/da.20783 · Cited by 40
“The observation of imbalanced activity in the amygdala–vPFC network, as shown by elevated amygdala and less vmPFC activity in high anxious individuals, is consistent with a variety of work in animals,([38,39]) humans, and in childhood and adolescent mood and anxiety disorders,([28,45]) implicating an inverse relations…”
Mild traumatic brain injury reduces spine density of projection neurons in the medial prefrontal cortex and impairs extinction of contextual fear memory
Zhao, J., Huynh, J., Hylin, M. J., O'Malley, J. J., Perez, A., Moore, A. N., & Dash, P. K. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2016.4898 · Cited by 39
Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology
Hudson, R., Rushlow, W. J., & Laviolette, S. R. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4766-7 · Cited by 40
“The prefrontal cortex is responsible for suppressing memory recall for aversive events and for increasing the rate of extinction for emotional memories (Depue et al. 2007; Milad and Quirk 2002).”
Background
Modulating reconsolidation and extinction to regulate drug reward memory
Liu, J., Tian, J., & Li, J. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14072 · Cited by 42
“Similar to the learning process, extinction also involves conditioning/acquisition, consolidation, retrieval, reconsolidation and storage (Quirk et al., 2000; Milad & Quirk, 2002; Burgos-Robles et al., 2007; Furini et al., 2014; Raio et al., 2014; Radiske et al., 2015).”
Background
Neuroepigenetics of Post-Traumatic Stress Disorder
Kim, G. S., Smith, A. K., Nievergelt, C. M., & Uddin, M. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2018.04.001 · Cited by 37
The Role of the Medial Prefrontal Cortex in Regulating Social Familiarity-Induced Anxiolysis
Lungwitz, E. A., Stuber, G. D., Johnson, P. L., Dietrich, A. D., Schartz, N. D., Hanrahan, B., Shekhar, A., & Truitt, W. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.302 · Cited by 39
“The rodent and human mPFC are implicated in both social processing and cortical regulation of anxiety/fear, making it a compelling target as the cortical site for regulation of SFiA (Adolphs, 2010; Fossati, 2012; Hartley and Phelps, 2010; Meyer-Lindenberg and Tost, 2012; Milad and Quirk, 2002; van Kerkhof et al, 2013a…”
BackgroundInfluential
The interaction of disrupted Type II Neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors
Taylor, S. B., Taylor, A. R., & Koenig, J. I. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.09.045 · Cited by 38
“Extinction of cue-conditioned fear memory is PFC-mediated (Morgan and LeDoux, 1995; Quirk et al., 2000; Milad and Quirk, 2002).”
Background
Extinction and Latent Inhibition Involve a Similar Form of Inhibitory Learning that is Stored in and Retrieved from the Infralimbic Cortex
Lingawi, N. W., Westbrook, R. F., & Laurent, V. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw322 · Cited by 38
The rostroventral part of the thalamic reticular nucleus modulates fear extinction
Lee, J.-H., Latchoumane, C., Park, J., Kim, J., Jeong, J., Lee, K.-H., & Shin, H.-S. (2019) · Nature Communications · doi:10.1038/s41467-019-12496-9 · Cited by 33
Depotentiation of Symptom-Producing Implicit Memory in Coherence Therapy
Ecker, B., & Toomey, B. (2008) · Journal of Constructivist Psychology · doi:10.1080/10720530701853685 · Cited by 43
“The latter forms a separate, second learning that competes against, but does not change, the original conditioned response (see, e.g., Bouton, 2004; Milad & Quirk, 2002; Milner, Squire, & Kandel, 1998; Myers & Davis, 2002).”
Background
Extinction-induced Neuroplasticity Attenuates Stress-induced Cocaine Seeking: A State-dependent Learning Hypothesis
Self, D. W., & Choi, K.-H. (2004) · Stress · doi:10.1080/10253890400012677 · Cited by 38
“…appetitive rewards like sucrose, and several recent studies suggest that neuroplasticity encoding extinction learning may involve the prefrontal cortex itself as discussed earlier (Quirk et al., 2000; Herry and Garcia, 2002; Milad and Quirk, 2002; Barrett et al., 2003; Lissek and Gunturkun, 2003).”
