Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuronal signalling of fear memory

Key Points

  • Plasticity in the CNS is essential for the representation of new information, and an important challenge is to understand how various forms of experience-dependent plasticity are reflected in the activity of neuronal populations that support behaviour. This article reviews recent single-unit recording studies that have provided considerable insight into the neuronal mechanisms of learning and memory, focusing particularly on Pavlovian fear conditioning.

  • The search for the neurophysiological mechanism of aversive memory began in the early 1960s with the observation that an auditory stimulus that was paired with an electric shock modified auditory-evoked field potentials in cats and rats. Subsequent single-unit recording studies in cats and monkeys showed conditioning-induced changes in evoked spike activity in several brain areas, including the midbrain, thalamus and cortex.

  • An influential study by Kapp and co-workers provided evidence that the central nucleus of the amygdala is required for Pavlovian fear conditioning. Subsequent single-unit recording studies of this nucleus revealed associative plasticity, indicating that the amygdala might be a site of plasticity in fear conditioning.

  • The lateral nucleus of the amygdala (LA) receives direct projections from the medial subdivision of the medial geniculate nucleus and the adjacent thalamic posterior intralaminar nucleus (MGm/PIN), and it relays this information by way of the basal amygdaloid nuclei to the central nucleus. Small lesions of the LA or the MGm/PIN prevent fear conditioning, whereas large lesions of the auditory cortex or striatum do not.

  • The expression of fear is neither sufficient nor necessary for the expression of associative plasticity in the LA, supporting the view that LA neurons encode fear memories. The essence of this mnemonic code seems to be contained in the rate at which LA neurons fire action potentials in response to auditory conditional stimuli, although the LA might also signal fear associations by the timing of spikes within a conditional stimulus-evoked spike train.

  • The amygdala also seems to have a vital role in the extinction of learned fear, an inhibitory learning process that has important clinical relevance as a treatment for anxiety disorders. The mediation of extinction by the amygdala is manifested in the firing of LA neurons.

  • This research opens up new avenues to investigate how the hippocampus, prefrontal cortex and amygdala interact during the acquisition, storage and retrieval of fear memories, and the cellular and synaptic mechanisms that encode inhibitory extinction memories together with excitatory fear memories.

Abstract

The learning and remembering of fearful events depends on the integrity of the amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we review recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies that combine unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex. Understanding the signalling of aversive memory by amygdala neurons opens new avenues for research into the neural systems that support fear behaviour.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Neural circuits that are necessary for auditory fear conditioning.
Figure 2: Effects of fear conditioning on lateral amygdala neurons.
Figure 3: Lateral amygdala neurons encode fear memory independently of fear behaviour.
Figure 4: Neuronal signalling of extinction in the prefrontal cortex and lateral amygdala.
Figure 5: Cortical modulation of amygdala fear memories in extinction.

References

  1. Hebb, D. O. The Organization of Behavior. (John Wiley and Sons, New York, 1949).

    Google Scholar 

  2. Nicolelis, M. A. & Ribeiro, S. Multielectrode recordings: the next steps. Curr. Opin. Neurobiol. 12, 602–606 (2002).

    CAS  PubMed  Article  Google Scholar 

  3. Buzsaki, G. Large-scale recording of neuronal ensembles. Nature Neurosci. 7, 446–451 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. Galambos, R., Myers, R. & Sheatz, G. Extralemniscal activation of auditory cortex in cats. Am. J. Physiol. 200, 23–28 (1961).

    CAS  PubMed  Article  Google Scholar 

  5. Gerken, G. M. & Neff, W. D. Experimental procedures affecting evoked responses recorded from auditory cortex. Electroencephalogr. Clin. Neurophysiol. 15, 947–957 (1963).

    CAS  PubMed  Article  Google Scholar 

  6. Hall, R. D. & Mark, R. G. Fear and the modification of acoustically evoked potentials during conditioning. J. Neurophysiol. 30, 893–910 (1967).

    CAS  PubMed  Article  Google Scholar 

  7. Kamikawa, K., Mcilwain, J. T. & Adey, W. R. Response of thalamic neurons during classical conditioning. Electroencephalogr. Clin. Neurophysiol. 17, 485–496 (1964).

