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Neurons in medial prefrontal cortex signal memory for fear extinction
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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In the citing paper
“vmPFC activation during recall of extinction memory inhibits the amygdala and dampens fear expression”
From Childhood adversity and neural development: Deprivation and threat as distinct dimensions of early experience (2014) · cites this paper as Milad and Quirk, 2002
In the citing paper
“This hypothesis was based on evidence that PFC (1) is critical for extinction retention (Herry and Garcia, 2003;Quirk et al, 2000;Milad and Quirk, 2002)”
From Impaired Extinction Retention in Adolescent Rats: Effects of D-Cycloserine (2010) · cites this paper as Milad and Quirk, 2002
In the citing paper
“A number of studies on rats suggest that activity in PrL underlies the expression of conditioned fear (27, 40, 41), whereas activity in IL underlies the extinction of conditioned fear (10, 27, 41, 42).”
From Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders (2012) · cites this paper as [10]
In the citing paper
“fear extinction studies suggest that both rat IL (10, 22, 27, 41, 42) and primate vmPFC (12, 15, 43) play a significant role in the successful recall of fear extinction.”
From Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders (2012) · cites this paper as [10]
In the citing paper
“Consistent with previous resting-state functional connectivity studies14,15 and effective connectivity studies,17,54 we found anticorrelations between the amygdala and medial prefrontal regions, including the dorsal and rostral ACC, consistent with our a priori hypothesis.”
From Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder (2012) · cites this paper as [54]
In the citing paper
“Such a lack of inhibition from dorsal medial regions to the amygdala can be interpreted as a deficit in automatic emotion regulation10 or a lack of cognitive control over emotion.54”
From Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder (2012) · cites this paper as [54]
In the citing paper
“electrical stimulation of infralimbic cortex reduces freezing to the CS even in animals that are resistant to extinction training108,112.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [108]
In the citing paper
“increased activity in the infralimbic cortex is associated with fear extinction108”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [108]
Citations
Cites
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-citationExtinction 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”
BackgroundQuirk, G. J., Repa, J. C., & LeDoux, J. E. (1995) · Neuron · doi:10.1016/0896-6273(95)90092-6 · Cited by 808
Self-citationBremner, 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
Morgan, M. A., & LeDoux, J. E. (1995) · Behavioral Neuroscience · doi:10.1037/0735-7044.109.4.681 · Cited by 717
McDonald, A. J., Mascagni, F., & Guo, L. (1996) · Neuroscience · doi:10.1016/0306-4522(95)00417-3 · Cited by 689
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- Pavlov, I. P. Conditioned Reflexes (Oxford Univ. Press, London, 1927)
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Items 501–600 of 1,010
Tottenham, N., Shapiro, M., Telzer, E. H., & Humphreys, K. L. (2012) · Developmental Science · doi:10.1111/j.1467-7687.2011.01128.x · Cited by 91
“…between the amygdala and the vmPFC in both primates and rodents (Amaral, Price, Pitkanen & Carmichael, 1992; Ghashghaei, Hilgetag & Barbas, 2007; Milad & Quirk, 2002), and in a recent review, Kim, Loucks, Palmer, Brown, Solomon, Marchante and Whalen (in press) have argued that, given their…”
BackgroundBartlett, A. A., Singh, R., & Hunter, R. G. (2017) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-53889-1_8 · Cited by 91
Kim, Y., Amidfar, M., & Won, E. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.06.008 · Cited by 96
Fonzo, G. A., Ramsawh, H. J., Flagan, T., Sullivan, S. G., Simmons, A. N., Paulus, M. P., & Stein, M. B. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.07.031 · Cited by 91
“, 2011), which serve to inhibit limbic responsivity (Quirk et al., 2003; Milad and Quirk, 2002).”
BackgroundMedial prefrontal cortical innervation of the intercalated nuclear region of the amygdala
Pinard, C. R., Mascagni, F., & McDonald, A. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.036 · Cited by 90
“…behavioral and electrophysiological studies uggest that it may rely in part on projections from the nfralimbic region (IL) of the medial prefrontal cortex mPFC) to the intercalated nuclei (ICNs) of the amygdala Milad and Quirk, 2002; Paré et al., 2004; Quirk and Muller, 2008; Herry et al., 2010).”
