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The contextual brain: implications for fear conditioning, extinction and psychopathology

Key Points

  • Contexts provide information that is central to understanding the meaning of events.

  • Studies of associative learning, including Pavlovian fear conditioning and extinction, in animal models and humans have revealed neural circuits for contextual information processing.

  • The hippocampus and medial prefrontal cortex are critical for encoding and retrieving contextual information. A major function of this circuit is in the disambiguation of cues that have different meanings in different contexts.

  • The neural circuits involved in processing discrete cues, such as conditional and unconditional stimuli, share some overlap with context circuits but are largely distinct.

  • Deficits in context processing and pathology in hippocampal–prefrontal circuits may accompany many forms of psychiatric illness, including post-traumatic stress disorder and substance abuse disorders.


Contexts surround and imbue meaning to events; they are essential for recollecting the past, interpreting the present and anticipating the future. Indeed, the brain's capacity to contextualize information permits enormous cognitive and behavioural flexibility. Studies of Pavlovian fear conditioning and extinction in rodents and humans suggest that a neural circuit including the hippocampus, amygdala and medial prefrontal cortex is involved in the learning and memory processes that enable context-dependent behaviour. Dysfunction in this network may be involved in several forms of psychopathology, including post-traumatic stress disorder, schizophrenia and substance abuse disorders.

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Figure 1: Stimulus elements, context and memory.
Figure 2: Context encoding, conditioning and retrieval tasks in rodents.
Figure 3: Brain circuits involved in cue and context processing in the human brain.
Figure 4: Context-dependent extinction of fear in rodents.
Figure 5: Context-dependence of neuronal activity in the rat amygdala.
Figure 6: Neural circuit for context-dependent regulation of fear memory.


  1. 1

    Barrett, L. & Kensinger, E. Context is routinely encoded during emotion perception. Psychol. Sci. 21, 595–599 (2010).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Spear, N. Retrieval of memory in animals. Psychol. Rev. 80, 163–194 (1973).

    Google Scholar 

  3. 3

    Fanselow, M. S. From contextual fear to a dynamic view of memory systems. Trends Cogn. Sci. 14, 7–15 (2010).

    PubMed  Google Scholar 

  4. 4

    Bouton, M. Context, time, and memory retrieval in the interference paradigms of Pavlovian learning. Psychol. Bull. 114, 80–99 (1993).

    CAS  PubMed  Google Scholar 

  5. 5

    Bouton, M. Context, ambiguity, and classical conditioning. Curr. Direct. Psychol. Sci. 3, 49–53 (1994).

    Google Scholar 

  6. 6

    Fanselow, M. Factors governing one-trial contextual conditioning. Anim. Learn. Behav. 18, 264–270 (1990).

    Google Scholar 

  7. 7

    Debiec, J., LeDoux, J. E. & Nader, K. Cellular and systems reconsolidation in the hippocampus. Neuron 36, 527–538 (2002).

    CAS  PubMed  Google Scholar 

  8. 8

    Holland, P. & Bouton, M. Hippocampus and context in classical conditioning. Curr. Opin. Neurobiol. 9, 195–202 (1999).

    CAS  PubMed  Google Scholar 

  9. 9

    Phillips, R. & LeDoux, J. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    CAS  PubMed  Google Scholar 

  10. 10

    Selden, N., Everitt, B., Jarrard, L. & Robbins, T. Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience 42, 335–350 (1991).

    CAS  PubMed  Google Scholar 

  11. 11

    Kim, J. & Fanselow, M. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).

    CAS  PubMed  Google Scholar 

  12. 12

    Frankland, P., Cestari, V., Filipkowski, R., McDonald, R. & Silva, A. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998).

    CAS  PubMed  Google Scholar 

  13. 13

    Maren, S., Aharonov, G. & Fanselow, M. S. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav. Brain Res. 88, 261–274 (1997).

    CAS  PubMed  Google Scholar 

  14. 14

    Anagnostaras, S. G., Maren, S. & Fanselow, M. S. Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J. Neurosci. 19, 1106–1114 (1999).

    CAS  PubMed  Google Scholar 

  15. 15

    Bayley, P., Gold, J., Hopkins, R. & Squire, L. The neuroanatomy of remote memory. Neuron 46, 799–810 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Wiltgen, B., Sanders, M., Anagnostaras, S., Sage, J. & Fanselow, M. Context fear learning in the absence of the hippocampus. J. Neurosci. 26, 5484–5491 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

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

    CAS  PubMed  Google Scholar 

  18. 18

    Fanselow, M. S. Contextual fear, gestalt memories, and the hippocampus. Behav. Brain Res. 110, 73–81 (2000).

    CAS  PubMed  Google Scholar 

  19. 19

    Rudy, J. W. Context representations, context functions, and the parahippocampal– hippocampal system. Learn. Mem. 16, 573–585 (2009).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Young, S., Bohenek, D. & Fanselow, M. NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: immunization against amnesia by context preexposure. Behav. Neurosci. 108, 19–29 (1994).

    CAS  PubMed  Google Scholar 

  21. 21

    Matus-Amat, P., Higgins, E., Barrientos, R. & Rudy, J. The role of the dorsal hippocampus in the acquisition and retrieval of context memory representations. J. Neurosci. 24, 2431–2439 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Good, M. & Honey, R. Conditioning and contextual retrieval in hippocampal rats. Behav. Neurosci. 105, 499–509 (1991).

    CAS  PubMed  Google Scholar 

  23. 23

    Butterly, D., Petroccione, M. & Smith, D. Hippocampal context processing is critical for interference free recall of odor memories in rats. Hippocampus 22, 906–913 (2011).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Wilson, A., Brooks, D. & Bouton, M. The role of the rat hippocampal system in several effects of context in extinction. Behav. Neurosci. 109, 828–836 (1995).

    CAS  PubMed  Google Scholar 

  25. 25

    Frohardt, R., Guarraci, F. & Bouton, M. The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction. Behav. Neurosci. 114, 227–240 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Fox, G. & Holland, P. Neurotoxic hippocampal lesions fail to impair reinstatement of an appetitively conditioned response. Behav. Neurosci. 112, 255–260 (1998).

    CAS  PubMed  Google Scholar 

  27. 27

    Maren, S. & Quirk, G. J. Neuronal signalling of fear memory. Nature Rev. Neurosci. 5, 844–852 (2004).

    CAS  Google Scholar 

  28. 28

    Fanselow, M. & Poulos, A. The neuroscience of mammalian associative learning. Annu. Rev. Psychol. 56, 207–234 (2005).

    PubMed  Google Scholar 

  29. 29

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

    CAS  PubMed  Google Scholar 

  30. 30

    Davis, M. & Whalen, P. The amygdala: vigilance and emotion. Mol. Psychiatry 6, 13–34 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Smith, D. & Mizumori, S. Hippocampal place cells, context, and episodic memory. Hippocampus 16, 716–729 (2006).

    PubMed  Google Scholar 

  32. 32

    Anderson, M. & Jeffery, K. Heterogeneous modulation of place cell firing by changes in context. J. Neurosci. 23, 8827–8835 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Hayman, R., Chakraborty, S., Anderson, M. & Jeffery, K. Context-specific acquisition of location discrimination by hippocampal place cells. Eur. J. Neurosci. 18, 2825–2834 (2003).

    PubMed  Google Scholar 

  34. 34

    Davidson, T. & Jarrard, L. A role for hippocampus in the utilization of hunger signals. Behav. Neural Biol. 59, 167–171 (1993).

    CAS  PubMed  Google Scholar 

  35. 35

    Davidson, T. et al. Hippocampal lesions impair retention of discriminative responding based on energy state cues. Behav. Neurosci. 124, 97–105 (2010).

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Kennedy, P. J. & Shapiro, M. L. Motivational states activate distinct hippocampal representations to guide goal-directed behaviors. Proc. Natl Acad. Sci. USA 106, 10805–10810 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Kennedy, P. J. & Shapiro, M. L. Retrieving memories via internal context requires the hippocampus. J. Neurosci. 24, 6979–6985 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Komorowski, R., Manns, J. & Eichenbaum, H. Robust conjunctive item-place coding by hippocampal neurons parallels learning what happens where. J. Neurosci. 29, 9918–9929 (2009). This paper reveals that in rats, hippocampal neurons exhibit context-dependent firing patterns that represent odour–reward associations in specific places.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    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  Google Scholar 

  40. 40

    Maren, S. & Fanselow, M. S. Electrolytic lesions of the fimbria/fornix, dorsal hippocampus, or entorhinal cortex produce anterograde deficits in contextual fear conditioning in rats. Neurobiol. Learn. Mem. 67, 142–149 (1997).

    CAS  PubMed  Google Scholar 

  41. 41

    Burwell, R. D., Bucci, D. J., Sanborn, M. R. & Jutras, M. J. Perirhinal and postrhinal contributions to remote memory for context. J. Neurosci. 24, 11023–11028 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Corcoran, K. et al. NMDA receptors in retrosplenial cortex are necessary for retrieval of recent and remote context fear memory. J. Neurosci. 31, 11655–11659 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Frankland, P., Bontempi, B., Talton, L., Kaczmarek, L. & Silva, A. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883 (2004).

    CAS  PubMed  Google Scholar 

  44. 44

    Quinn, J., Ma, Q., Tinsley, M., Koch, C. & Fanselow, M. Inverse temporal contributions of the dorsal hippocampus and medial prefrontal cortex to the expression of long-term fear memories. Learn. Mem. 15, 368–372 (2008).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Sutherland, R. & Lehmann, H. Alternative conceptions of memory consolidation and the role of the hippocampus at the systems level in rodents. Curr. Opin. Neurobiol. 21, 446–451 (2011).

    CAS  PubMed  Google Scholar 

  46. 46

    Armony, J. & Dolan, R. Modulation of auditory neural responses by a visual context in human fear conditioning. Neuroreport 12, 3407–3411 (2001).

    CAS  PubMed  Google Scholar 

  47. 47

    Lang, S. et al. Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex. Eur. J. Neurosci. 29, 823–832 (2009).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Alvarez, R., Biggs, A., Chen, G., Pine, D. & Grillon, C. Contextual fear conditioning in humans: cortical–hippocampal and amygdala contributions. J. Neurosci. 28, 6211–6219 (2008). An influential study substantiating the role of amygdala–hippocampal brain circuits in representing context during fear conditioning in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Marschner, A., Kalisch, R., Vervliet, B., Vansteenwegen, D. & Büchel, C. Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning. J. Neurosci. 28, 9030–9036 (2008). This paper differentiates amygdala and hippocampal activity during cued and context fear conditioning in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Hasler, G. et al. Cerebral blood flow in immediate and sustained anxiety. J. Neurosci. 27, 6313–6319 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Pohlack, S. et al. Hippocampal but not amygdalar volume affects contextual fear conditioning in humans. Hum. Brain Mapp. 33, 478–488 (2012).

    PubMed  Google Scholar 

  52. 52

    Ploghaus, A. et al. Dissociating pain from its anticipation in the human brain. Science 284, 1979–1981 (1999).

    CAS  PubMed  Google Scholar 

  53. 53

    Wager, T. et al. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303, 1162–1167 (2004).

    CAS  PubMed  Google Scholar 

  54. 54

    Kalisch, R. et al. Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network. J. Neurosci. 26, 9503–9511 (2006). This study is among the first to report that the ventromedial prefrontal–hippocampal network is involved in context-dependent recall of human extinction memory.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Nitschke, J., Sarinopoulos, I., Mackiewicz, K., Schaefer, H. & Davidson, R. Functional neuroanatomy of aversion and its anticipation. Neuroimage 29, 106–116 (2006).

    PubMed  Google Scholar 

  56. 56

    Bannerman, D. et al. Ventral hippocampal lesions affect anxiety but not spatial learning. Behav. Brain Res. 139, 197–213 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

    Fanselow, M. S. & Dong, H.-W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Bouton, M., Nelson, J., Schmajuk, N. & Holland, P. in Occasion Setting: Associative Learning And Cognition In Animals (Schmajuk, N. & Holland, P.) 69–112 (American Psychological Association, 1998).

    Google Scholar 

  59. 59

    Harris, J., Jones, M., Bailey, G. & Westbrook, R. Contextual control over conditioned responding in an extinction paradigm. J. Exp. Psychol. Anim. Behav. Process. 26, 174–185 (2000).

    CAS  PubMed  Google Scholar 

  60. 60

    Bouton, M. Context and ambiguity in the extinction of emotional learning: implications for exposure therapy. Behav. Res. Ther. 26, 137–149 (1988).

    CAS  PubMed  Google Scholar 

  61. 61

    Bouton, M. Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol. Psychiatry 52, 976–986 (2002).

    PubMed  Google Scholar 

  62. 62

    Ehrlich, I. et al. Amygdala inhibitory circuits and the control of fear memory. Neuron 62, 757–771 (2009).

    CAS  PubMed  Google Scholar 

  63. 63

    Quirk, G. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008).

    PubMed  Google Scholar 

  64. 64

    Falls, W., Miserendino, M. & 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  Google Scholar 

  65. 65

    Herry, C. et al. Neuronal circuits of fear extinction. Eur. J. Neurosci. 31, 599–612 (2010).

    PubMed  Google Scholar 

  66. 66

    Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008). A key paper revealing different populations of amygdala neurons that respond either during the expression of extinction or during the renewal of fear; these populations received different patterns of hippocampal and prefrontal input.

    CAS  PubMed  Google Scholar 

  67. 67

    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  Google Scholar 

  68. 68

    Maren, S., Poremba, A. & Gabriel, M. Basolateral amygdaloid multi-unit neuronal correlates of discriminative avoidance learning in rabbits. Brain Res. 549, 311–316 (1991).

    CAS  PubMed  Google Scholar 

  69. 69

    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  Google Scholar 

  70. 70

    Quirk, G., Repa, C. & LeDoux, J. Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995).

    CAS  PubMed  Google Scholar 

  71. 71

    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  Google Scholar 

  72. 72

    Tye, K., Cone, J., Schairer, W. & Janak, P. Amygdala neural encoding of the absence of reward during extinction. J. Neurosci. 30, 116–125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

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

    CAS  PubMed  Google Scholar 

  74. 74

    Hobin, J. A., Ji, J. & Maren, S. Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats. Hippocampus 16, 174–182 (2006).

    CAS  PubMed  Google Scholar 

  75. 75

    Maren, S. & Hobin, J. A. Hippocampal regulation of context-dependent neuronal activity in the lateral amygdala. Learn. Mem. 14, 318–324 (2007).

    PubMed  PubMed Central  Google Scholar 

  76. 76

    Zelikowsky, M., Pham, D. L. & Fanselow, M. S. Temporal factors control hippocampal contributions to fear renewal after extinction. Hippocampus 22, 1096–1106 (2011). This paper reveals that the hippocampus has a critical role in the context-dependent retrieval of extinction memories but that animals that underwent extinction without a hippocampus exhibit contextual control under some conditions.

    PubMed  PubMed Central  Google Scholar 

  77. 77

    Holt, W. & Maren, S. Muscimol inactivation of the dorsal hippocampus impairs contextual retrieval of fear memory. J. Neurosci. 19, 9054–9062 (1999).

    CAS  PubMed  Google Scholar 

  78. 78

    Wang, S., Teixeira, C. L., Wheeler, A. & Frankland, P. The precision of remote context memories does not require the hippocampus. Nature Neurosci. 12, 253–255 (2009).

    PubMed  Google Scholar 

  79. 79

    Crombag, H., Bossert, J., Koya, E. & Shaham, Y. Context-induced relapse to drug seeking: a review. Phil. Trans. R. Soc. B 363, 3233–3243 (2008).

    PubMed  Google Scholar 

  80. 80

    Holland, P., Lamoureux, J., Han, J. & Gallagher, M. Hippocampal lesions interfere with Pavlovian negative occasion setting. Hippocampus 9, 143–157 (1999).

    CAS  PubMed  Google Scholar 

  81. 81

    Maren, S. & Holt, W. The hippocampus and contextual memory retrieval in Pavlovian conditioning. Behav. Brain Res. 110, 97–108 (2000).

    CAS  PubMed  Google Scholar 

  82. 82

    Yoon, T., Graham, L. & Kim, J. Hippocampal lesion effects on occasion setting by contextual and discrete stimuli. Neurobiol. Learn. Mem. 95, 176–184 (2011).

    PubMed  Google Scholar 

  83. 83

    Vlachos, I., Herry, C., Lüthi, A., Aertsen, A. & Kumar, A. Context-dependent encoding of fear and extinction memories in a large-scale network model of the basal amygdala. PLoS Comp. Biol. 7, e1001104 (2011).

    CAS  Google Scholar 

  84. 84

    Krasne, F. B., Fanselow, M. S. & Zelikowsky, M. Design of a neurally plausible model of fear learning. Front. Behav. Neurosci. 5, 41 (2011).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Knapska, E. et al. Functional anatomy of neural circuits regulating fear and extinction. Proc. Natl Acad. Sci. USA 109, 17093–17098 (2012). This study uses a novel transgenic rat to localize convergent hippocampal and prefrontal projections onto amygdala neurons that are differentially active during the expression of extinction or during the renewal of fear.

    CAS  PubMed  Google Scholar 

  86. 86

    Gordon, J. A. Oscillations and hippocampal-prefrontal synchrony. Curr. Opin. Neurobiol. 21, 486–491 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Adhikari, A., Topiwala, M. A. & Gordon, J. A. Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity. Neuron 71, 898–910 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A. & Gordon, J. A. Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010). An important paper linking aberrant neuronal synchronization of hippocampal–prefrontal circuits to an animal model of schizophrenia.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Sotres-Bayon, F., Sierra-Mercado, D., Pardilla-Delgado, E. & Quirk, G. J. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76, 804–812 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    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  PubMed Central  Google Scholar 

  91. 91

    Likhtik, E., Popa, D., Apergis-Schoute, J., Fidacaro, G. A. & Paré, D. Amygdala intercalated neurons are required for expression of fear extinction. Nature 454, 642–645 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Corcoran, K. & Quirk, G. Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J. Neurosci. 27, 840–844 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Maren, S. Seeking a spotless mind: extinction, deconsolidation, and erasure of fear memory. Neuron 70, 830–845 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Knapska, E. & Maren, S. Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. Learn. Mem. 16, 486–493 (2009).

    PubMed  PubMed Central  Google Scholar 

  95. 95

    Orsini, C. A., Kim, J. H., Knapska, E. & Maren, S. Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction. J. Neurosci. 31, 17269–17277 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Milad, M. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).

    PubMed  Google Scholar 

  97. 97

    Gottfried, J. & Dolan, R. Human orbitofrontal cortex mediates extinction learning while accessing conditioned representations of value. Nature Neurosci. 7, 1145–1153 (2004).

    Google Scholar 

  98. 98

    LaBar, K. S., Gatenby, J. C., Gore, J. C., LeDoux, J. E. & Phelps, E. A. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron 20, 937–945 (1998). This is the first study to implicate the vmPFC in fear extinction learning in humans.

    CAS  PubMed  Google Scholar 

  99. 99

    Phelps, E., Delgado, M., Nearing, K. & LeDoux, J. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897–905 (2004).

    CAS  PubMed  Google Scholar 

  100. 100

    Knight, D., Cheng, D., Smith, C., Stein, E. & Helmstetter, F. Neural substrates mediating human delay and trace fear conditioning. J. Neurosci. 24, 218–228 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Veit, R. et al. Brain circuits involved in emotional learning in antisocial behavior and social phobia in humans. Neurosci. Lett. 328, 233–236 (2002).

    CAS  PubMed  Google Scholar 

  102. 102

    Molchan, S., Sunderland, T., McIntosh, A., Herscovitch, P. & Schreurs, B. A. Functional anatomical study of associative learning in humans. Proc. Natl Acad. Sci. USA 91, 8122–8126 (1994).

    CAS  PubMed  Google Scholar 

  103. 103

    Sehlmeyer, C. et al. Human fear conditioning and extinction in neuroimaging: a systematic review. PLoS ONE 4, e5865 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Sotres-Bayon, F. & Quirk, G. Prefrontal control of fear: more than just extinction. Curr. Opin. Neurobiol. 20, 231–235 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Labar, K. S. & Phelps, E. A. Reinstatement of conditioned fear in humans is context dependent and impaired in amnesia. Behav. Neurosci. 119, 677–686 (2005).

    PubMed  Google Scholar 

  106. 106

    Bechara, A. et al. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269, 1115–1118 (1995).

    CAS  PubMed  Google Scholar 

  107. 107

    LaBar, K., LeDoux, J., Spencer, D. & Phelps, E. Impaired fear conditioning following unilateral temporal lobectomy in humans. J. Neurosci. 15, 6846–6855 (1995).

    CAS  PubMed  Google Scholar 

  108. 108

    Milad, M. et al. Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc. Natl Acad. Sci. USA 102, 10706–10711 (2005).

    CAS  PubMed  Google Scholar 

  109. 109

    Ressler, K. & Mayberg, H. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nature Neurosci. 10, 1116–1124 (2007).

    CAS  PubMed  Google Scholar 

  110. 110

    Rauch, S., Shin, L. & Phelps, E. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research - past, present, and future. Biol. Psychiatry 60, 376–382 (2006).

    PubMed  Google Scholar 

  111. 111

    Milad, M. & Quirk, G. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Liberzon, I. & Sripada, C. The functional neuroanatomy of PTSD: a critical review. Prog. Brain Res. 167, 151–169 (2007).

    Google Scholar 

  113. 113

    Milad, M. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009). This is the first functional neuroimaging study to implicate the vmPFC and hippocampus in contextual retrieval deficits in patients with PTSD.

    PubMed  PubMed Central  Google Scholar 

  114. 114

    Rougemont-Bücking, A. et al. Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci. Ther. 17, 227–236 (2010).

    PubMed  PubMed Central  Google Scholar 

  115. 115

    MacKillop, J. & Lisman, S. Effects of a context shift and multiple context extinction on reactivity to alcohol cues. Exp. Clin. Psychopharmacol. 16, 322–331 (2008).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Badiani, A., Belin, D., Epstein, D., Calu, D. & Shaham, Y. Opiate versus psychostimulant addiction: the differences do matter. Nature Rev. Neurosci. 12, 685–700 (2011).

    CAS  Google Scholar 

  117. 117

    Badiani, A., Anagnostaras, S. & Robinson, T. The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment. Psychopharmacol. 117, 443–452 (1995).

    CAS  Google Scholar 

  118. 118

    Anagnostaras, S. & Robinson, T. Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning. Behav. Neurosci. 110, 1397–1414 (1996).

    CAS  PubMed  Google Scholar 

  119. 119

    Siegel, S. Morphine analgesic tolerance - situation specificity supports a pavlovian conditioning model. Science 193, 323–325 (1976).

    CAS  PubMed  Google Scholar 

  120. 120

    Childs, E. & de Wit, H. Contextual conditioning enhances the psychostimulant and incentive properties of d-amphetamine in humans. Addict. Biol. 29 Nov 2011 (doi:10.1111/j.1369-1600.2011.00416.x).

    PubMed  PubMed Central  Google Scholar 

  121. 121

    Wilson, S., Sayette, M. & Fiez, J. Prefrontal responses to drug cues: a neurocognitive analysis. Nature Neurosci. 7, 211–214 (2004).

    PubMed  Google Scholar 

  122. 122

    Carter, B. & Tiffany, S. Meta-analysis of cue-reactivity in addiction research. Addiction 94, 327–340 (1999).

    CAS  PubMed  Google Scholar 

  123. 123

    Barch, D., Carter, C., MacDonald, A., Braver, T. & Cohen, J. Context-processing deficits in schizophrenia: diagnostic specificity, 4-week course, and relationships to clinical symptoms. J. Abnorm. Psychol. 112, 132–143 (2003).

    PubMed  Google Scholar 

  124. 124

    Cohen, J., Barch, D., Carter, C. & Servan-Schreiber, D. Context-processing deficits in schizophrenia: converging evidence from three theoretically motivated cognitive tasks. J. Abnorm. Psychol. 108, 120–133 (1999).

    CAS  PubMed  Google Scholar 

  125. 125

    Taylor, S. et al. Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia. Biol. Psychiatry 71, 136–145 (2012).

    PubMed  Google Scholar 

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Work from the authors' laboratories described in this paper is supported by grants from the US National Institutes of Health to S.M. (R01MH065961), K.L.P. (R01MH086517 and R01MH071698) and I.L. (R24MH075999).

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Maren, S., Phan, K. & Liberzon, I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14, 417–428 (2013).

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