Background
Abnormal medial prefrontal cortex connectivity and defective fear extinction in the presymptomatic G93A SOD1 mouse model of ALS
Sgobio, C., Trabalza, A., Spalloni, A., Zona, C., Carunchio, I., Longone, P., & Ammassari‐Teule, M. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00367.x · Cited by 38
“…that mPFC regions govern response flexibility, that is, the capa- bility of forming new associations inhibiting those formerly established, largely derives from evidence implicating PL/IL neurons in extinction of conditioned fear (Milad & Quirk 2002; Morgan et al. 1993; Quirk et al. 2006).”
Background
A genome-wide panel of congenic mice reveals widespread epistasis of behavior quantitative trait loci
Gale, G., Yazdi, R. D., Khan, A. H., Lusis, A. J., Davis, R. C., & Smith, D. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.4 · Cited by 38
C57BL/6J and DBA/2J mice differ in extinction and renewal of extinguished conditioned fear.
Waddell, J., Dunnett, C., & Falls, W. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.03.025 · Cited by 44
Adaptive contextualization: a new role for the default mode network in affective learning
Marstaller, L., Burianová, H., & Reutens, D. C. (2017) · Human Brain Mapping · doi:10.1002/hbm.23442 · Cited by 37
“In humans, neuroimaging studies have provided evidence for a similar neural mechanism of safety learning by demonstrating increased vmPFC activity during extinction [Kalisch et al., 2006; Milad and Quirk, 2010].”
Background
Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development
Lori, A., Schultebraucks, K., Galatzer‐Levy, I. R., Daskalakis, N. P., Katrinli, Ş., Smith, A. K., Myers, A., Richholt, R., Huentelman, M. J., Guffanti, G., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01073-8 · Cited by 38
Role of the basolateral amygdala and NMDA receptors in higher-order conditioned fear
Parkes, S. L., & Westbrook, R. F. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.025 · Cited by 40
“…extinction can be enhanced by manipulations that increase IL function, for example, long-term potentiation of the thalamo-mPFC (Herry and Garcia , 2002 ) or the hippocampal-mPFC (Farinelli et al. , 2006 ) pathways or local microstimulation of the IL (Milad and Quirk , 2002 ; Milad et al. , 2004 ).”
Background
Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation
Reznikov, R., & Hamani, C. (2016) · Neuromodulation Technology at the Neural Interface · doi:10.1111/ner.12551 · Cited by 38
“stimulation varied according to the timing of current delivery and target (53,99).”
Background
Neural activity in the prelimbic and infralimbic cortices of freely moving rats during social interaction: Effect of isolation rearing
Minami, C., Shimizu, T., & Mitani, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0176740 · Cited by 42
Altering gain of the infralimbic-to-accumbens shell circuit alters economically dissociable decision-making algorithms
Sweis, B. M., Larson, E. B., Redish, A. D., & Thomas, M. J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803084115 · Cited by 37
Differential fear conditioning generates prefrontal neural ensembles of safety signals
Corches, A., Hiroto, A., Bailey, T. W., Speigel, J. H., Pastore, J., Mayford, M. R., & Korzus, E. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.11.042 · Cited by 39
“demonstrated that the CS-evoked responses in the IL coincide with learned fear suppression [27].”
Methylene blue facilitates the extinction of fear in an animal model of susceptibility to learned helplessness
Wrubel, K. M., Barrett, D. W., Shumake, J., Johnson, S. E., & Gonzalez-Lima, F. (2006) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2006.08.009 · Cited by 37
The inhibition of acquired fear
Izquierdo, I., Cammarota, M., Vianna, M. R. M. R., & Bevilaqua, L. R. (2004) · Neurotoxicity Research · doi:10.1007/bf03033220 · Cited by 38
“In addition, pairing of the tone CS with brief electrical stimulation of this region, mimicks extinction in the sense that it reduces freezing responses (CRs) in animals that had not been extinguished ( Milad and Quirk, 2002 ).”
Background
Lorazepam in catatonia – Past, present and future of a clinical success story
Hirjak, D., Fricchione, G., Wolf, R. C., & Northoff, G. (2024) · Schizophrenia Research · doi:10.1016/j.schres.2023.02.015 · Cited by 36
Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning
Paydar, A., Lee, B., Gangadharan, G., Lee, S., Hwang, E. M., & Shin, H.-S. (2014) · Molecular Brain · doi:10.1186/1756-6606-7-39 · Cited by 37
“GABA has an essential role in fear extinction through modulating cellular activities in the amygdala, medial prefrontal cortex (mPFC), and hippocampus, key structures involved in fear extinction [3,6-12].”
Background
A theory of the neural mechanisms underlying negative cognitive bias in major depression
Jiang, Y. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1348474 · Cited by 43
Re-emergence of extinguished auditory-cued conditioned fear following a sub-conditioning procedure: Effects of hippocampal and prefrontal tetanic stimulations
Deschaux, O., Motanis, H., Spennato, G., Moreau, J., & Garcia, R. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.03.002 · Cited by 36
Dysfunction in amygdala–prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability
Fragale, J. E. C., Khariv, V., Gregor, D. M., Smith, I. M., Jiao, X., Elkabes, S., Servatius, R. J., Pang, K. C. H., & Beck, K. D. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.11.002 · Cited by 39
“Extinction of conditioned fear is primarily mediated by the infralimbic (IL) cortex, a subregion of the PFC (Laurent and Westbrook, 2009; Milad and Quirk, 2002; SierraMercado et al., 2011).”
Background
Extinction and Retrieval + Extinction of Conditioned Fear Differentially Activate Medial Prefrontal Cortex and Amygdala in Rats
Lee, H. J., Haberman, R. P., Roquet, R. F., & Monfils, M. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00369 · Cited by 36
“The involvement of these brain structures intensified in the 10 CSs group, suggesting the continued and increasing engagement of the IL as extinction processes were recruited (in line with previously reported findings from the literature, Quirk et al., 1997; Milad and Quirk, 2002; Knapska and Maren, 2009; Do-Monte et…”
Result
Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation
Thome, J., Koppe, G., Hauschild, S., Liebke, L., Schmahl, C. G., Lis, S., & Bohus, M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161044 · Cited by 38
Fear Expression Suppresses Medial Prefrontal Cortical Firing in Rats
Giustino, T. F., Fitzgerald, P. J., & Maren, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165256 · Cited by 41
Optogenetic Activation of the Infralimbic Cortex Suppresses the Return of Appetitive Pavlovian-Conditioned Responding Following Extinction
Villaruel, F. R., Lacroix, F., Sanio, C., Sparks, D. W., Chapman, C. A., & Chaudhri, N. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhx275 · Cited by 36
Inhibitory Learning for Anxiety-Related Disorders
Tolin, D. F. (2018) · Cognitive and Behavioral Practice · doi:10.1016/j.cbpra.2018.07.008 · Cited by 35
Neuromodulation Strategies in Post-Traumatic Stress Disorder: From Preclinical Models to Clinical Applications
Gouveia, F. V., Gidyk, D. C., Giacobbe, P., Ng, E., Meng, Y., Davidson, B., Abrahão, A., Lipsman, N., & Hamani, C. (2019) · Brain Sciences · doi:10.3390/brainsci9020045 · Cited by 39
“While the IL is important for inhibiting fear CRs following extinction learning [52,53], the PL is primarily involved in the long-term behavioral expression of fear [53,54].”
Background
A single exposure to an enriched environment stimulates the activation of discrete neuronal populations in the brain of the fos-tau-lacZ mouse
Ali, A. E. A., Wilson, Y. M., & Murphy, M. (2009) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2009.05.004 · Cited by 36
“This involvement in stress is not simple and also includes a clear role in suppression of stress or fear responses seen in fear memory extinction (Milad & Quirk, 2002; Mueller, Porter, & Quirk, 2008; Santini, Ge, Ren, Pena de Ortiz, & Quirk, 2004; Santini, Quirk, & Porter, 2008).”
Background
Maternal separation exaggerates spontaneous recovery of extinguished contextual fear in adult female rats.
Xiong, G.-J., Yang, Y., Wang, L.-P., Xu, L., & Mao, R.-R. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.04.015 · Cited by 43
Prior cocaine exposure disrupts extinction of fear conditioningPreprint
Burke, K. A., Franz, T. M., Gugsa, N., & Schoenbaum, G. M. (2006) · Learning & Memory · doi:10.1101/lm.216206 · Cited by 36
“Clearly, enhanced responding to fear-associated cues during extinction learning might reflect the impact of drug-induced changes on the ability of the MPFC to modulate encoding in amygdala.”