BackgroundHoltzman-Assif, O., Laurent, V., & Westbrook, R. F. (2010) · Learning & Memory · doi:10.1101/lm.1668310 · Cited by 96
“In contrast, the infralimbic (IL) subregion of the mPFC is required for consolidation and retrieval of that inhibition (Quirk et al. 2000; Milad and Quirk 2002; Santini et al. 2004; Hugues et al. 2006; Sierra-Mercado et al. 2006; Burgos-Robles et al. 2007; Laurent and Westbrook 2008, 2009;…”
BackgroundBailey, C. R., Cordell, E., Sobin, S. M., & Neumeister, A. (2013) · CNS Drugs · doi:10.1007/s40263-013-0051-4 · Cited by 89
“Early studies using the a2-selective antagonist yohimbine, which acts on both pre- and post-synaptic receptors and increases noradrenaline activity, helped form a model suggesting that increased noradrenaline activity leads to impaired medial prefrontal cortex functioning [27, 37] and fear extinction [38, 39], explain…”
BackgroundWells, T. S., Miller, S. C., Adler, A. B., Engel, C. C., Smith, T. C., & Fairbank, J. A. (2011) · International Review of Psychiatry · doi:10.3109/09540261.2011.558833 · Cited by 93
Marek, R., Coelho, C. M., Sullivan, R., Baker‐Andresen, D., Li, X., Ratnu, V. S., Dudley, K. J., Meyers, D. J., Mukherjee, C., Cole, P. A., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0133-11.2011 · Cited by 90
“DOI:10.1523/JNEUROSCI.0133-11.2011 Copyright © 2011 the authors 0270-6474/11/317486-06$15.00/0 (ILPFC) (Milad and Quirk, 2002; Santini, 2004; Burgos-Robles et al., 2007; Laurent and Westbrook, 2009), we investigated whether p300 activity, within the ILPFC, is required for the formation of fear…”
BackgroundInfluentialEyes Wide Shut: Amygdala Mediates Eyes-Closed Effect on Emotional Experience with Music
Lerner, Y., Papo, D., Zhdanov, A. V., Belozersky, L., & Hendler, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006230 · Cited by 96
“experience via appraisal mechanisms [45] and affective decision [44,46].”
BackgroundPretreatment biomarkers predicting PTSD psychotherapy outcomes: A systematic review
Colvonen, P. J., Glassman, L. H., Crocker, L. D., Buttner, M. M. A., Orff, H. J., Schiehser, D. M., Norman, S. B., & Afari, N. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.027 · Cited by 89
Vouimba, R., & Maroun, M. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.115 · Cited by 95
Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors
Monte, F. H. D., de Souza, R. R., de Bitencourt, R. M., Kroon, J. A. V., & Takahashi, R. N. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.04.045 · Cited by 94
Lane, R. D., & Garfield, D. (2005) · Neuropsychoanalysis · doi:10.1080/15294145.2005.10773468 · Cited by 89
Molecular Specificity of Multiple Hippocampal Processes Governing Fear Extinction
Radulović, J., & Tronson, N. C. (2010) · Reviews in the Neurosciences · doi:10.1515/revneuro.2010.21.1.1 · Cited by 83
Amygdala-Prefrontal Synchronization Underlies Resistance to Extinction of Aversive Memories
Livneh, U., & Paz, R. (2012) · Neuron · doi:10.1016/j.neuron.2012.05.016 · Cited by 87
“This includes the rodent infralimbic cortex (IL) (Milad and Quirk, 2002; Sierra-Mercado et al., 2011) and the primate vmPFC (Phelps et al.”
Lindner, K., Neubert, J., Pfannmöller, J. P., Lotze, M., Hamm, A. O., & Wendt, J. (2015) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2015.02.025 · Cited by 92
Sex Differences in the Development of the Rodent Corticolimbic System
Premachandran, H., Zhao, M., & Arruda-Carvalho, M. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.583477 · Cited by 96
The Promise of Extinction Research for the Prevention and Treatment of Anxiety Disorders
Anderson, K. C., & Insel, T. R. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.022 · Cited by 89
“It is now well accepted that this circuitry includes the amygdala, prefrontal cortex, and hippocampus, and recent studies have implicated the medial prefrontal cortex as a potential site for the consolidation and expression of extinction learning (Milad and Quirk 2002).”
BackgroundPeters, J., Vallone, J., Laurendi, K., & Kalivas, P. W. (2007) · Psychopharmacology · doi:10.1007/s00213-007-1034-2 · Cited by 87
“is consistent with studies on spontaneous recovery of conditioned fear (Sierra-Mercado et al. 2006; Quirk 2002; Milad and Quirk 2002) and appetitive Pavlovian conditioning (Rhodes and Killcross 2004).”
ResultLi, G., Nair, S. S., & Quirk, G. J. (2008) · Journal of Neurophysiology · doi:10.1152/jn.90765.2008 · Cited by 92
Self-citationNeural circuits for a top-down control of fear and extinction
Marek, R., Sun, Y., & Sah, P. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5033-2 · Cited by 97
Borgomaneri, S., Battaglia, S., Sciamanna, G., Tortora, F., & Laricchiuta, D. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.036 · Cited by 90
Durable fear memories require PSD-95
Fitzgerald, P. J., Pinard, C. R., Camp, M., Feyder, M. J., Sah, A., Bergstrom, H. C., Graybeal, C., Liu, Y., Schlüter, O. M., Grant, S. G. N., et al. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.161 · Cited by 89
Wout‐Frank, M. V. ‘., Longo, S. M., Reddy, M. K., Philip, N. S., Bowker, M., & Greenberg, B. D. (2017) · Brain and Behavior · doi:10.1002/brb3.681 · Cited by 91
“…facilitating endogenous vmPFC activity using brain stimulation techniques, in the context of extinction learning, may be one method to improve fear extinction and retention (i.e., recall of safety memories; Milad & Quirk, 2002; Milad, Vidal- Gonzalez, & Quirk, 2004) in those suffering from PTSD.”
MethodActivation of the infralimbic cortex in a fear context enhances extinction learningPreprint
Thompson, B. M., Baratta, M. V., Biedenkapp, J. C., Rudy, J. W., Watkins, L. R., & Maier, S. F. (2010) · Learning & Memory · doi:10.1101/lm.1920810 · Cited by 90
Endocannabinoids in brain plasticity: Cortical maturation, HPA axis function and behavior
Dow-Edwards, D. L., & Silva, L. (2016) · Brain Research · doi:10.1016/j.brainres.2016.08.037 · Cited by 92
Powell, N. J., & Redish, A. D. (2016) · Nature Communications · doi:10.1038/ncomms12830 · Cited by 91
Neural Mechanisms and Psychology of Psychedelic Ego Dissolution
Stoliker, D., Egan, G. F., Friston, K. J., & Razi, A. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000508 · Cited by 96
Ryu, J., Futai, K., Feliú-Mójer, M. I., Weinberg, R. J., & Sheng, M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1944-08.2008 · Cited by 84
“Fear extinction is thought to be mediated primarily by the amygdala and the prefrontal cortex (PFC) (Lu et al., 2001; Milad and Quirk, 2002; Myers and Davis, 2002, 2007; Lebrón et al., 2004; Milad et al., 2006, 2007).”
BackgroundDHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli
Sripada, R. K., Marx, C. E., King, A. P. J., Rajaram, N., Garfinkel, S. N., Abelson, J. L., & Liberzon, I. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.79 · Cited by 85
“Animal studies of fear conditioning implicate mPFC in the extinction of conditioned fear (Milad and Quirk, 2002), and in humans, a recent Granger causality analysis demonstrated an inhibitory influence of the rACC on the amygdala (Zhou et al, 2009).”
BackgroundZuj, D. V., & Norrholm, S. D. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.08.014 · Cited by 89
“network impairs extinction learning (Bloodgood et al., 2018; Laurent and Westbrook, 2009; Milad and Quirk, 2002; Milad et al., 2004; Quirk et al., 2000).”
Hugues, S., & Garcia, R. (2007) · Learning & Memory · doi:10.1101/lm.625407 · Cited by 83
“Firstly, studies using rodents have repeatedly shown that the levels of changes in prefrontal neuronal activity strongly correlate with the degree of expression of extinction memory (Herry and Garcia 2002; Milad and Quirk 2002; Farinelli et al. 2006; Hugues et al. 2006).”
BackgroundInfluentialiPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants
Umemori, J., Winkel, F., Didio, G., Llach Pou, M., & Castrén, E. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12683 · Cited by 80
Prefrontal-amygdala fear networks come into focus
Arruda-Carvalho, M., & Clem, R. L. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00145 · Cited by 89
“Accordingly, IL unit activity positively correlates with fear inhibition (Milad and Quirk, 2002; Barrett et al., 2003; Burgos-Robles et al., 2007).”