    CAS  PubMed  Article  Google Scholar 

  8. O'Brien, J. H. & Fox, S. S. Single-cell activity in cat motor cortex. I. Modifications during classical conditioning procedures. J. Neurophysiol. 32, 267–284 (1969).

    CAS  PubMed  Article  Google Scholar 

  9. Woody, C. D., Vassilevsky, N. N. & Engel, J. Conditioned eye blink: unit activity at coronal-precruciate cortex of the cat. J. Neurophysiol. 33, 851–864 (1970).

    CAS  PubMed  Article  Google Scholar 

  10. Oleson, T. D., Ashe, J. H. & Weinberger, N. M. Modification of auditory and somatosensory system activity during pupillary conditioning in the paralyzed cat. J. Neurophysiol. 38, 1114–1139 (1975).

    CAS  PubMed  Article  Google Scholar 

  11. Weinberger, N. M., Imig, T. J. & Lippe, W. R. Modification of unit discharges in the medial geniculate nucleus by click-shock pairing. Exp. Neurol. 36, 46–58 (1972).

    CAS  PubMed  Article  Google Scholar 

  12. Olds, J., Disterhoft, J. F., Segal, M., Kornblith, C. L. & Hirsh, R. Learning centers of rat brain mapped by measuring latencies of conditioned unit responses. J. Neurophysiol. 35, 202–219 (1972). A landmark study that describes a methodology for using single-unit response latencies to auditory stimuli to localize sites of neuronal plasticity in the brain during learning.

    CAS  PubMed  Article  Google Scholar 

  13. Gabriel, M. Short-latency discriminative unit response: Engram or bias? Physiol. Psychol. 4, 275–280 (1976).

    Article  Google Scholar 

  14. Disterhoft, J. F. & Stuart, D. K. Trial sequence of changed unit activity in auditory system of alert rat during conditioned response acquisition and extinction. J. Neurophysiol. 39, 266–281 (1976).

    CAS  PubMed  Article  Google Scholar 

  15. Disterhoft, J. F. & Olds, J. Differential development of conditioned unit changes in thalamus and cortex of rat. J. Neurophysiol. 35, 665–679 (1972).

    CAS  PubMed  Article  Google Scholar 

  16. Medina, J. F., Christopher, R. J., Mauk, M. D. & LeDoux, J. E. Parallels between cerebellum- and amygdala-dependent conditioning. Nature Rev. Neurosci. 3, 122–131 (2002).

    CAS  Article  Google Scholar 

  17. Christian, K. M. & Thompson, R. F. Neural substrates of eyeblink conditioning: acquisition and retention. Learn. Mem. 10, 427–455 (2003).

    PubMed  Article  Google Scholar 

  18. Ben Ari, Y. & Le Gal la Salle, G. Plasticity at unitary level. II. Modifications during sensory–sensory association procedures. Electroencephalogr. Clin. Neurophysiol. 32, 667–679 (1972).

    CAS  PubMed  Article  Google Scholar 

  19. McGaugh, J. L. Hormonal influences on memory. Annu. Rev. Psychol. 34, 297–323 (1983).

    CAS  PubMed  Article  Google Scholar 

  20. Kapp, B. S., Frysinger, R. C., Gallagher, M. & Haselton, J. R. Amygdala central nucleus lesions: effect on heart rate conditioning in the rabbit. Physiol. Behav. 23, 1109–1117 (1979). One of the earliest reports to describe a disruption of Pavlovian fear conditioning after selective amygdala lesions, indicating that the amygdala might be a site of plasticity in fear learning.

    CAS  PubMed  Article  Google Scholar 

  21. Krettek, J. E. & Price, J. L. A description of the amygdaloid complex in the rat and cat with observations on intra-amygdaloid axonal connections. J. Comp. Neurol. 178, 255–280 (1978).

    CAS  PubMed  Article  Google Scholar 

  22. Hopkins, D. A. & Holstege, G. Amygdaloid projections to the mesencephalon, pons and medulla oblongata in the cat. Exp. Brain Res. 32, 529–547 (1978).

    CAS  PubMed  Article  Google Scholar 

  23. Applegate, C. D., Frysinger, R. C., Kapp, B. S. & Gallagher, M. Multiple unit activity recorded from amygdala central nucleus during Pavlovian heart rate conditioning in rabbit. Brain Res. 238, 457–462 (1982).

    CAS  PubMed  Article  Google Scholar 

  24. Pascoe, J. P. & Kapp, B. S. Electrophysiological characteristics of amygdaloid central nucleus neurons during Pavlovian fear conditioning in the rabbit. Behav. Brain Res. 16, 117–133 (1985).

    CAS  PubMed  Article  Google Scholar 

  25. Iwata, J., LeDoux, J. E., Meeley, M. P., Arneric, S. & Reis, D. J. Intrinsic neurons in the amygdaloid field projected to by the medial geniculate body mediate emotional responses conditioned to acoustic stimuli. Brain Res. 383, 195–214 (1986).

    CAS  PubMed  Article  Google Scholar 

  26. LeDoux, J. E., Sakaguchi, A. & Reis, D. J. Subcortical efferent projections of the medial geniculate nucleus mediate emotional responses conditioned to acoustic stimuli. J. Neurosci. 4, 683–698 (1984).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. LeDoux, J. E., Sakaguchi, A., Iwata, J. & Reis, D. J. Interruption of projections from the medial geniculate body to an archi-neostriatal field disrupts the classical conditioning of emotional responses to acoustic stimuli. Neuroscience 17, 615–627 (1986).

    CAS  PubMed  Article  Google Scholar 

  28. Pitkanen, A., Savander, V. & LeDoux, J. E. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci. 20, 517–523 (1997).

    CAS  PubMed  Article  Google Scholar 

  29. Paré, D. & Smith, Y. Intrinsic circuitry of the amygdaloid complex: common principles of organization in rats and cats. Trends Neurosci. 21, 240–241 (1998).

    PubMed  Article  Google Scholar 

  30. LeDoux, J. E., Farb, C. & Ruggiero, D. A. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J. Neurosci. 10, 1043–1054 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. LeDoux, J. E., Ruggiero, D. A. & Reis, D. J. Projections to the subcortical forebrain from anatomically defined regions of the medial geniculate body in the rat. J. Comp. Neurol. 242, 182–213 (1985).

    CAS  PubMed  Article  Google Scholar 

  32. LeDoux, J. E., Cicchetti, P., Xagoraris, A. & Romanski, L. M. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J. Neurosci. 10, 1062–1069 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. Romanski, L. M. & LeDoux, J. E. Equipotentiality of thalamo–amygdala and thalamo–cortico–amygdala circuits in auditory fear conditioning. J. Neurosci. 12, 4501–4509 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. Fanselow, M. S. & LeDoux, J. E. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23, 229–232 (1999).

    CAS  PubMed  Article  Google Scholar 

  35. Vazdarjanova, A. & McGaugh, J. L. Basolateral amygdala is not critical for cognitive memory of contextual fear conditioning. Proc. Natl Acad. Sci. USA 95, 15003–15007 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Killcross, A. S., Robbins, T. W. & Everitt, B. J. Different types of fear-conditioned behavior mediated by separate nuclei within the amygdala. Nature 388, 377–380 (1997).

    CAS  PubMed  Article  Google Scholar 

  37. Uwano, T., Nishijo, H., Ono, T. & Tamura, R. Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala. Neuroscience 68, 339–361 (1995).

    CAS  PubMed  Article  Google Scholar 

  38. Ben Ari, Y. & Le Gal la Salle, G. Lateral amygdala unit activity: II. Habituating and non-habituating neurons. Electroencephalogr. Clin. Neurophysiol. 37, 463–472 (1974).

    CAS  PubMed  Article  Google Scholar 

  39. Quirk, G. J., Repa, C. & LeDoux, J. E. Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995). This study was the first to use multiple single-unit recordings to describe short-latency plasticity in LA neurons, consistent with potentiation of inputs from the auditory thalamus during fear conditioning.

    CAS  Article  PubMed  Google Scholar 

  40. Li, X. F., Stutzmann, G. E. & LeDoux, J. E. Convergent but temporally separated inputs to lateral amygdala neurons from the auditory thalamus and auditory cortex use different postsynaptic receptors: in vivo intracellular and extracellular recordings in fear conditioning pathways. Learn. Mem. 3, 229–242 (1996).

    CAS  PubMed  Article  Google Scholar 

  41. Maren, S. Auditory fear conditioning increases CS-elicited spike firing in lateral amygdala neurons even after extensive overtraining. Eur. J. Neurosci. 12, 4047–4054 (2000).

    CAS  PubMed  Article  Google Scholar 

  42. Clugnet, M. C. & LeDoux, J. E. Synaptic plasticity in fear conditioning circuits: induction of LTP in the lateral nucleus of the amygdala by stimulation of the medial geniculate body. J. Neurosci. 10, 2818–2824 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. Chapman, P. F., Kairiss, E. W., Keenan, C. L. & Brown, T. H. Long-term synaptic potentiation in the amygdala. Synapse 6, 271–278 (1990). A seminal paper that demonstrated for the first time that amygdala neurons show long-term synaptic potentiation in vitro.

    CAS  PubMed  Article  Google Scholar 

  44. Maren, S. & Fanselow, M. S. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J. Neurosci. 15, 7548–7564 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. Rogan, M. T., Staubli, U. V. & LeDoux, J. E. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604–607 (1997). An important paper showing that the acquisition of conditional fear responses is associated with physiological changes in auditory-evoked potentials in the amygdala, consistent with the induction of LTP.

    CAS  Article  PubMed  Google Scholar 

  46. McKernan, M. G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

    CAS  Article  PubMed  Google Scholar 

  47. Tsvetkov, E., Carlezon, W. A., Benes, F. M., Kandel, E. R. & Bolshakov, V. Y. Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34, 289–300 (2002). An elegant study using behavioural and in vitro electrophysiological techniques to show that training occludes synaptic increases in presynaptic neurotransmitter release after LTP induction in LA neurons. This provides strong evidence that fear conditioning is mediated by LTP in the amygdala.

    CAS  PubMed  Article  Google Scholar 

  48. Bordi, F. & LeDoux, J. E. Response properties of single units in areas of rat auditory thalamus that project to the amygdala. II. Cells receiving convergent auditory and somatosensory inputs and cells antidromically activated by amygdala stimulation. Exp. Brain Res. 98, 275–286 (1994).

    CAS  PubMed  Article  Google Scholar 

  49. Romanski, L. M., Clugnet, M. C., Bordi, F. & LeDoux, J. E. Somatosensory and auditory convergence in the lateral nucleus of the amygdala. Behav. Neurosci. 107, 444–450 (1993).

    CAS  PubMed  Article  Google Scholar 

  50. Edeline, J. M. & Weinberger, N. M. Associative retuning in the thalamic source of input to the amygdala and auditory cortex: receptive field plasticity in the medial division of the medial geniculate body. Behav. Neurosci. 106, 81–105 (1992).

    CAS  PubMed  Article  Google Scholar 

  51. Edeline, J. M., Neuenschwander-el Massioui, N. & Dutrieux, G. Discriminative long-term retention of rapidly induced multiunit changes in the hippocampus, medial geniculate and auditory cortex. Behav. Brain Res. 39, 145–155 (1990).

    CAS  PubMed  Article  Google Scholar 

  52. Quirk, G. J., Armony, J. L. & LeDoux, J. E. Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 19, 613–624 (1997).

    CAS  PubMed  Article  Google Scholar 

  53. LeDoux, J. E., Farb, C. R. & Romanski, L. M. Overlapping projections to the amygdala and striatum from auditory processing areas of the thalamus and cortex. Neurosci. Lett. 134, 139–144 (1991).

    CAS  PubMed  Article  Google Scholar 

  54. Romanski, L. M. & LeDoux, J. E. Information cascade from primary auditory cortex to the amygdala: corticocortical and corticoamygdaloid projections of temporal cortex in the rat. Cereb. Cortex 3, 515–532 (1993).

    CAS  PubMed  Article  Google Scholar 

  55. Helmstetter, F. J. & Bellgowan, P. S. Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats. Behav. Neurosci. 108, 1005–1009 (1994).

    CAS  PubMed  Article  Google Scholar 

  56. Muller, J., Corodimas, K. P., Fridel, Z. & LeDoux, J. E. Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli. Behav. Neurosci. 111, 683–691 (1997).

    CAS  PubMed  Article  Google Scholar 

  57. Wilensky, A. E., Schafe, G. E. & LeDoux, J. E. Functional inactivation of the amygdala before but not after auditory fear conditioning prevents memory formation. J. Neurosci. 19, RC48 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. Maren, S., Yap, S. A. & Goosens, K. A. The amygdala is essential for the development of neuronal plasticity in the medial geniculate nucleus during auditory fear conditioning in rats. J. Neurosci. 21, RC135 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. Poremba, A. & Gabriel, M. Amygdalar efferents initiate auditory thalamic discriminative training-induced neuronal activity. J. Neurosci. 21, 270–278 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. Armony, J. L., Quirk, G. J. & LeDoux, J. E. Differential effects of amygdala lesions on early and late plastic components of auditory cortex spike trains during fear conditioning. J. Neurosci. 18, 2592–2601 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. Weinberger, N. M. Specific long-term memory traces in primary auditory cortex. Nature Rev. Neurosci. 5, 279–290 (2004).

    CAS  Article  Google Scholar 

  62. Armony, J. L. & LeDoux, J. E. How the brain processes emotional information. Ann. NY Acad. Sci. 821, 259–270 (1997).

    CAS  PubMed  Article  Google Scholar 

  63. Roozendaal, B., McReynolds, J. R. & McGaugh, J. L. The basolateral amygdala interacts with the medial prefrontal cortex in regulating glucocorticoid effects on working memory impairment. J. Neurosci. 24, 1385–1392 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. McGaugh, J. L. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu. Rev. Neurosci. 27, 1–28 (2004).

    CAS  PubMed  Article  Google Scholar 

  65. Cahill, L. Neurobiological mechanisms of emotionally influenced, long-term memory. Prog. Brain Res. 126, 29–37 (2000).

    CAS  PubMed  Article  Google Scholar 

  66. Collins, D. R. & Paré, D. Differential fear conditioning induces reciprocal changes in the sensory responses of lateral amygdala neurons to the CS+ and CS. Learn. Mem. 7, 97–103 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    CAS  Article  PubMed  Google Scholar 

  68. Davis, M. in The Amygdala (ed. Aggleton, J. P.) 213–288 (Oxford Univ. Press, Oxford, 2000).

    Google Scholar 

  69. Maren, S. Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897–931 (2001).

    CAS  PubMed  Article  Google Scholar 

  70. Paré, D. & Collins, D. R. Neuronal correlates of fear in the lateral amygdala: multiple extracellular recordings in conscious cats. J. Neurosci. 20, 2701–2710 (2000).

    PubMed  Article  PubMed Central  Google Scholar 

  71. Rosenkranz, J. A. & Grace, A. A. Dopamine-mediated modulation of odour-evoked amygdala potentials during Pavlovian conditioning. Nature 417, 282–287 (2002). This study was the first to use intracellular recording methods to show that fear conditioning increases the excitability of LA neurons.

    CAS  Article  PubMed  Google Scholar 

  72. Repa, J. C. et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nature Neurosci. 4, 724–731 (2001).

    CAS  PubMed  Article  Google Scholar 

  73. Goosens, K. A., Hobin, J. A. & Maren, S. Auditory-evoked spike firing in the lateral amygdala and Pavlovian fear conditioning: mnemonic code or fear bias? Neuron 40, 1013–1022 (2003). This is an important paper that shows that conditioning-related changes in CS-evoked single-unit activity in the LA can be dissociated from fear behaviour, providing support for a role for the amygdala in coding fear memories.

    CAS  PubMed  Article  Google Scholar 

  74. Seidenbecher, T., Laxmi, T. R., Stork, O. & Pape, H. C. Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval. Science 301, 846–850 (2003).

    CAS  PubMed  Article  Google Scholar 

  75. Pelletier, J. G. & Paré, D. Role of amygdala oscillations in the consolidation of emotional memories. Biol. Psychiatry 55, 559–562 (2004).

    PubMed  Article  Google Scholar 

  76. Bouton, M. E., Mineka, S. & Barlow, D. H. A modern learning theory perspective on the etiology of panic disorder. Psychol. Rev. 108, 4–32 (2001).

    CAS  PubMed  Article  Google Scholar 

  77. Rothbaum, B. O. & Schwartz, A. C. Exposure therapy for posttraumatic stress disorder. Am. J. Psychother. 56, 59–75 (2002).

    PubMed  Article  Google Scholar 

  78. Bouton, M. E., Rosengard, C., Achenbach, G. G., Peck, C. A. & Brooks, D. C. Effects of contextual conditioning and unconditional stimulus presentation on performance in appetitive conditioning. Q. J. Exp. Psychol. 46, 63–95 (1993).

    CAS  Google Scholar 

  79. Quirk, G. J. Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery. Learn. Mem. 9, 402–407 (2002).

    PubMed  PubMed Central  Article  Google Scholar 

  80. Myers, K. M. & Davis, M. Behavioral and neural analysis of extinction. Neuron 36, 567–584 (2002).

    CAS  Article  PubMed  Google Scholar 

  81. Quirk, G. J. Learning not to fear, faster. Learn. Mem. 11, 125–126 (2004).

    PubMed  Article  Google Scholar 

  82. Falls, W. A., Miserendino, M. J. & Davis, M. Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J. Neurosci. 12, 854–863 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. Lu, K. T., Walker, D. L. & Davis, M. Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J. Neurosci. 21, RC162 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. Hobin, J. A., Goosens, K. A. & Maren, S. Context-dependent neuronal activity in the lateral amygdala represents fear memories after extinction. J. Neurosci. 23, 8410–8416 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Quirk, G. J., Russo, G. K., Barron, J. L. & Lebron, K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J. Neurosci. 20, 6225–6231 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. Lebron, K., Milad, M. R. & Quirk, G. J. Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. Learn. Mem. 11, 544–548 (2004).

    PubMed  Article  Google Scholar 

  87. Morgan, M. A., Romanski, L. M. & LeDoux, J. E. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci. Lett. 163, 109–113 (1993).

    CAS  PubMed  Article  Google Scholar 

  88. Milad, M. R. & Quirk, G. J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002). This study provides neurophysiological support for Pavlov's hypothesis that extinction involves inhibition, by showing that extinction increases the firing rate of prefrontal cortical neurons, and electrical stimulation of the prefrontal cortex inhibits fear responses.

    CAS  Article  PubMed  Google Scholar 

  89. Herry, C. & Garcia, R. Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J. Neurosci. 22, 577–583 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. Rosenkranz, J. A., Moore, H. & Grace, A. A. The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J. Neurosci. 23, 11054–11064 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. Quirk, G. J., Likhtik, E., Pelletier, J. G. & Paré, D. Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J. Neurosci. 23, 8800–8807 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. Milad, M. R., Vidal-Gonzalez, I. & Quirk, G. J. Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner. Behav. Neurosci. 118, 389–395 (2004).

    CAS  PubMed  Article  Google Scholar 

  93. Royer, S., Martina, M. & Paré, D. An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J. Neurosci. 19, 10575–10583 (1999). This study showed that amygdala output could be inhibited by GABA-releasing intercalated neurons, implying that there is complex processing of fear signals within the amygdala. The inhibition of amygdala output by this mechanism might be important for fear extinction.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. Szinyei, C., Heinbockel, T., Montagne, J. & Pape, H. C. Putative cortical and thalamic inputs elicit convergent excitation in a population of GABAergic interneurons of the lateral amygdala. J. Neurosci. 20, 8909–8915 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. Corcoran, K. A. & Maren, S. Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J. Neurosci. 21, 1720–1726 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. Pitkanen, A., Pikkarainen, M., Nurminen, N. & Ylinen, A. Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat. A review. Ann. NY Acad. Sci. 911, 369–391 (2000).

    CAS  PubMed  Article  Google Scholar 

  97. Thierry, A. M., Gioanni, Y., Degenetais, E. & Glowinski, J. Hippocampo–prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus 10, 411–419 (2000).

    CAS  PubMed  Article  Google Scholar 

  98. Maren, S. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci. 22, 561–567 (1999).

    CAS  PubMed  Article  Google Scholar 

  99. Blair, H. T., Schafe, G. E., Bauer, E. P., Rodrigues, S. M. & LeDoux, J. E. Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn. Mem. 8, 229–242 (2001). An excellent review covering the cellular and synaptic mechanisms in the lateral amygdala that underlie the acquisition of long-term fear memories.

    CAS  PubMed  Article  Google Scholar 

  100. Schafe, G. E., Nader, K., Blair, H. T. & LeDoux, J. E. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 24, 540–546 (2001).

    CAS  PubMed  Article  Google Scholar 

  101. Miserendino, M. J., Sananes, C. B., Melia, K. R. & Davis, M. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345, 716–718 (1990). This is the first report to reveal a crucial role for amygdala NMDA receptors in the acquisition of Pavlovian fear conditioning.

    CAS  Article  PubMed  Google Scholar 

  102. Maren, S., Aharonov, G., Stote, D. L. & Fanselow, M. S. N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. Behav. Neurosci. 110, 1365–1374 (1996).

    CAS  PubMed  Article  Google Scholar 

  103. Fendt, M. Injections of the NMDA receptor antagonist aminophosphonopentanoic acid into the lateral nucleus of the amygdala block the expression of fear-potentiated startle and freezing. J. Neurosci. 21, 4111–4115 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. Rodrigues, S. M., Schafe, G. E. & LeDoux, J. E. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J. Neurosci. 21, 6889–6896 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. Goosens, K. A. & Maren, S. NMDA receptors are essential for the acquisition, but not expression, of conditional fear and associative spike firing in the lateral amygdala. Eur. J. Neurosci. 20, 537–548 (2004).

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

The authors thank K. Goosens and two anonymous reviewers for helpful comments on the manuscript. This work was supported by grants from the National Institute of Mental Health.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Encyclopedia of Life Sciences

GABAA receptors

Long-term potentiation

Neural information processing

NMDA receptors

Maren's laboratory

Quirk's laboratory

Glossary

TETRODE

An extracellular electrode that comprises four juxtaposed recording channels, which can be used to disambiguate the signals emitted by individual point sources. Because each neuron occupies a unique position in space, its spikes are 'seen' slightly differently by each electrode, providing a unique signature. This technique allows the identification of many more neurons than there are sampling electrodes.

LONG-TERM POTENTIATION

(LTP) An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic cell-population spike. LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

BASOLATERAL AMYGDALA

The region of the amygdala that encompasses the lateral, basolateral and basomedial nuclei.

INSTRUMENTAL AVOIDANCE LEARNING

Instrumental learning is a form of learning that takes place through reinforcement (or punishment) that is contingent on the performance (or withholding) of a particular behaviour. So, the subject's response is instrumental in producing an outcome. Compare with Pavlovian learning.

EXTINCTION

The reduction in the conditioned response after non-reinforced presentations of the conditional stimulus.

RECEPTIVE FIELD

That limited domain of the sensory environment to which a given sensory neuron is responsive, such as a limited frequency band in audition or a limited area of space in vision.

CONDITIONED LEVER-PRESS SUPPRESSION

The reduction in pressing for food reward in the presence of a fear-conditioned stimulus.

THETA OSCILLATIONS

Rhythmic neural activity with a frequency of 4–8 Hz.

PREFRONTAL CORTEX

(PFC) The non-motor sectors of the frontal lobe that receive input from the dorsomedial thalamic nucleus and subserve working memory, complex attentional processes and executive functions such as planning, behavioural inhibition, logical reasoning, action monitoring and social cognition.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maren, S., Quirk, G. Neuronal signalling of fear memory. Nat Rev Neurosci 5, 844–852 (2004). https://doi.org/10.1038/nrn1535

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1535

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing