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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]
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Items 101–200 of 1,010
How the Neurocircuitry and Genetics of Fear Inhibition May Inform Our Understanding of PTSD
Jovanović, T., & Ressler, K. J. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.09071074 · Cited by 457
“Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL.”
BackgroundInfluentialInduction of Fear Extinction with Hippocampal-Infralimbic BDNF
Peters, J., Dieppa-Perea, L. M., Melendez, L. M., & Quirk, G. J. (2010) · Science · doi:10.1126/science.1186909 · Cited by 462
Self-citationThe hippocampal–prefrontal pathway: The weak link in psychiatric disorders?
Godsil, B. P., Kiss, J., Spedding, M., & Jay, T. M. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.10.018 · Cited by 459
“Evidence supporting this idea includes that IL neurons show increased spiking during the recall of extinction learning and electrical stimulation of the IL generates extinction-like effects (Milad and Quirk, 2002), while the disruption of IL targets in the amygdala prevents extinction recall (Falls et al.”
Brain mediators of cardiovascular responses to social threat
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“It is IL in particular in which stimulation potentiates fear extinction and lesions reduce it (Milad & Quirk, 2002; Quirk, Russo, Barron, & Lebron, 2000).”
BackgroundSotres-Bayon, F., Cain, C. K., & LeDoux, J. E. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.10.012 · Cited by 433
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“Recall of fear extinction relies heavily on an intact infralimbic cortex in animals (47), which corresponds to the rostral anterior cingulate cortex, medial orbitofrontal cortex, and subcallosal cortex (including the subgenual ACC) in humans.”
BackgroundConsolidation of Fear Extinction Requires Protein Synthesis in the Medial Prefrontal Cortex
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“Consistent with this, recall of extinction is correlated with plasticity in mPFC single units (Milad and Quirk, 2002), mPFC-evoked potentials (Herry and Garcia, 2002), and mPFC glucose utilization (Barrett et al.”
InfluentialSelf-citationD'Angelo, E., & Casali, S. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2012.00116 · Cited by 407
“Moreover, this cortical area plays a key role in fear extinction processes (Morgan et al., 1993; Milad and Quirk, 2002).”
BackgroundThickness of ventromedial prefrontal cortex in humans is correlated with extinction memory
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Self-citationEmotional Perseveration: An Update on Prefrontal-Amygdala Interactions in Fear ExtinctionPreprint
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“Particularly dramatic is the finding that pairing the tone CS with brief IL stimulation reduces freezing in rats, suggesting that IL stimulation is sufficient to simulate extinction learning (Milad and Quirk 2002; Milad et al. 2004).”
BackgroundInfluentialHofmann, S. G. (2008) · Clinical Psychology Review · doi:10.1016/j.cpr.2007.04.009 · Cited by 397
“The modern learning perspective of fear acquisition by Öhman and Mineka (2001) and Mineka and Zinbarg (2006) places a particular emphasis on cognitive processes, such as the controllability and predictability of the aversive event. At the same time, however, Öhman and Mineka (2001) assume that the fear module is impen…”
BackgroundInfluentialAltered fear learning across development in both mouse and human
Pattwell, S. S., Duhoux, S., Hartley, C. A., Johnson, D. C., Jing, D., Elliott, M. D., Ruberry, E. J., Powers, A., Mehta, N., Yang, R. R., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206834109 · Cited by 404
“Unlike the IL neurons, we observed a significant increase in frequency [F(2, 50) = 4.”
BackgroundBehavioral and neurobiological mechanisms of pavlovian and instrumental extinction learning
Bouton, M. E., Maren, S., & McNally, G. P. (2020) · Physiological Reviews · doi:10.1152/physrev.00016.2020 · Cited by 440
Contextual modulation of amygdala responsivity to surprised faces
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“Milad and Quirk (2002) and Quirk et al. (2000) have elegantly demonstrated that vmPFC activity is related to the ''memory'' of extinction, not the process per se.”
BackgroundInfluentialFacial expressions and complex IAPS pictures: Common and differential networks
Britton, J. C., Taylor, S. F., Sudheimer, K. D., & Liberzon, I. (2006) · NeuroImage · doi:10.1016/j.neuroimage.2005.12.050 · Cited by 425
“, 2003), extinguished fear (Milad and Quirk, 2002; Milad et al., 2004; Quirk et al., 2003), and cognitive-emotion interactions (Liberzon et al.”
BackgroundOpposite effects of fear conditioning and extinction on dendritic spine remodelling.
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Hippocampal Inactivation Disrupts the Acquisition and Contextual Encoding of Fear Extinction
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“, 2003), prefrontal cortex (Milad and Quirk, 2002; Santini et al., 2004), and hippocampus (Corcoran and Maren, 2001, 2004) has been identified in mediating these processes, respectively, although functional overlap among these structures does exist.”
Kim, M. J., Gee, D. G., Loucks, R. A., Davis, F. C., & Whalen, P. J. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhq237 · Cited by 388
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“In addition, changes in IL spike firing and immediate early gene expression accompany both the acquisition (Milad and Quirk, 2002; Muigg et al, 2008; Fitzgerald et al, 2014b) and expression (Hefner et al, 2008; Knapska and Maren, 2009; Whittle et al, 2010; Chang and Maren, 2010b; Knapska et al,…”
BackgroundRevisiting the Role of Infralimbic Cortex in Fear Extinction with Optogenetics
Do-Monte, F. H., Manzano-Nieves, G., Quiñones-Laracuente, K., Ramos-Medina, L., & Quirk, G. J. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3137-14.2015 · Cited by 385
“Unit recording and immunocytochemical data show that increased neuronal activity in IL correlates with extinction retrieval (Milad and Quirk, 2002; Holmes et al., 2012; Knapska et al., 2012; but see Fitzgerald et al., 2014), consistent with IL-mediating retrieval.”
BackgroundResultInfluentialSelf-citationWellman, C. L., Izquierdo, A., Garrett, J. E., Martin, K. P., Carroll, J., Millstein, R., Lesch, K.-P., Murphy, D. L., & Holmes, A. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4595-06.2007 · Cited by 366
“These effects are localized to neurons in the IL (Milad and Quirk, 2002).”
BackgroundRedish, A. D., Jensen, S., Johnson, A., & Kurth-Nelson, Z. (2007) · Psychological Review · doi:10.1037/0033-295x.114.3.784 · Cited by 346
“This may be because prefrontal cortex is only recruited into the process during extinction (Milad and Quirk, 2002; Milad et al., 2004), while hippocampus always provides input to accumbens functionality.”
BackgroundGuyer, A. E., Lau, J. Y. F., McClure-Tone, E. B., Parrish, J., Shiffrin, N. D., Reynolds, R. C., Chen, G., Blair, R. J. R., Leibenluft, E., Fox, N. A., et al. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.11.1303 · Cited by 371
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“Instead, they respond primarily to a predictive CS presented 24 h later, perhaps reflecting retention of the extinction memory (Milad and Quirk, 2002).”
BackgroundResultInfluentialSynaptic correlates of fear extinction in the amygdala
Amano, T., Ünal, Ç. T., & Paré, D. (2010) · Nature Neuroscience · doi:10.1038/nn.2499 · Cited by 384
Synaptic Encoding of Fear Extinction in mPFC-amygdala Circuits
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“Previous studies have specifically implicated the activity of the infralimbic division of the mPFC (IL/mPFC) in the formation of extinction memory (Milad and Quirk, 2002; Burgos-Robles et al., 2009).”
BackgroundInfluentialQuirk, G. J. (2002) · Learning & Memory · doi:10.1101/lm.49602 · Cited by 360
“1999), and tone responses of infralimbic neurons (Milad and Quirk 2002) are potentiated.”
BackgroundSelf-citationZeidan, M. A., Igoe, S. A., Linnman, C., Vitalo, A., Levine, J. B., Klibanski, A., Goldstein, J. M., & Milad, M. R. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.016 · Cited by 354
Self-citationPrefrontal Control of the Amygdala
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“This finding may be relevant to previous studies demonstrating complementary but separate roles for dorsal vs ventral regions of the mPFC in the evaluation of predictive biologically relevant stimuli [4,5,13,14].”
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“On Day 3, the 0.1-s group continued to have significantly lower values than controls, showing 30% freezing as compared with 62.1% for the control group (see Figure 2B), replicating our previous observation that IL stimulation strengthens extinction memory (Milad & Quirk, 2002).”
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Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder
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“Consistent with this, studies have demonstrated that the mPFC is involved in extinction or recovery of affective behaviors (Eichenbaum et al., 1974; Quirk et al., 2000; Milad and Quirk, 2002; Myers and Davis, 2002).”
ResultBrenhouse, H. C., & Andersen, S. L. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.04.013 · Cited by 363
“This function is performed by dopaminergic signals in the mPFC (Jackson and Moghaddam, 2004), which encode additional information of salience and novelty with emotional information (Cardinal et al., 2002; Milad and Quirk, 2002) to influence goal-directed, motivated behavior.”
BackgroundGoldwater, D. S., Pavlides, C., Hunter, R. G., Bloss, E. B., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.08.053 · Cited by 333
“By recording from the mPFC during fear conditioning, extinction, and extinction recall, Milad and Quirk (2002) showed that IL neurons were active only in extinction recall (Milad and Quirk, 2002), suggesting active IL suppression of amygdala output during this behavior.”
MethodStress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling
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“In particular, aversive extinction (in which aversive outcomes are omitted) is known to be mediated by active learning that involves inputs from medial prefrontal cortex, in contrast to the more direct acquisition of excitatory values (Maren and Quirk, 2004; Milad and Quirk, 2002).”
BackgroundStress and the adolescent brain
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“The PFC sends projections to the amygdala that modulate amygdala reactivity (Milad & Quirk, 2002).”
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“…in activation that have been observed in both the medial prefrontal cortex and the amygdala in PTSD may reflect a functional relationship between these two structures, in which the medial prefrontal cortex exerts a modulatory or inhibitory activity on the amygdala (Milad and Quirk, 2002).”
BackgroundThe Role of the Orbitofrontal Cortex in Anxiety Disorders
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Self-citationInhibition of the Amygdala: Key to Pathological States?
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Self-citationThe amygdala and medial prefrontal cortex: partners in the fear circuit
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“…stimuli that are clearly dangerous in one setting initially evoke an aversive response, but continue to be perceived as threatening even when circumstances change, thereby leading to inappropriate responses in conditions where a fear response is no longer appropriate (Milad & Quirk, 2012).”
BackgroundDistinct hippocampal engrams control extinction and relapse of fear memory
Lacagnina, A. F., Brockway, E. T., Crovetti, C. R., Shue, F., McCarty, M. J., Sattler, K. P., Lim, S. C., Santos, S. L., Denny, C. A., & Drew, M. R. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0361-z · Cited by 311
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“The ventral medial prefrontal cortex (VMPFC), which consists of infra- and prelimbic cortex, is not a clearly defined structure [Milad and Quirk, 2002] and has been considered to include both BA 11 (Paulus et al.”
BackgroundFear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala
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“, 2009) and the IL in safety (Milad and Quirk, 2002) may be defined by segregated amygdala afferents.”
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“…see Tamminga, 2006), substantial evidence suggests that mPFC plays a critical role in the representation of fear extinction (Quirk et al., 2000; Milad and Quirk, 2002; for review, see Stotres-Bayon et al., 2004; Quirk et al., 2006), and hippocampal modulation of mPFC may control LA projections…”
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“Moreover, mPFC lesions induce sensitized stress responses and deficits in fear extinction (Holson, 1986; Silva et al., 1986; Diorio et al., 1993; Milad and Quirk, 2002), suggesting that stress-induced impairment of mPFC, mediated partly via FosB induction, could contribute to depression and other…”
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“Lesions [26-28], pharmacological manipulations [24,29,30] and electrophysiological recording [31] studies implicate the IL in extinction memory consolidation and expression.”
BackgroundSelf-citationOrsini, C. A., Kim, J. H., Knapska, E., & Maren, S. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4095-11.2011 · Cited by 315
“Collectively, these data support the view that the IL has an important role in the retrieval of extinction memories (Milad and Quirk, 2002; Sierra-Mercado et al., 2006).”
BackgroundMcCrory, E. J., & Viding, E. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000115 · Cited by 295
“For example, the amygdala plays a critical role in fear extinction (where an individual ceases to regard a given stimulus as threatening) along with several other brain areas (in particular the ventromedial prefrontal cortex; Milad & Quirk, 2002).”
BackgroundNeuroanatomical circuits modulating fear and anxiety behaviors
Charney, D. S. (2003) · Acta Psychiatrica Scandinavica · doi:10.1034/j.1600-0447.108.s417.3.x · Cited by 293
Mueller, D., Porter, J. T., & Quirk, G. J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3248-07.2008 · Cited by 284
“This raises the question, does arousal-evoked NE release strengthen memory for extinction as it does for conditioning? To investigate the effects of NE on extinction memory, we focused on the infralimbic (IL) prefrontal cortex, a structure critical for consolidation and retrieval of fear extinction (Quirk et al., 2000…”
BackgroundSelf-citationChronic Pain and Chronic Stress: Two Sides of the Same Coin?
Abdallah, C. G., & Geha, P. (2017) · Chronic Stress · doi:10.1177/2470547017704763 · Cited by 311
“The hippocampus, amygdala, and PFC each play a critical role in fear learning and extinction.(45,52,53) The neurochemical properties of the learning circuitry and its adaptive response to chronic stress or pain are believed to be crucial in determining remission or persistence of pain and stress response beyond what i…”
BackgroundDevelopment of anxiety: the role of threat appraisal and fear learning
Britton, J. C., Lissek, S. M., Grillon, C., Norcross, M. A., & Pine, D. S. (2010) · Depression and Anxiety · doi:10.1002/da.20733 · Cited by 303
“Rodents with IL lesions not only show normal conditioning and extinction but also show an exaggerated return of fear on retesting one day after extinction training.([89]) Neuroimaging studies of extinction recall among adults demonstrate the clinical relevance of such findings.”
BackgroundAkirav, I., & Maroun, M. (2007) · Neural Plasticity · doi:10.1155/2007/30873 · Cited by 293
“For example, Milad and Quirk [66] found that stimulation of the mPFC decreases the responsiveness of central amygdala neurons that regularly fire in response to the CS only when animals are recalling extinction of a fear task learned using that CS.”
BackgroundInfluentialPuberty and adolescence as a time of vulnerability to stressors that alter neurobehavioral processes
Holder, M. K., & Blaustein, J. D. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.10.004 · Cited by 279
Amygdala Reward Neurons Form and Store Fear Extinction Memory
Zhang, X., Kim, J., & Tonegawa, S. (2019) · Neuron · doi:10.1016/j.neuron.2019.12.025 · Cited by 280
Context modulation of memory for fear extinction in humans
Milad, M. R., Orr, S. P., Pitman, R. K., & Rauch, S. L. (2005) · Psychophysiology · doi:10.1111/j.1469-8986.2005.00302.x · Cited by 297
Self-citationActive Avoidance Learning Requires Prefrontal Suppression of Amygdala-Mediated Defensive Reactions
Moscarello, J. M., & LeDoux, J. E. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2596-12.2013 · Cited by 277
“Although ilPFC can attenuate CeA activity and the reactive behaviors it governs (Milad and Quirk, 2002; Quirk et al., 2003; Likhtik et al., 2005), this must occur via an intervening mechanism for excitatory cortical inputs to inhibit amygdalar outputs.”
BackgroundSantini, E., Quirk, G. J., & Porter, J. T. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2623-07.2008 · Cited by 270
“Moreover, extinction potentiates IL activity relative to conditioning, and this potentiation is correlated with expression of extinction memory (Herry and Garcia, 2002; Milad and Quirk, 2002; Barrett et al., 2003).”
BackgroundSelf-citationSotres-Bayón, F., Bush, D. E. A., & LeDoux, J. E. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301316 · Cited by 298
“Other likely candidate sites are the medial prefrontal cortex (Morgan et al, 1993; Quirk et al, 2000; Milad and Quirk, 2002; Santini et al, 2004), the periaqueductal gray matter (McNally et al, 2004), and the hippocampus (Corcoran et al, 2005).”
BackgroundCallaghan, B. L., & Tottenham, N. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.204 · Cited by 268
Knapska, E., & Maren, S. (2009) · Learning & Memory · doi:10.1101/lm.1463909 · Cited by 264
“It has also been shown that pairing CSs with electrical stimulation of the IL accelerates extinction and reduces conditioned freezing (Milad and Quirk 2002; Milad et al. 2004).”
BackgroundSeeking a Spotless Mind: Extinction, Deconsolidation, and Erasure of Fear Memory
Maren, S. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.023 · Cited by 259
“Prefrontal cortical neurons also exhibit physiological changes, including increased bursting, during extinction learning (Burgos-Robles et al., 2007; Chang et al., 2010; Milad and Quirk, 2002).”
BackgroundAltered Processing of Contextual Information during Fear Extinction in PTSD: An fMRI Study
Rougemont-Bücking, A., Linnman, C., Zeffiro, T. A., Zeidan, M. A., Lebron-Milad, K., Rodriguez-Romaguera, J., Rauch, S. L., Pitman, R. K., & Milad, M. R. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00152.x · Cited by 292
“IL facilitates fear inhibition [22], whereas PL facilitates fear expression [23].”
BackgroundSelf-citationCorticolimbic blood flow in posttraumatic stress disorder during script-driven imagery
Britton, J. C., Phan, K. L., Taylor, S. F., Fig, L. M., & Liberzon, I. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.12.025 · Cited by 265
Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling
Azad, S. C., Monory, K., Marsicano, G., Cravatt, B. F., Lutz, B., Zieglgänsberger, W., & Rammes, G. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.2134-04.2004 · Cited by 263
Kern, S., Oakes, T. R., Stone, C. K., McAuliff, E. M., Kirschbaum, C., & Davidson, R. J. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.01.010 · Cited by 272
“This hypothesis is supported by rodent data, which implicate a central role of the mPFC in extinction of aversive learning with lesions of this region resulting in impairments of extinction (Milad and Quirk, 2002).”
ResultSierra‐Mercado, D., Corcoran, K. A., Lebrón‐Milad, K., & Quirk, G. J. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05014.x · Cited by 255
“Moreover, tone-evoked responses of IL mPFC neurones are increased during recall of extinction (Milad & Quirk, 2002).”
BackgroundSelf-citationBryant, R. A., Kemp, A. H., Felmingham, K. L., Liddell, B. J., Olivieri, G., Peduto, A. J., Gordon, E., & Williams, L. M. (2007) · Human Brain Mapping · doi:10.1002/hbm.20415 · Cited by 251
“Animal research in fear conditioning lend support to biological models of PTSD suggesting that exaggerated amygdala responses to fear reflect a lack of ‘‘top-down’’ inhibition by the MPFC [Milad and Quirk, 2002; Morgan et al., 1993].”
BackgroundThe Bed Nucleus of the Stria Terminalis Mediates Inter-individual Variations in Anxiety and Fear
Duvarci, S., Bauer, E. P., & Paré, D. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2119-09.2009 · Cited by 251
“In some instances, these variations were seen between subjects of the same strain (Milad and Quirk, 2002; Burgos-Robles et al., 2007).”
BackgroundAmygdala and hippocampal activity during acquisition and extinction of human fear conditioning
Knight, D. C., Smith, C. N., Cheng, D. T., Stein, E. A., & Helmstetter, F. J. (2004) · Cognitive, Affective, & Behavioral Neuroscience · doi:10.3758/cabn.4.3.317 · Cited by 249
“Short-term extinction processes appear to be mediated through amygdala-dependent circuitry, and modulation of this circuitry by the ventromedial prefrontal cortex may be critical for long-term extinction ( Milad & Quirk, 2002; Quirk, Russo, Barron, & Lebron, 2000; Santini et al., 2001).”
BackgroundExperimental extinction in Pavlovian conditioning: Behavioural and neuroscience perspectives
Delamater, A. R. (2004) · The Quarterly Journal of Experimental Psychology Section B · doi:10.1080/02724990344000097 · Cited by 257
Stress and cardiovascular disease: an update
Vaccarino, V., & Bremner, J. (2024) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01024-y · Cited by 229
Lehmann, M. L., & Herkenham, M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0577-11.2011 · Cited by 234
“Accordingly, stimulation of the IL cortex promotes extinction of conditioned fear (Milad and Quirk, 2002), whereas neurochemical IL inactivation (Santini et al.”
BackgroundLearning models of PTSD: Theoretical accounts and psychobiological evidence
Lissek, S. M., & van Meurs, B. (2014) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2014.11.006 · Cited by 271
Amygdala BDNF signaling is required for consolidation but not encoding of extinction
Chhatwal, J. P., Rattiner, L. M., Davis, M., & Ressler, K. J. (2006) · Nature Neuroscience · doi:10.1038/nn1718 · Cited by 243
Carhart-Harris, R. L., Leech, R., Williams, T. M., Erritzoe, D., Abbasi, N., Bargiotas, T., Hobden, P., Sharp, D. J., Evans, J., Feilding, A., et al. (2012) · British Journal of Psychiatry · doi:10.1192/bjp.bp.111.103309 · Cited by 237
Lesions of the Basal Amygdala Block Expression of Conditioned Fear But Not Extinction
Anglada-Figueroa, D., & Quirk, G. J. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2600-05.2005 · Cited by 238
“The LA and IL are reciprocally connected (Condé et al., 1995; Vertes, 2004), and recent data suggest that the IL is a site of consolidation of extinction memory (Milad and Quirk, 2002; Hugues et al., 2004; Santini et al., 2004) (but see Gewirtz et al., 1997).”
BackgroundInfluentialSelf-citationThe self in context: brain systems linking mental and physical health
Koban, L., Gianaros, P. J., Hedy Kober, A., & Wager, T. D. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00446-8 · Cited by 258
Role of corticotropin releasing factor in anxiety disorders: A translational research perspective
Risbrough, V. B., & Stein, M. B. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2006.06.019 · Cited by 243
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript animal models of extinction may be well suited for translational studies of pathologies underlying abnormal fear learning and extinction, as proposed in PTSD (Milad and Quirk, 2002;Myers and Davis, 2002).”
MethodLaviolette, S. R., Lipski, W. J., & Grace, A. A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1168-05.2005 · Cited by 235
“…division of the amygdala (BLA) are anatomically and functionally interconnected (Aggleton, 2000) and are critical for the processing and integration of emotionally salient sensory information and learning (Garcia et al., 1999; Milad and Quirk, 2002; Rosenkranz and Grace, 2002; Milad et al., 2004).”
BackgroundPrefrontal inputs to the amygdala instruct fear extinction memory formation
Bukalo, O., Pinard, C. R., Silverstein, S., Brehm, C., Hartley, N. D., Whittle, N., Colacicco, G., Busch, E., Patel, S., Singewald, N., et al. (2015) · Science Advances · doi:10.1126/sciadv.1500251 · Cited by 234
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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