Backgroundvan den Oever, M. C., Rotaru, D. C., Heinsbroek, J. A., Gouwenberg, Y., Deisseroth, K. A., Stuber, G. D., Mansvelder, H. D., & Smit, A. B. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2412-13.2013 · Cited by 85
“Substantial evidence also implicates the vmPFC in extinction of conditioned responding to aversive as well as appetitive cues (Milad and Quirk, 2002; Peters et al., 2009).”
BackgroundBarrett, J., & Armony, J. L. (2008) · Psychological Medicine · doi:10.1017/s0033291708003516 · Cited by 93
Maroun, M. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05169.x · Cited by 82
Katzman, M., & Sternat, T. (2016) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s111818 · Cited by 83
“39,40 In individuals who have been conditioned to fear, or those with panic disorders, dysfunction in this circuitry leads to an inability to extinguish or contextualize fear.”
Gold, A. L., Shechner, T., Farber, M. J., Spiro, C. N., Leibenluft, E., Pine, D. S., & Britton, J. C. (2016) · Depression and Anxiety · doi:10.1002/da.22470 · Cited by 82
“[73] Evidence suggests that successful response to CBT may arise through alterations in amygdala–vmPFC connectivity, given the role of this circuitry in the maintenance of extinction.[5, 10, 23].”
BackgroundPrefrontal oscillations during recall of conditioned and extinguished fear in humans
Mueller, E. M., Panitz, C., Hermann, C., & Pizzagalli, D. A. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3427-13.2014 · Cited by 89
“Instead, vmPFC gamma activity differed between extinguished CS and CS , which supports the following hypotheses: (1) a particular safety signal becomes associated with the CS during extinction (Myers and Davis, 2007); (2) the retention and recall of this safety signal involve the vmPFC or infralimbic cortex (Milad and…”
BackgroundMethodResultInfluentialInhibitory networks of the amygdala for emotional memory
Lee, S. H., Kim, S.-J., Kwon, O., Lee, J. H., & Kim, J. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00129 · Cited by 96
“…such as depotentiation of LA synapses (Kim et al., 2007), transitions from fear neurons to extinction neurons in BA (Herry et al., 2008; Amano et al., 2011), dynamic activity of CElon neurons (Duvarci et al., 2011), and enhanced activity of IL after extinction training (Milad and Quirk, 2002).”
BackgroundBremner, J. D., Mishra, S., Campanella, C., Shah, M., Kasher, N., Evans, S., Fani, N., Shah, A. J., Reiff, C. M., Davis, L. L., et al. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00157 · Cited by 87
“It has connections to limbic areas that mediate threat response and extinction of conditioned fear responses that are characteristic of PTSD (135) as well as with the insula in the regulation of peripheral autonomic and neurohormonal responses to stress (69, 133, 134, 136).”
BackgroundFarinelli, M., Deschaux, O., Hugues, S., Thévenet, A., & Garcia, R. (2006) · Learning & memory (Cold Spring Harbor, N.Y.) · doi:10.1101/lm.204806 · Cited by 84
Olatunji, B. O., Ferreira-Garcia, R., Caseras, X., Fullana, M. A., Wooderson, S., Speckens, A., Lawrence, N., Giampietro, V., Brammer, M. J., Phillips, M. L., et al. (2014) · Psychological Medicine · doi:10.1017/s0033291713002766 · Cited by 81
“These findings are also in line with prior research showing that dysregulation in brain regions such as the medial prefrontal cortex and the anterior cingulate may interfere with extinction learning and its retention (Milad & Quirk, 2002; Phelps et al. 2004; Milad et al. 2005).”
ResultTan, H., Lauzon, N. M., Bishop, S. F., Bechard, M. A., & Laviolette, S. R. (2010) · Cerebral Cortex · doi:10.1093/cercor/bhp210 · Cited by 81
“Post hoc analyses were performed with Fisher’s least significant difference tests or Newman--Keuls tests.”
BackgroundMethodInfluentialFear relief—toward a new conceptual frame work and what endocannabinoids gotta do with it
Riebe, C. J. N., Pamplona, F. A., Kamprath, K., & Wotjak, C. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.11.057 · Cited by 84
“There is evidence that the infralimbic cortex not only executes inhibitory control over fear responses (Milad and Quirk, 2002; Vidal-Gonzalez et al., 2006) but also encodes the new inhibitory memory trace (Santini et al.”
BackgroundConsolidative mechanisms of emotional processing in REM sleep and PTSD
Murkar, A., & Koninck, J. D. (2018) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2018.03.001 · Cited by 87
Bajaj, J. S., Sikaroodi, M., Fagan, A., Heuman, D. M., Gilles, H., Gavis, E. A., Fuchs, M. A., González‐Maeso, J., Nizam, S., Gillevet, P. M., et al. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00194.2019 · Cited by 84
Roth, M. K., Bingham, B. C., Shah, A. P., Joshi, A., Frazer, A., Strong, R., & Morilak, D. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.07.034 · Cited by 82
“The mPFC, particularly the infralimbic cortex, is a key region involved in extinction learning (Milad and Quirk, 2002; Milad et al., 2004; Morgan et al., 1993; Quirk et al., 2000; Sutker et al., 1995).”
BackgroundWhittle, N., Hauschild, M., Lübec, G., Holmes, A., & Singewald, N. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0849-10.2010 · Cited by 83
“These findings agree with data showing that IL activity in rodents (Quirk et al., 2000, 2003; Herry and Garcia, 2002; Milad and Quirk, 2002; Barrett et al., 2003) and ventromedial PFC activity in humans (Phelps et al.”
BackgroundCan Transcranial Direct Current Stimulation Augment Extinction of Conditioned Fear?
Wout‐Frank, M. V. ‘., Mariano, T. Y., Garnaat, S. L., Reddy, M. K., Rasmussen, S. A., & Greenberg, B. D. (2016) · Brain stimulation · doi:10.1016/j.brs.2016.03.004 · Cited by 81
“Specifically, invasive electrical stimulation of the rat infralimbic subregion of the rat vmPFC during presentation of conditioned stimulus reduced fear expression, thereby simulating extinction in non-extinguished rats [12].”
BackgroundAmygdala-ventral striatum circuit activation decreases long-term fear
Correia, S. S., McGrath, A. G., Lee, A., Graybiel, A. M., & Goosens, K. A. (2016) · eLife · doi:10.7554/elife.12669 · Cited by 87
“…in rats that experience fear extinction with reward conditioning is comparable to the decrease of fear recall in animals subjected to microstimulation of the IL during fear extinction: in previous studies, IL activity was positively correlated with fear extinction recall (Milad and Quirk, 2002).”
ResultSensitive periods in affective development: nonlinear maturation of fear learning
Hartley, C. A., & Lee, F. S. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.179 · Cited by 80
“Following extinction training, presentation of the CS evokes activity within IL neurons that is associated with reduced conditioned fear expression (Milad and Quirk, 2002).”
Backgroundde Bitencourt, R. M., Pamplona, F. A., & Takahashi, R. N. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.05.039 · Cited by 80
“On the other hand, direct activation of the IL PFC enhances extinction learning (Milad and Quirk, 2002; Milad et al., 2004; Mueller et al., 2008).”
Wang, W., Kang, S., Liu, W., Li, M., Liu, Y., Yu, C. F., Chen, J., Chi, Z., He, L., & Liu, J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1991-12.2012 · Cited by 81
“Results Lesions of the vmPFC of rats block extinction of morphine withdrawal-induced conditioned place aversion Lesion and pharmacological manipulation studies show that the vmPFC is critical for the storage and recall of extinction memories (Milad and Quirk, 2002; Phelps et al., 2004).”
BackgroundZavala, A. R., Biswas, S., Harlan, R. E., & Neisewander, J. L. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.12.038 · Cited by 77
“Consistent with this explanation, the IL has been implicated in extinction learning of both aversive and appetitive conditioned responses (Quirk et al., 2000,Milad and Quirk, 2002,Milad et al., 2004,Rhodes and Killcross, 2004).”
BackgroundFear extinction in rodents: basic insight to clinical promise
Barad, M. (2005) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2005.10.005 · Cited by 82
Evolution of the Amygdala in Vertebrates
Martínez‐Garciá, F., Novejarque, A., & Lanuza, E. (2007) · Elsevier eBooks · doi:10.1016/b0-12-370878-8/00139-7 · Cited by 80
A unifying model of the role of the infralimbic cortex in extinction and habitsPreprint
Barker, J. M., Taylor, J. R., & Chandler, L. J. (2014) · Learning & Memory · doi:10.1101/lm.035501.114 · Cited by 89
Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex
Maroun, M., Kavushansky, A., Holmes, A., Wellman, C., & Motanis, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035853 · Cited by 79
Towards new approaches to disorders of fear and anxiety
Dias, B. G., Banerjee, S. B., Goodman, J. V., & Ressler, K. J. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.01.013 · Cited by 79
“Divisions of the prefrontal cortex (PFC)-medial PFC (mPFC) and infralimbic PFC (iPFC) are pivotal sites of consolidation and extinction of fear [19–21].”
BackgroundStein, D. J., Ives-Deliperi, V. L., & Thomas, K. G. F. (2008) · CNS Spectrums · doi:10.1017/s1092852900013869 · Cited by 80
“COGNITIVE-AFFECTIVE NEUROSCIENCE Mindfulness is a construct with a long and rich history; it is not a unitary phenomenon, and there is ongoing work on optimal operational definition.(13) As an initial step, mindfulness has been described in terms of sustained and non-evaluative moment-to-moment awareness and attention…”
BackgroundGlucocorticoid-induced enhancement of extinction—from animal models to clinical trials
de Quervain, D. J. ‐., Wolf, O. T., & Roozendaal, B. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5116-0 · Cited by 82
Hong, I., Song, B., Lee, S., Kim, J., Kim, J., & Choi, S. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07004.x · Cited by 80
“…on the amygdala, fear extinction is known to be supported by multiple afferent brain regions, including the prefrontal cortex (Morgan et al., 1993; Milad & Quirk, 2002; Burgos-Robles et al., 2007; for a review, see Quirk & Mueller, 2008), hippocampus (Maren & Hobin, 2007), entorhinal cortex…”
BackgroundStress and Amygdala Suppression of Metaplasticity in the Medial Prefrontal Cortex
Richter‐Levin, G., & Maroun, M. (2010) · Cerebral Cortex · doi:10.1093/cercor/bhp311 · Cited by 79
CONCEPT FORMATION: 'OBJECT' ATTRIBUTES DYNAMICALLY INHIBITED FROM CONSCIOUS AWARENESS
Snyder, A. W., Bossomaier, T. R. J., & Mitchell, D. J. (2004) · Journal of Integrative Neuroscience · doi:10.1142/s0219635204000361 · Cited by 79
A Upf3b-mutant mouse model with behavioral and neurogenesis defects
Huang, L., Shum, E. Y., Jones, S. H., Lou, C.-H., Chousal, J. N., Kim, H. Y., Roberts, A. J., Jolly, L. A., Espinoza, J. L., Skarbrevik, D., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.173 · Cited by 79
“The amygdala, hippocampus, and the prefrontal cortex are all critical for fear memory recognition and downstream processes 72–74 , including storing fear memories 72 .”
Teed, A. R., Feinstein, J. S., Puhl, M., Lapidus, R. C., Upshaw, V., Kuplicki, R. T., Bodurka, J., Ajijola, O. A., Kaye, W. H., Thompson, W. K., et al. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2021.4225 · Cited by 79
Mechanisms of fear learning and extinction: synaptic plasticity–fear memory connection
Luchkina, N. V., & Bolshakov, V. Y. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5104-4 · Cited by 87
Liu, A., Jain, N. K., Vyas, A., & Lim, L. W. (2015) · eLife · doi:10.7554/elife.04803 · Cited by 80
“Furthermore, HFS of the vmPFC has been 466 shown to reduce conditioned fear and enhance the extinction of aversive memory (53, 54), in 467 contrast to LFS, which induced impairment in extinction of conditioned fear (55).”
Blockade of amygdala metabotropic glutamate receptor subtype 1 impairs fear extinction
Kim, J., Lee, S., Park, H., Song, B., Hong, I., Geum, D., Shin, K., & Choi, S. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.01.125 · Cited by 78
“Lesioning and pharmacological studies have identified two critical structures for extinction, the basolateral amygdala and prefrontal cortex [2–4].”
BackgroundPark, J., Wood, J. T., Bondi, C. O., Arco, A. D., & Moghaddam, B. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4250-15.2016 · Cited by 78
“Although these studies have revealed a role for PFC in regulating freezing and avoidance behaviors (Milad and Quirk, 2002; Burgos-Robles et al., 2009), they cannot reveal how the PFC neural correlates of cognitive and motivated behavioral events are modulated by anxiety.”
Brain Mechanisms of Extinction of the Classically Conditioned Eyeblink ResponsePreprint
Robleto, K., Poulos, A. M., & Thompson, R. F. (2004) · Learning & Memory · doi:10.1101/lm.80004 · Cited by 77
“In particular, the medial prefrontal cortex (rat) seems to play a more important role in extinction than in acquisition (Morgan et al. 1993; Quirk et al. 2000; Herry and Garcia 2002; Milad and Quirk 2002; but, see Gewirtz et al. 1997; R. Garcia et al. 1999).”
BackgroundZhou, F., Geng, Y., Xin, F., Li, J., Feng, P., Liu, C., Zhao, W., Feng, T., Guastella, A. J., Ebstein, R. P., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.07.007 · Cited by 70
Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding
Rhodes, S. E., & Killcross, A. S. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05486.x · Cited by 80
“Electrophysiological studies have also demonstrated that activity in this region increases during recall of extinction, but not necessarily during acquisition of extinction (Milad & Quirk, 2002).”
BackgroundModulation of fear extinction processes using transcranial electrical stimulation
Abend, R., Jalon, I., Gurevitch, G., Sar-El, R., Shechner, T., Pine, D. S., Hendler, T., & Bar‐Haim, Y. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.197 · Cited by 80
Galatzer-Levy, I. R., Bonanno, G. A., Bush, D. E. A., & LeDoux, J. E. (2013) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00055 · Cited by 75
Amygdala inactivation reverses fear's ability to impair divided attention and make time stand still.
Meck, W. H., & MacDonald, C. J. (2007) · Behavioral Neuroscience · doi:10.1037/0735-7044.121.4.707 · Cited by 79
The role of basal forebrain cholinergic neurons in fear and extinction memory
Knox, D. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.06.001 · Cited by 81
Amount of fear extinction changes its underlying mechanisms
An, B., Kim, J., Park, K., Lee, S., Song, S., & Choi, S. (2017) · eLife · doi:10.7554/elife.25224 · Cited by 79
Post-Traumatic Stress Disorder: The Relationship Between the Fear Response and Chronic Stress
Maeng, L. Y., & Milad, M. R. (2017) · Chronic Stress · doi:10.1177/2470547017713297 · Cited by 92
Self-citationDeep brain stimulation in clinical trials and animal models of depression
Hamani, C., & Nóbrega, J. N. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07414.x · Cited by 80
“…the IL seems to play a role in mechanisms of stress (Diorio et al., 1993; Ostrander et al., 2003), autonomic responses (Hardy & Holmes, 1988; Tavares et al., 2004; Resstel & Correa, 2005) and the extinction of conditioned responses (Quirk et al., 2000; Milad & Quirk, 2002; Milad et al., 2004).”
BackgroundVentromedial prefrontal cortex and the regulation of physiological arousal
Zhang, S., Hu, S., Chao, H. H., Ide, J. S., Luo, X., Farr, O. M., & Li, C. R. (2013) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nst064 · Cited by 82
“Numerous non-human and human studies indicated that the vmPFC is both functionally and anatomically connected with the amygdala (Milad and Quirk, 2002; Ghashghaei et al., 2007; Hare et al., 2008; Myers-Schulz and Koenigs, 2012).”
BackgroundNegrón-Oyarzo, I., Aboitiz, F., & Fuentealba, P. (2016) · Neural Plasticity · doi:10.1155/2016/7539065 · Cited by 79
“Milad and Quirk [104] found that neurons in the IL, but not PL, fire to the tone only when rats are recalling extinction of conditioned fear on the following day, which correlated to reduced freezing.”
BackgroundIdentification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence
Çalışkan, G., Müller, I., Semtner, M., Winkelmann, A., Raza, A. S., Hollnagel, J., Rösler, A., Heinemann, U., Stork, O., & Meier, J. C. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw001 · Cited by 73
Howland, J. G., Ito, R., Lapish, C. C., & Villaruel, F. R. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104569 · Cited by 85
Social ties and health: a social neuroscience perspective
Eisenberger, N. I. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.01.006 · Cited by 82
“As such, stimulating the infralimbic cortex in rats inhibits the central nucleus of the amygdala [58] and diminishes fear responding to fear cues [59].”
Lattal, K. M., Radulović, J., & Lukowiak, K. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.05.038 · Cited by 74
“…of synaptic plasticity in the prefrontal cortex has been implicated in extinction of tone-dependent fear conditioning (Herry and Garcia 2002; Milad and Quirk 2002), whereas a decrease of neuronal activity in the cerebellum paralleled extinction of eyelid conditioning (Mauk and Ohyama 2004).”
BackgroundAnxiety-control strategies: Is there room for neutralization in successful exposure treatment?
Parrish, C. L., Radomsky, A. S., & Dugas, M. J. (2008) · Clinical Psychology Review · doi:10.1016/j.cpr.2008.07.007 · Cited by 73
Negative affective pictures can elicit physical symptoms in high habitual symptom reporters
Bogaerts, K., Janssens, T., Peuter, S. D., Diest, I. V., & den Bergh, O. V. (2009) · Psychology and Health · doi:10.1080/08870440902814639 · Cited by 74
“Importantly, the same prefrontal regions seem to be involved in the extinction of conditioned fear responses (Milad & Quirk, 2002), suggesting that these regions may also inhibit the activation of emotional representations of past experiences consolidated in memory.”
BackgroundYang, Y.-L., Chao, P.-K., Ro, L., Wo, Y., & Lu, K.-T. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301215 · Cited by 79
“Numerous studies suggest that several brain structures are also involved in the extinction of conditioned fear that includes the BLA (Maren, 2001; Davis and Whalen, 2001; LeDoux, 2002), medial prefrontal cortex (mPFC) (Quirk et al, 2000; Grace and Rosenkranz, 2002; Barrett et al, 2003; Quirk and Milad, 2002) and dorsa…”
BackgroundTransgenic Inhibition of Neuronal Protein Kinase A Activity Facilitates Fear Extinction
Isiegas, C., Park, A., Kandel, E. R., Abel, T. G., & Lattal, K. M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2743-06.2006 · Cited by 75
PSA-NCAM expression in the rat medial prefrontal cortex
Varea, E., Nácher, J., Blasco‐Ibáñez, J. M., Gómez‐Climent, M. Á., Castillo-Gómez, E., Crespo, C., & Martinez-Guijarro, F. J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.08.009 · Cited by 74
Kim, H.-S., Cho, H.-Y., Augustine, G. J., & Han, J. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.276 · Cited by 83
Common neurocircuitry mediating drug and fear relapse in preclinical models
Goode, T. D., & Maren, S. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5024-3 · Cited by 77
Liljeholm, M., Dunne, S., & O’Doherty, J. P. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12897 · Cited by 71
“It should be noted, however, that the rodent infralimbic cortex is primarily known for its involvement in the extinction of Pavlovian responses (Milad & Quirk, 2002; Rhodes & Killcross, 2004, 2007; Santini et al., 2008), whereas the human subgenual cortex has predominantly featured in studies on…”
Prefrontal single-unit firing associated with deficient extinction in mice
Fitzgerald, P. J., Whittle, N., Flynn, S., Graybeal, C., Pinard, C. R., Gunduz‐Cinar, O., Kravitz, A. V., Singewald, N., & Holmes, A. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.11.002 · Cited by 76
“A pioneering study by Milad and Quirk revealed a significant increase in neuronal activity in the rat infralimbic (IL) subregion of mPFC in rats retrieving an extinction memory (Milad & Quirk, 2002).”
BackgroundResultYamada, D., Zushida, K., Wada, K., & Sekiguchi, M. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.86 · Cited by 72
“The facilitating action of PEPA on extinction can be explained by activation of the mPFC, which is one of the crucial factors in consolidation and retrieval of extinction (Milad and Quirk, 2002; Milad et al, 2004).”
BackgroundMedial prefrontal cortex stimulation modulates the processing of conditioned fear
Guhn, A., Dresler, T., Andreatta, M., Müller, L. D., Hahn, T., Tupak, S. V., Polak, T. T., Deckert, J., & Herrmann, M. J. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00044 · Cited by 76
“The use of rTMS as a method to facilitate extinction has been already proposed a decade ago (Milad and Quirk, 2002), but was not accomplished so far.”
BackgroundMethodResultInfluential
Metadata
- Authors
- Milad, M. R., & Quirk, G. J.
- Affiliations
- Ponce Health Sciences University (PR)
- Corresponding author
- Quirk, Gregory J.
- Venue
- Nature
- Published
- 2002-11
- Volume
- 420
- Issue
- 6911
- Pages
- 70-74
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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