BackgroundInfluential
Prefrontal cortical and nucleus accumbens contributions to discriminative conditioned suppression of reward-seekingPreprint
Piantadosi, P. T., Yeates, D. C. M., & Floresco, S. (2020) · Learning & Memory · doi:10.1101/lm.051912.120 · Cited by 35
IGF-1 facilitates extinction of conditioned fear
Noriega‐Prieto, J. A., Maglio, L. E., Maroto, I. B., Martín-Cortecero, J., Muñoz‐Callejas, A., Callejo-Móstoles, M., & de Sevilla, D. F. (2021) · eLife · doi:10.7554/elife.67267 · Cited by 33
Two Parallel Medial Prefrontal Cortex-Amygdala Circuits Mediate Memory Deficit via Glutamatergic Projection in Surgery Mice
Sun, X., Le, L., Song, Y., Wu, T., Zheng, T., Hao, J., Cao, J., & Gao, C. (2022) · Cell Reports · doi:10.1016/j.celrep.2023.112719 · Cited by 35
Memory Trace for Fear Extinction: Fragile yet Reinforceable
Liu, Y., Ye, S., Li, X.-N., & Li, W. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01129-3 · Cited by 35
“The IL/ mPFC plays a central role in the acquisition of fear extinction memories [71], where the adaptive changes associated with extinction learning, such as NMDAR-dependent bursting [72], are required for the consolidation of fear extinction memory.”
Background
Extinction resistant changes in the human auditory association cortex following threat learning
Apergis-Schoute, A. M., Schiller, D., LeDoux, J. E., & Phelps, E. A. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.01.016 · Cited by 32
Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear
Kim, J. H., Perry, C. J., Ganella, D. E., & Madsen, H. B. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.10.018 · Cited by 34
Infralimbic cortex activity is required for the expression but not the acquisition of conditioned safety
Kreutzmann, J. C., Jovanović, T., & Fendt, M. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05527-7 · Cited by 31
A reciprocal inhibition model of alternations between under-/overemotional modulatory states in patients with PTSD
Chiba, T., Ide, K., Taylor, J. E., Boku, S., Toda, H., Kanazawa, T., Kato, S., Horiuchi, Y., Hishimoto, A., Maruyama, T., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0827-0 · Cited by 41
The role of gastrin-releasing peptide on conditioned fear: differential cortical and amygdaloid responses in the rat
Mountney, C., Sillberg, V. A. H., Kent, P., Anisman, H., & Merali, Z. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0585-y · Cited by 35
“In terms of neurocircuitry mediating the conditioned emotional response, it is important to note that the amygdala and mPFC share reciprocal connections, and it was suggested that the mPFC gates or inhibits responses from the CeA via projections through either the lateral amygdala or through intercalated cells located…”
BackgroundInfluential
The prelimbic cortex is critical for context-dependent fear expression
Kim, E. J., Kim, N., Kim, H. T., & Choi, J.-S. (2013) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00073 · Cited by 37
“For example, no significant changes in the activation of the PL have been observed during simple fear extinction (Milad and Quirk, 2002; Chang et al., 2010).”
BackgroundResult
Imaging genetics and development: Challenges and promises
Casey, B. J., Soliman, F., Bath, K. G., & Glatt, C. E. (2010) · Human Brain Mapping · doi:10.1002/hbm.21047 · Cited by 34
Pharmacological enhancement of drug cue extinction learning: translational challenges
Kantak, K. M., & Dhonnchadha, B. Á. N. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05899.x · Cited by 35
Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear
Norrholm, S. D., Anderson, K. M., Olin, I. W., Jovanovic, T., Kwon, C., Warren, V. T., McCarthy, A., Bosshardt, L., Sabree, J., Duncan, E. J., et al. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00077 · Cited by 34
“However, the large foundation of pre-clinical animal studies that have informed human fear extinction investigations have employed auditory CSs (e.g., Cain et al., 2001; Milad and Quirk, 2002; Morris et al., 2005; Monfils et al., 2009).”
Background
Cannabinoids: Revealing their complexity and role in central networks of fear and anxiety
Murkar, A., Koninck, J. D., & Merali, Z. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.002 · Cited by 35
Therapygenetics: anterior cingulate cortex–amygdala coupling is associated with 5-HTTLPR and treatment response in panic disorder with agoraphobia
Lueken, U., Straube, B., Wïttchen, H., Konrad, C., Ströhle, A., Wittmann, A., Pfleiderer, B., Arolt, V., Kircher, T. T. J., Deckert, J., et al. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1311-2 · Cited by 35
“However, 5-HTTLPR modulated the ACC-amygdala neurocircuit that is involved in fear extinction in animals and humans (Milad and Quirk 2002; Phelps et al. 2004) and is associated with treatment response in PD/AG patients (Lueken et al.”
Background
Overexpression of Protein Kinase Mζ in the Prelimbic Cortex Enhances the Formation of Long-Term Fear Memory
Xue, Y.-X., Zhu, Z., Han, H.-B., Liu, J., Meng, S., Chen, C., Yang, J., Wu, P., & Lü, L. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.56 · Cited by 34
“Different subregions of the mPFC appear to have distinct functions in fear memory, and the IL appears to control extinction learning, in which a new conditioned stimulus-no unconditioned stimulus association is formed (Milad and Quirk 2002; Milad et al, 2007; Peters et al, 2010; Quirk et al, 2006b).”
Background
Emotional intelligence correlates with functional responses to dynamic changes in facial trustworthiness
Killgore, W. D. S., Schwab, Z. J., Tkachenko, O. N., Webb, C. A., DelDonno, S. R., Kipman, M., Rauch, S. L., & Weber, M. (2013) · Social Neuroscience · doi:10.1080/17470919.2013.807300 · Cited by 34
“Importantly, the vmPFC has been shown to play a role in the maintenance of extinction memory following fear conditioning in humans (Milad et al., 2007), leading to inhibition of fear responses when encountering a previously feared stimulus (Milad & Quirk, 2002).”
Aversive-Bias and Stage-Selectivity in Neurons of the Primate Amygdala during Acquisition, Extinction, and Overnight Retention
Livneh, U., & Paz, R. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0323-12.2012 · Cited by 36
“, 2011) which are activated from the ventral/medial-prefrontalcortices (v/mPFC; Milad and Quirk, 2002; Paré et al., 2004).”
Background
The learning of prospective and retrospective cognitive maps within neural circuits
Namboodiri, V. M. K., & Stuber, G. D. (2021) · Neuron · doi:10.1016/j.neuron.2021.09.034 · Cited by 32
“In contrast, the infralimbic cortex (IL) that lies ventral to PL, appears especially important for extinction learning and habitual behaviors (Barker et al., 2014, 2017; Ghazizadeh et al., 2012; Milad and Quirk, 2002; Peters et al., 2009).”
Background
Unrelenting Fear Under Stress: Neural Circuits and Mechanisms for the Immediate Extinction Deficit
Maren, S. (2022) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2022.888461 · Cited by 37
“Neuronal activity within the IL correlates with suppression of conditioned freezing (Milad and Quirk, 2002; Chang et al., 2010; Wilber et al., 2011; Giustino et al., 2016a, 2019), electrical or optogenetic activation of the IL can facilitate extinction learning (Milad et al., 2004; Do-Monte et al.,…”
Background
Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory
Awad, W., Ferreira, G., & Maroun, M. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.103 · Cited by 35
“(Akirav et al, 2006a, b; Maroun et al, 2012; Milad and Quirk, 2002; Peters et al, 2009; Slouzkey et al, 2013) and suggest a dissociation in the engagement of the IL in learning and consolidation of COA extinction over time.”
Background
Amyloid and Tau Neuropathology Differentially Affect Prefrontal Synaptic Plasticity and Cognitive Performance in Mouse Models of Alzheimer's Disease
Lo, A. C., Iscru, E., Blum, D. L., Tesseur, I. C., Callaerts‐Vegh, Z., Buée, L., Strooper, B. D., Balschun, D., & D’Hooge, R. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122296 · Cited by 39
“Hip-pocampal plasticity has been tested in AD mouse models and related to spatial learning defects 24–26], but prefrontal cortex (PFC) has been [20 shown to play a central role in various aspects of rodent behavior as well [27, 28].”
Dynamics of neural coding in the accumbens during extinction and reinstatement of rewarded behavior
Janak, P. H., Chen, M.-T., & Caulder, T. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.02.003 · Cited by 34
Know thy SEFL: Fear sensitization and its relevance to stressor-related disorders
Nishimura, K., Poulos, A. M., Drew, M. R., & Rajbhandari, A. K. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104884 · Cited by 38

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Neurons in medial prefrontal cortex signal memory for fear extinction

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks