Switching on and off fear by distinct neuronal circuits
Abstract
Switching between exploratory and defensive behaviour is fundamental to survival of many animals, but how this transition is achieved by specific neuronal circuits is not known. Here, using the converse behavioural states of fear extinction and its context-dependent renewal as a model in mice, we show that bi-directional transitions between states of high and low fear are triggered by a rapid switch in the balance of activity between two distinct populations of basal amygdala neurons. These two populations are integrated into discrete neuronal circuits differentially connected with the hippocampus and the medial prefrontal cortex. Targeted and reversible neuronal inactivation of the basal amygdala prevents behavioural changes without affecting memory or expression of behaviour. Our findings indicate that switching between distinct behavioural states can be triggered by selective activation of specific neuronal circuits integrating sensory and contextual information. These observations provide a new framework for understanding context-dependent changes of fear behaviour.
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There are distinct engrams for fear and extinction memories within the amygdala.
“there do appear to be distinct engrams for fear and extinction memories within the amygdala (Herry et al., 2008)”
From Retrieval-Dependent Mechanisms Affecting Emotional Memory Persistence: Reconsolidation, Extinction, and the Space in Between (2020) · cites this paper as Herry et al., 2008
Principal neurons and interneurons in the BLA receive monosynaptic input from the mPFC and vHPC, and send reciprocal projections to both of these regions.
“principal neurons and interneurons in the BLA have been shown to receive monosynaptic input from mPFC and vHPC, and send reciprocal projections to both of these regions66-68.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [67]
Neighboring cells in the basal amygdala that are innervated by PFC afferents fire in response to extinguished conditioned stimuli and project reciprocally to the PFC.
“Neighboring cells in the basal amygdala that are innervated by PFC afferents fire in response to conditioned stimuli that have been extinguished, and they project reciprocally to the PFC67.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [67]
Activation of fear-encoding neurons in the basal amygdala is necessary for fear renewal after extinction.
“the activation of these cells is necessary for fear renewal after extinction67.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [67]
The vHPC specifically targets fear-encoding neurons in the basal amygdala.
“the vHPC specifically targets fear-encoding neurons in the basal amygdala (which themselves project to the mPFC)”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [67]
AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons necessary for the encoding of extinction memories.
“This suggests a scheme in which AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons [50,51,86] necessary for the encoding of extinction memories [102] (Figure 2).”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [102]
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444 · see citing works
mouse brain in stereotaxic coordinates
Franklin, K. B. J., & Paxinos, G. (1997) · Cited by 3,258 · see citing works
THE AMYGDALA MODULATES THE CONSOLIDATION OF MEMORIES OF EMOTIONALLY AROUSING EXPERIENCES
McGaugh, J. L. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144157 · Cited by 2,296 · see citing works
Neurons in medial prefrontal cortex signal memory for fear extinction
Milad, M. R., & Quirk, G. J. (2002) · Nature · doi:10.1038/nature01138 · Cited by 1,836 · see citing works
Context, ambiguity, and unlearning: sources of relapse after behavioral extinction
Bouton, M. E. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01546-9 · Cited by 1,662 · see citing works
Neuronal signalling of fear memory
Maren, S., & Quirk, G. J. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1535 · Cited by 1,428 · see citing works
Myers, K. M., & Davis, M. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001939 · Cited by 1,277 · see citing works
Pitkänen, A., Pikkarainen, M., Nurminen, N., & Ylinen, A. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06738.x · Cited by 962 · see citing works
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 · see citing works
New Vistas on Amygdala Networks in Conditioned Fear
Paré, D., Quirk, G. J., & Ledoux, J. E. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00153.2004 · Cited by 841 · see citing works
Quirk, G. J., Repa, J. C., & LeDoux, J. E. (1995) · Neuron · doi:10.1016/0896-6273(95)90092-6 · Cited by 808 · see citing works
Chronic, multisite, multielectrode recordings in macaque monkeys
Nicolelis, M. A. L., Dimitrov, D., Carmena, J. M., Crist, R., Lehew, G., Kralik, J. D., & Wise, S. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1934665100 · Cited by 740 · see citing works
McDonald, A. J., Mascagni, F., & Guo, L. (1996) · Neuroscience · doi:10.1016/0306-4522(95)00417-3 · Cited by 689 · see citing works
Prefrontal mechanisms in extinction of conditioned fear
Quirk, G. J., Garcia, R., & González-Lima, F. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.010 · Cited by 682 · see citing works
Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala
Falls, W., Miserendino, M., & Davis, M. (1992) · The Journal of Neuroscience · doi:10.1523/jneurosci.12-03-00854.1992 · Cited by 673 · see citing works
Contextual and temporal modulation of extinction: behavioral and biological mechanisms
Bouton, M. E., Westbrook, R. F., Corcoran, K. A., & Maren, S. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.12.015 · Cited by 671 · see citing works
A receptor that mediates the post-mating switch in Drosophila reproductive behaviour
Yapici, N., Kim, Y., Ribeiro, C., & Dickson, B. J. (2007) · Nature · doi:10.1038/nature06483 · Cited by 590 · see citing works
The learning curve: implications of a quantitative analysis.
Gallistel, C., Fairhurst, S. P., & Balsam, P. (2004) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0404965101 · Cited by 587 · see citing works
Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat
McDonald, A. J. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90247-l · Cited by 463 · see citing works
Hippocampal Inactivation Disrupts Contextual Retrieval of Fear Memory after Extinction
Corcoran, K. A., & Maren, S. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-05-01720.2001 · Cited by 455 · see citing works
Goosens, K. A., & Maren, S. (2001) · Learning & Memory · doi:10.1101/lm.37601 · Cited by 451 · see citing works
Two different lateral amygdala cell populations contribute to the initiation and storage of memory
Repa, J. C., Muller, J., Apergis, J., Desrochers, T. M., Zhou, Y., & LeDoux, J. E. (2001) · Nature Neuroscience · doi:10.1038/89512 · Cited by 440 · see citing works
Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction.Preprint
Sotres-Bayon, F., Bush, D. E. A., & LeDoux, J. E. (2004) · Learning & memory (Cold Spring Harbor, N.Y.) · doi:10.1101/lm.79504 · Cited by 437 · see citing works
Processing of Temporal Unpredictability in Human and Animal Amygdala
Herry, C., Bach, D. R., Esposito, F., Di Salle, F., Perrig, W. J., Scheffler, K., Lüthi, A., & Seifritz, E. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5218-06.2007 · Cited by 401 · see citing works
Self-citationHippocampal Inactivation Disrupts the Acquisition and Contextual Encoding of Fear Extinction
Corcoran, K., Desmond, T., Frey, K., & Maren, S. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2246-05.2005 · Cited by 390 · see citing works
Amorapanth, P., LeDoux, J. E., & Nader, K. (2000) · Nature Neuroscience · doi:10.1038/71145 · Cited by 374 · see citing works
Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning
Rosenkranz, J. A., & Grace, A. A. (2002) · Nature · doi:10.1038/417282a · Cited by 348 · see citing works
Rosenkranz, J. A., Moore, H., & Grace, A. A. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-35-11054.2003 · Cited by 344 · see citing works
Herry, C., & Garcia, R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-02-00577.2002 · Cited by 323 · see citing works
Self-citationSotres-Bayon, F., Bush, D. E. A., & LeDoux, J. E. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301316 · Cited by 293 · see citing works
Context modulation of memory for fear extinction in humans.
Milad, M., Orr, S., Pitman, R., & Rauch, S. (2005) · Psychophysiology · doi:10.1111/j.1469-8986.2005.00302.x · Cited by 289 · see citing works
Role of the basolateral amygdala in memory consolidation
Paré, D. (2003) · Progress in Neurobiology · doi:10.1016/s0301-0082(03)00104-7 · Cited by 288 · see citing works
Nader, K., Majidishad, P., Amorapanth, P., & LeDoux, J. E. (2001) · Learning & Memory · doi:10.1101/lm.38101 · Cited by 272 · see citing works
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 · see citing works
Infralimbic cortex activation increases c-fos expression in intercalated neurons of the amygdala
Berretta, S., Pantazopoulos, H., Caldera, M., Pantazopoulos, P., & Paré, D. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.01.020 · Cited by 223 · see citing works
Lu, K., Walker, D. L., & Davis, M. E. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-16-j0005.2001 · Cited by 222 · see citing works
Hobin, J. A., Ji, J.-Z., & Maren, S. (2006) · Hippocampus · doi:10.1002/hipo.20144 · Cited by 211 · see citing works
Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala
Herry, C., Trifilieff, P., Micheau, J., Lüthi, A., & Mons, N. E. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.04893.x · Cited by 203 · see citing works
Self-citationHerry, C., & Mons, N. E. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03542.x · Cited by 192 · see citing works
Self-citationBasolateral Amygdala Lesions Abolish Orbitofrontal-Dependent Reversal Impairments
Stalnaker, T. A., Franz, T. M., Singh, T., & Schoenbaum, G. M. (2007) · Neuron · doi:10.1016/j.neuron.2007.02.014 · Cited by 178 · see citing works
Compact Movable Microwire Array for Long-Term Chronic Unit Recording in Cerebral Cortex of Primates
Jackson, A., & Fetz, E. E. (2007) · Journal of Neurophysiology · doi:10.1152/jn.00569.2007 · Cited by 174 · see citing works
Collins, D. R., & Paré, D. (2000) · Learning & Memory · doi:10.1101/lm.7.2.97 · Cited by 171 · see citing works
Emotional enhancement of memory via amygdala-driven facilitation of rhinal interactions
Paz, R., Pelletier, J. G., Bauer, E. P., & Paré, D. (2006) · Nature Neuroscience · doi:10.1038/nn1771 · Cited by 167 · see citing works
Context-specificity of relapse: effects of therapist and environmental context on return of fear.
Rodriguez, B. I., Craske, M., Mineka, S., & Hladek, D. (1999) · Behaviour Research and Therapy · doi:10.1016/s0005-7967(98)00106-5 · Cited by 152 · see citing works
Auditory-Evoked Spike Firing in the Lateral Amygdala and Pavlovian Fear Conditioning
Goosens, K. A., Hobin, J. A., & Maren, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00728-1 · Cited by 135 · see citing works
Rat amygdaloid neuron responses during auditory discrimination
Muramoto, K., Ono, T., Nishijo, H., & Fukuda, M. (1993) · Neuroscience · doi:10.1016/0306-4522(93)90411-8 · Cited by 121 · see citing works
Maren, S., Poremba, A., & Michael, G. (1991) · Brain Research · doi:10.1016/0006-8993(91)90473-9 · Cited by 96 · see citing works
Jing, J., & Gillette, R. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.83.3.1346 · Cited by 70 · see citing works
Likhtik, E., Pelletier, J. G., Popescu, A. T., & Paré, D. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00577.2006 · Cited by 66 · see citing works
Cocaine-induced decision-making deficits are mediated by miscoding in basolateral amygdala
Stalnaker, T. A., Roesch, M. R., Franz, T. M., Calu, D. J., Singh, T., & Schoenbaum, G. M. (2007) · Nature Neuroscience · doi:10.1038/nn1931 · Cited by 53 · see citing works
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From circuits to behaviour in the amygdala
Janak, P. H., & Tye, K. M. (2015) · Nature · doi:10.1038/nature14188 · Cited by 2,011 · see citing works
Neuronal circuits for fear and anxiety
Tovote, P., Fadok, J. P., & Lüthi, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3945 · Cited by 1,786 · see citing works
Self-citationYang, J. C., Mun, J., Kwon, S. Y., Park, S., Bao, Z., & Park, S. (2019) · Advanced Materials · doi:10.1002/adma.201904765 · Cited by 1,641 · see citing works
The contextual brain: implications for fear conditioning, extinction and psychopathology
Maren, S., Phan, K. L., & Liberzon, I. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3492 · Cited by 1,547 · see citing works
Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress
Milad, M. R., & Quirk, G. J. (2012) · Annual Review of Psychology · doi:10.1146/annurev.psych.121208.131631 · Cited by 1,466 · see citing works
Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder
Milad, M. R., Pitman, R. K., Ellis, C. B., Gold, A. L., Shin, L. M., Lasko, N. B., Zeidan, M. A., Handwerger, K., Orr, S. P., & Rauch, S. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.026 · Cited by 1,339 · see citing works
Sierra-Mercado, D., Padilla-Coreano, N., & Quirk, G. J. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.184 · Cited by 1,190 · see citing works
Pape, H.-C., & Pare, D. (2010) · Physiological Reviews · doi:10.1152/physrev.00037.2009 · Cited by 994 · see citing works
Encoding of conditioned fear in central amygdala inhibitory circuits
Ciocchi, S., Herry, C., Grenier, F., Wolff, S. B. E., Letzkus, J. J., Vlachos, I., Ehrlich, I., Sprengel, R., Deisseroth, K., Stadler, M. B., et al. (2010) · Nature · doi:10.1038/nature09559 · Cited by 924 · see citing works
Self-citationFunctional identification of an aggression locus in the mouse hypothalamus
Lin, D., Boyle, M. P., Dollar, P., Lee, H., Lein, E. S., Perona, P., & Anderson, D. J. (2011) · Nature · doi:10.1038/nature09736 · Cited by 914 · see citing works
Amygdala inhibitory circuits and the control of fear memory
Ehrlich, I., Humeau, Y., Grenier, F., Ciocchi, S., Herry, C., & Lüthi, A. (2009) · Neuron · doi:10.1016/j.neuron.2009.05.026 · Cited by 878 · see citing works
Self-citationGenetic dissection of an amygdala microcircuit that gates conditioned fear
Haubensak, W., Kunwar, P. S., Cai, H., Ciocchi, S., Wall, N. R., Ponnusamy, R., Biag, J., Dong, H.-W., Deisseroth, K., Callaway, E. M., et al. (2010) · Nature · doi:10.1038/nature09553 · Cited by 840 · see citing works
Self-citationPerineuronal Nets Protect Fear Memories from Erasure
Gogolla, N., Caroni, P., Lüthi, A., & Herry, C. (2009) · Science · doi:10.1126/science.1174146 · Cited by 760 · see citing works
Self-citationResolving the neural circuits of anxiety
Calhoon, G. G., & Tye, K. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4101 · Cited by 766 · see citing works
Extinction circuits for fear and addiction overlap in prefrontal cortex
Peters, J., Kalivas, P. W., & Quirk, G. J. (2009) · Learning & Memory · doi:10.1101/lm.1041309 · Cited by 736 · see citing works
Amygdala Microcircuits Controlling Learned Fear
Duvarci, S., & Pare, D. (2014) · Neuron · doi:10.1016/j.neuron.2014.04.042 · Cited by 751 · see citing works
Neural recording and modulation technologies
Chen, R., Canales, A., & Anikeeva, P. (2017) · Nature Reviews Materials · doi:10.1038/natrevmats.2016.93 · Cited by 655 · see citing works
Prefrontal control of fear: more than just extinction
Sotres-Bayon, F., & Quirk, G. J. (2010) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2010.02.005 · Cited by 625 · see citing works
“Focal inactivation of BA prevented not only renewal of fear after extinction, but also expression of extinction, depending on the time point of inactivation [38 ].”
BackgroundInfluentialPrefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety
Likhtik, E., Stujenske, J. M., A Topiwala, M., Harris, A. Z., & Gordon, J. A. (2014) · Nature Neuroscience · doi:10.1038/nn.3582 · Cited by 577 · see citing works
Burgos-Robles, A., Vidal-Gonzalez, I., & Quirk, G. J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0378-09.2009 · Cited by 530 · see citing works
Bidirectional switch of the valence associated with a hippocampal contextual memory engram
Redondo, R. L., Kim, J., Arons, A. L., Ramirez, S., Liu, X., & Tonegawa, S. (2014) · Nature · doi:10.1038/nature13725 · Cited by 512 · see citing works
Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression
Courtin, J., Chaudun, F., Rozeske, R. R., Karalis, N., Gonzalez-Campo, C., Wurtz, H., Abdi, A., Baufreton, J., Bienvenu, T. C. M., & Herry, C. (2014) · Nature · doi:10.1038/nature12755 · Cited by 524 · see citing works
Self-citationLong-range connectivity defines behavioral specificity of amygdala neurons
Senn, V., Wolff, S. B. E., Herry, C., Grenier, F., Ehrlich, I., Gründemann, J., Fadok, J. P., Müller, C., Letzkus, J. J., & Lüthi, A. (2014) · Neuron · doi:10.1016/j.neuron.2013.11.006 · Cited by 522 · see citing works
The ecology of human fear: survival optimization and the nervous system
Mobbs, D., Hagan, C. C., Dalgleish, T., Silston, B., & Prévost, C. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00055 · Cited by 498 · see citing works
The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear
Giustino, T. F., & Maren, S. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00298 · Cited by 519 · see citing works
The neurobiology of depression and antidepressant action
Willner, P., Scheel-Krüger, J., & Belzung, C. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.12.007 · Cited by 519 · see citing works
Neuronal circuits of fear extinction
Herry, C., Ferraguti, F., Singewald, N., Letzkus, J. J., Ehrlich, I., & Lüthi, A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07101.x · Cited by 484 · see citing works
Self-citationEncoding of fear learning and memory in distributed neuronal circuits
Herry, C., & Johansen, J. P. (2014) · Nature Neuroscience · doi:10.1038/nn.3869 · Cited by 474 · see citing works
Self-citationStress-induced prefrontal reorganization and executive dysfunction in rodents
Holmes, A., & Wellman, C. L. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.11.005 · Cited by 469 · see citing works
Neural and cellular mechanisms of fear and extinction memory formation
Orsini, C. A., & Maren, S. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.12.014 · Cited by 429 · see citing works
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A., & Ressler, K. J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.12.004 · Cited by 390 · see citing works
“The basal AMY (BA) contains extinction-encoding neurons which drive GABAergic cells in themedial intercalated cell masses (ITC) and neurons in the centrolateral AMY (CeL) to inhibit the CeM and the expression of fear (Duvarci & Pare, 2014; Herry et al., 2008).”
BackgroundOpposite effects of fear conditioning and extinction on dendritic spine remodelling.
Lai, C. S. W., Franke, T. F., & Gan, W.-B. (2012) · Nature · doi:10.1038/nature10792 · Cited by 392 · see citing works
Hare, B. D., & Duman, R. S. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0685-9 · Cited by 366 · see citing works
Zeidan, 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 · see citing works
Neural ensemble dynamics underlying a long-term associative memory
Grewe, B. F., Gründemann, J., Kitch, L. J., Lecoq, J. A., Parker, J. G., Marshall, J. D., Larkin, M. C., Jercog, P. E., Grenier, F., Li, J. Z., et al. (2017) · Nature · doi:10.1038/nature21682 · Cited by 351 · see citing works
Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment
Burgos-Robles, A., Kimchi, E. Y., Izadmehr, E. M., Porzenheim, M. J., Ramos-Guasp, W. A., Nieh, E. H., Felix-Ortiz, A. C., Namburi, P., Leppla, C. A., Presbrey, K. N., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4553 · Cited by 318 · see citing works
Laurent, V., & Westbrook, R. F. (2009) · Learning & Memory · doi:10.1101/lm.1474609 · Cited by 311 · see citing works
The amygdala and medial prefrontal cortex: partners in the fear circuit
Marek, R., Strobel, C., Bredy, T. W., & Sah, P. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2012.248575 · Cited by 304 · see citing works
Prefrontal-Hippocampal Interactions in Memory and Emotion
Jin, J., & Maren, S. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00170 · Cited by 313 · see citing works
“Ultimately, the hippocampus appears to gate reciprocal mPFC-amygdala circuits involved in the expression and inhibition of fear (Herry et al., 2008; Knapska and Maren, 2009; Knapska et al., 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 · see citing works
Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala
Stujenske, J. M., Likhtik, E., Topiwala, M. A., & Gordon, J. A. (2014) · Neuron · doi:10.1016/j.neuron.2014.07.026 · Cited by 303 · see citing works
Overlapping neural systems mediating extinction, reversal and regulation of fear
Schiller, D., & Delgado, M. R. (2010) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2010.04.002 · Cited by 294 · see citing works
Reactivations of emotional memory in the hippocampus-amygdala system during sleep
Girardeau, G., Inema, I., & Buzsáki, G. (2017) · Nature Neuroscience · doi:10.1038/nn.4637 · Cited by 266 · see citing works
Stress, anxiety, and dendritic spines: What are the connections?
Leuner, B., & Shors, T. J. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.021 · Cited by 284 · see citing works
Lesting, J., Narayanan, R. T., Kluge, C., Sangha, S., Seidenbecher, T., & Pape, H.-C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021714 · Cited by 275 · see citing works
Knapska, E., & Maren, S. (2009) · Learning & Memory · doi:10.1101/lm.1463909 · Cited by 264 · see citing works
Seeking 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 · see citing works
Merlo, E., Milton, A. L., Goozée, Z. Y., Theobald, D. E., & Everitt, B. J. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.4001-13.2014 · Cited by 242 · see citing works
Neurobiology of fear and specific phobias
Garcia, R. (2017) · Learning & Memory · doi:10.1101/lm.044115.116 · Cited by 239 · see citing works
Prefrontal 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 · see citing works
Amygdala FAAH and anandamide: mediating protection and recovery from stress
Gunduz-Cinar, O., Hill, M. N., McEwen, B. S., & Holmes, A. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.08.008 · Cited by 229 · see citing works
Marek, R., Jin, J., Goode, T. D., Giustino, T. F., Wang, Q., Acca, G. M., Holehonnur, R., Ploski, J. E., Fitzgerald, P. J., Lynagh, T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0073-9 · Cited by 226 · see citing works
Post-training reversible inactivation of the hippocampus enhances novel object recognition memory
Oliveira, A. M. M., Hawk, J. D., Abel, T., & Havekes, R. (2010) · Learning & Memory · doi:10.1101/lm.1625310 · Cited by 222 · see citing works
Amygdala microcircuits mediating fear expression and extinction
Pare, D., & Duvarci, S. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.02.014 · Cited by 193 · see citing works
Pathological circuit function underlying addiction and anxiety disorders
Lüthi, A., & Lüscher, C. (2014) · Nature Neuroscience · doi:10.1038/nn.3849 · Cited by 192 · see citing works
Self-citationRegulating anxiety with extrasynaptic inhibition
Botta, P., Demmou, L., Kasugai, Y., Markovic, M., Xu, C., Fadok, J. P., Lu, T., Poe, M. M., Xu, L., Cook, J. M., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4102 · Cited by 192 · see citing works
Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex
McGarry, L. M., & Carter, A. G. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.0874-16.2016 · Cited by 169 · see citing works
Pattwell, S. S., Liston, C., Jing, D., Ninan, I., Yang, R. R., Witztum, J., Murdock, M. H., Dincheva, I., Bath, K. G., Casey, B. J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11475 · Cited by 175 · see citing works
Reactivation of recall-induced neurons contributes to remote fear memory attenuation
Khalaf, O., Resch, S., Dixsaut, L., Gorden, V., Glauser, L., & Gräff, J. (2018) · Science · doi:10.1126/science.aas9875 · Cited by 146 · see citing works
Pavlovian fear memory circuits and phenotype models of PTSD
Johnson, L. R., McGuire, J., Lazarus, R., & Palmer, A. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.07.004 · Cited by 140 · see citing works
Tronson, N. C., Schrick, C., Guzman, Y. F., Huh, K. H., Srivastava, D. P., Penzes, P., Guedea, A. L., Gao, C., & Radulovic, J. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5619-08.2009 · Cited by 136 · see citing works
Failure of Neural Responses to Safety Cues in Schizophrenia
Holt, D. J., Coombs, G., Zeidan, M. A., Goff, D. C., & Milad, M. R. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.2310 · Cited by 121 · see citing works
The learning of fear extinction
Furini, C., Myskiw, J., & Izquierdo, I. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.10.016 · Cited by 124 · see citing works
Jiang, Y., Oathes, D., Hush, J., Darnall, B., Charvat, M., Mackey, S., & Etkin, A. (2016) · Pain · doi:10.1097/j.pain.0000000000000606 · Cited by 120 · see citing works
Amygdala signaling during foraging in a hazardous environment
Amir, A., Lee, S.-C., Headley, D. B., Herzallah, M. M., & Pare, D. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.0407-15.2015 · Cited by 104 · see citing works
“Consistent with this, many BLA neurons acquire robust responses to negatively or positively valenced CSs after conditioning (Rorick-Kehn and Steinmetz, 2005; Belova et al., 2008; Herry et al., 2008; Shabel and Janak, 2009; Amano et al., 2011).”
BackgroundHübner, C., Bosch, D., Gall, A., Lüthi, A., & Ehrlich, I. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00064 · Cited by 115 · see citing works
Self-citationMoscarello, J. M., & Penzo, M. A. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01130-5 · Cited by 112 · see citing works
Toth, I., Neumann, I. D., & Slattery, D. A. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2702-4 · Cited by 107 · see citing works
Lesting, J., Daldrup, T., Narayanan, V., Himpe, C., Seidenbecher, T., & Pape, H.-C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077707 · Cited by 105 · see citing works
Fear thou not: activity of frontal and temporal circuits in moments of real-life courage
Nili, U., Goldberg, H., Weizman, A., & Dudai, Y. (2010) · Neuron · doi:10.1016/j.neuron.2010.06.009 · Cited by 100 · see citing works
Orexins and fear: Implications for the treatment of anxiety disorders
Flores, Á., Saravia, R., Maldonado, R., & Berrendero, F. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.06.005 · Cited by 102 · see citing works
Rusiecki, J. A., Byrne, C., Galdzicki, Z., Srikantan, V., Chen, L., Poulin, M., Yan, L., & Baccarelli, A. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00056 · Cited by 99 · see citing works
Levy, I., & Schiller, D. (2021) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2020.11.007 · Cited by 95 · see citing works
p300/CBP-Associated Factor Selectively Regulates the Extinction of Conditioned Fear
Wei, W., Coelho, C. M., Li, X., Marek, R., Yan, S., Anderson, S., Meyers, D., Mukherjee, C., Sbardella, G., Castellano, S., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0178-12.2012 · Cited by 93 · see citing works
Bartlett, 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 · see citing works
de Novellis, V., Vita, D., Gatta, L., Luongo, L., Bellini, G., De Chiaro, M., Marabese, I., Siniscalco, D., Boccella, S., Piscitelli, F., et al. (2011) · Molecular Pain · doi:10.1186/1744-8069-7-7 · Cited by 90 · see citing works
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 · see citing works
Hippocampal network oscillations at the interplay between innate anxiety and learned fear
Çalışkan, G., & Stork, O. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5109-z · Cited by 72 · see citing works
Sensitive 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 · see citing works
Sparta, D. R., Smithuis, J., Stamatakis, A. M., Jennings, J. H., Kantak, P. A., Ung, R. L., & Stuber, G. D. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00129 · Cited by 75 · see citing works
Raber, J., Arzy, S., Bertolus, J. B., Depue, B., Haas, H. E., Hofmann, S. G., Kangas, M., Kensinger, E., Lowry, C. A., Marusak, H. A., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.03.015 · Cited by 62 · see citing works
A mismatch-based model for memory reconsolidation and extinction in attractor networks
Osan, R., Tort, A. B. L., & Amaral, O. B. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023113 · Cited by 63 · see citing works
Hetzel, A., & Rosenkranz, J. A. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.60 · Cited by 62 · see citing works
Functional connectivity of the main intercalated nucleus of the mouse amygdala
Mańko, M., Geracitano, R., & Capogna, M. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2010.201475 · Cited by 60 · see citing works
Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit
Do-Monte, F. H., Rodriguez-Romaguera, J., Rosas-Vidal, L. E., & Quirk, G. J. (2013) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00102 · Cited by 58 · see citing works
Prefrontal-Amygdala Connectivity and State Anxiety during Fear Extinction Recall in Adolescents
Ganella, D. E., Barendse, M. E. A., Kim, J. H., & Whittle, S. (2017) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2017.00587 · Cited by 56 · see citing works
A dimensional approach to modeling symptoms of neuropsychiatric disorders in the marmoset monkey
Oikonomidis, L., Santangelo, A. M., Shiba, Y., Clarke, F. H., Robbins, T. W., & Roberts, A. C. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22446 · Cited by 54 · see citing works
Design of a Neurally Plausible Model of Fear Learning
Krasne, F. B., Fanselow, M. S., & Zelikowsky, M. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00041 · Cited by 51 · see citing works
Neurogliaform cells of amygdala: a source of slow phasic inhibition in the basolateral complex
Mańko, M., Bienvenu, T. C. M., Dalezios, Y., & Capogna, M. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.236745 · Cited by 51 · see citing works
McCullough, K. M., Choi, D., Guo, J., Zimmerman, K., Walton, J., Rainnie, D. G., & Ressler, K. J. (2016) · Nature Communications · doi:10.1038/ncomms13149 · Cited by 51 · see citing works
“Highly specific micro-iontophoresis of muscimol specifically into the BLA blocks extinction consolidation without within-session effects 10 .”
BackgroundMerlo, E., Milton, A. L., & Everitt, B. J. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.3273-17.2018 · Cited by 41 · see citing works
Identification of a novel gene regulating amygdala-mediated fear extinction
Gunduz-Cinar, O., Brockway, E., Lederle, L., Wilcox, T., Halladay, L. R., Ding, Y., Oh, H., Busch, E. F., Kaugars, K., Flynn, S., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-017-0003-3 · Cited by 38 · see citing works
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 · see citing works
Vaverková, Z., Milton, A. L., & Merlo, E. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.574358 · Cited by 27 · see citing works
“While there do appear to be distinct engrams for fear and extinction memories within the amygdala (Herry et al., 2008), there is also evidence suggesting that extinction learning requires the reactivation of the original memory in both the hippocampus and amygdala (Khalaf et al.”
BackgroundExpanding the canon: An inclusive neurobiology of thalamic and subthalamic fear circuits
Venkataraman, A., & Dias, B. G. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109380 · Cited by 26 · see citing works
Amygdala EphB2 signaling regulates glutamatergic neuron maturation and innate fear
Zhu, X.-N., Liu, X.-D., Zhuang, H., Henkemeyer, M., Yang, J.-Y., & Xu, N.-J. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.0845-16.2016 · Cited by 22 · see citing works
Layer-specific input to medial prefrontal cortex is linked to stress susceptibility
Solakoğlu, S. T., Erdener, Ş. E., Gliko, O., Can, A., Sümbül, U., & Eren-Koçak, E. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03258-x · Cited by 5 · see citing works
- Authors
- Herry, C., Ciocchi, S., Senn, V., Demmou, L., Müller, C., & Lüthi, A.
- Affiliations
- Friedrich Miescher Institute (CH)
- Corresponding author
- Herry, Cyril
- Lüthi, Andreas
- Venue
- Nature
- Published
- 2008-07
- Volume
- 454
- Issue
- 7204
- Pages
- 600-606
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2042479971
- Cited by
- 950
- References
- 51
- Citations by year
- 2026: 20 · 2025: 35 · 2024: 40 · 2023: 33 · 2022: 62 · 2021: 55 · 2020: 51 · 2019: 61 · 2018: 67 · 2017: 69 · 2016: 68 · 2015: 67 · 2014: 59 · 2013: 75 · 2012: 52
- FWCI
- 22.98
- 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
- Austrian Science Fund
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- fear extinction, fear renewal, basolateral amygdala, neural circuits, hippocampus, medial prefrontal cortex, neural inactivation, anxiety disorders, contextual fear
- MeSH terms
- Amygdala, Animals, Conditioning, Psychological, Extinction, Psychological, Fear, Male, Mice, Inbred C57BL, Muscimol, Neural Pathways, Neurons, Models, Animal, Freezing Reaction, Cataleptic, Mice
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