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Encoding of fear learning and memory in distributed neuronal circuits

Abstract

How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.

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Figure 1: Working circuit model of the fear learning circuit.
Figure 2: Hypothetical circuit construction of prediction error coding during fear learning.
Figure 3: Classical and updated circuit model of fear expression.
Figure 4: Neuronal mechanisms of fear expression.

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References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  5. Duvarci, S. & Pare, D. Amygdala microcircuits controlling learned fear. Neuron 82, 966–980 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pape, H.C. & Pare, D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol. Rev. 90, 419–463 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Morrison, S.E. & Salzman, C.D. Re-valuing the amygdala. Curr. Opin. Neurobiol. 20, 221–230 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. LeDoux, J.E. Coming to terms with fear. Proc. Natl. Acad. Sci. USA 111, 2871–2878 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Sah, P., Faber, E.S., Lopez De Armentia, M. & Power, J. The amygdaloid complex: anatomy and physiology. Physiol. Rev. 83, 803–834 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Bienvenu, T.C., Busti, D., Magill, P.J., Ferraguti, F. & Capogna, M. Cell type–specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo. Neuron 74, 1059–1074 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. McDonald, A.J., Mascagni, F., Mania, I. & Rainnie, D.G. Evidence for a perisomatic innervation of parvalbumin-containing interneurons by individual pyramidal cells in the basolateral amygdala. Brain Res. 1035, 32–40 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Johansen, J.P., Tarpley, J.W., LeDoux, J.E. & Blair, H.T. Neural substrates for expectation-modulated fear learning in the amygdala and periaqueductal gray. Nat. Neurosci. 13, 979–986 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Johansen, J.P., Cain, C.K., Ostroff, L.E. & LeDoux, J.E. Molecular mechanisms of fear learning and memory. Cell 147, 509–524 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Pitkänen, 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).

    Article  PubMed  Google Scholar 

  21. Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Amano, T., Duvarci, S., Popa, D. & Pare, D. The fear circuit revisited: contributions of the basal amygdala nuclei to conditioned fear. J. Neurosci. 31, 15481–15489 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wilensky, A.E., Schafe, G.E., Kristensen, M.P. & LeDoux, J.E. Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation and expression of Pavlovian fear conditioning. J. Neurosci. 26, 12387–12396 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zimmerman, J.M., Rabinak, C.A., McLachlan, I.G. & Maren, S. The central nucleus of the amygdala is essential for acquiring and expressing conditional fear after overtraining. Learn. Mem. 14, 634–644 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Goosens, K.A. & Maren, S. Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of conditional fear. Behav. Neurosci. 117, 738–750 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Watabe, A.M. et al. Synaptic potentiation in the nociceptive amygdala following fear learning in mice. Mol. Brain 6, 11 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Li, H. et al. Experience-dependent modification of a central amygdala fear circuit. Nat. Neurosci. 16, 332–339 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kholodar-Smith, D.B., Allen, T.A. & Brown, T.H. Fear conditioning to discontinuous auditory cues requires perirhinal cortical function. Behav. Neurosci. 122, 1178–1185 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Boatman, J.A. & Kim, J.J. A thalamo-cortico-amygdala pathway mediates auditory fear conditioning in the intact brain. Eur. J. Neurosci. 24, 894–900 (2006).

    Article  PubMed  Google Scholar 

  31. Campeau, S. & Davis, M. Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J. Neurosci. 15, 2312–2327 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sacco, T. & Sacchetti, B. Role of secondary sensory cortices in emotional memory storage and retrieval in rats. Science 329, 649–656 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Letzkus, J.J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480, 331–335 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Weinberger, N.M. Associative representational plasticity in the auditory cortex: a synthesis of two disciplines. Learn. Mem. 14, 1–16 (2007).

    Article  PubMed  Google Scholar 

  35. Weinberger, N.M. The medial geniculate, not the amygdala, as the root of auditory fear conditioning. Hear. Res. 274, 61–74 (2011).

    Article  PubMed  Google Scholar 

  36. Johansen, J.P., Wolff, S.B., Luthi, A. & LeDoux, J.E. Controlling the elements: an optogenetic approach to understanding the neural circuits of fear. Biol. Psychiatry 71, 1053–1060 (2012).

    Article  PubMed  Google Scholar 

  37. Aitkin, L.M. Medial geniculate body of the cat: responses to tonal stimuli of neurons in medial division. J. Neurophysiol. 36, 275–283 (1973).

    Article  CAS  PubMed  Google Scholar 

  38. Linke, R. & Schwegler, H. Convergent and complementary projections of the caudal paralaminar thalamic nuclei to rat temporal and insular cortex. Cereb. Cortex 10, 753–771 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Calford, M.B. & Webster, W.R. Auditory representation within principal division of cat medial geniculate body: an electrophysiology study. J. Neurophysiol. 45, 1013–1028 (1981).

    Article  CAS  PubMed  Google Scholar 

  40. Ryugo, D.K. & Weinberger, N.M. Differential plasticity of morphologically distinct neuron populations in the medical geniculate body of the cat during classical conditioning. Behav. Biol. 22, 275–301 (1978).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Han, J.H. et al. Increasing CREB in the auditory thalamus enhances memory and generalization of auditory conditioned fear. Learn. Mem. 15, 443–453 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Parsons, R.G., Riedner, B.A., Gafford, G.M. & Helmstetter, F.J. The formation of auditory fear memory requires the synthesis of protein and mRNA in the auditory thalamus. Neuroscience 141, 1163–1170 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Antunes, R. & Moita, M.A. Discriminative auditory fear learning requires both tuned and nontuned auditory pathways to the amygdala. J. Neurosci. 30, 9782–9787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schafe, G.E., Doyere, V. & LeDoux, J.E. Tracking the fear engram: the lateral amygdala is an essential locus of fear memory storage. J. Neurosci. 25, 10010–10014 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tye, K.M. & Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat. Rev. Neurosci. 13, 251–266 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Johansen, J.P. & Fields, H.L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat. Neurosci. 7, 398–403 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Shi, C. & Davis, M. Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J. Neurosci. 19, 420–430 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brunzell, D.H. & Kim, J.J. Fear conditioning to tone, but not to context, is attenuated by lesions of the insular cortex and posterior extension of the intralaminar complex in rats. Behav. Neurosci. 115, 365–375 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Lanuza, E., Nader, K. & Ledoux, J.E. Unconditioned stimulus pathways to the amygdala: effects of posterior thalamic and cortical lesions on fear conditioning. Neuroscience 125, 305–315 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Gross, C.T. & Canteras, N.S. The many paths to fear. Nat. Rev. Neurosci. 13, 651–658 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Di Scala, G., Mana, M.J., Jacobs, W.J. & Phillips, A.G. Evidence of Pavlovian conditioned fear following electrical stimulation of the periaqueductal grey in the rat. Physiol. Behav. 40, 55–63 (1987).

    Article  CAS  PubMed  Google Scholar 

  53. Kim, E.J. et al. Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats. Proc. Natl. Acad. Sci. USA 110, 14795–14800 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Johansen, J.P. et al. Optical activation of lateral amygdala pyramidal cells instructs associative fear learning. Proc. Natl. Acad. Sci. USA 107, 12692–12697 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Wolff, S.B. et al. Amygdala interneuron subtypes control fear learning through disinhibition. Nature 509, 453–458 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Johansen, J.P. et al. Hebbian and neuromodulatory mechanisms interact to trigger associative memory formation. Proc. Natl. Acad. Sci. USA (in the press).

  57. Bajic, D. & Proudfit, H.K. Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception. J. Comp. Neurol. 405, 359–379 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Watabe-Uchida, M., Zhu, L., Ogawa, S.K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. McNally, G.P., Johansen, J.P. & Blair, H.T. Placing prediction into the fear circuit. Trends Neurosci. 34, 283–292 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tang, J. et al. Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol. Pain 1, 6 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schultz, W., Dayan, P. & Montague, P.R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Schultz, W. Updating dopamine reward signals. Curr. Opin. Neurobiol. 23, 229–238 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Young, S.L. & Fanselow, M.S. Associative regulation of Pavlovian fear conditioning: unconditional stimulus intensity, incentive shifts, and latent inhibition. J. Exp. Psychol. Anim. Behav. Process. 18, 400–413 (1992).

    Article  CAS  PubMed  Google Scholar 

  64. Rescorla, R.A. & Wagner, A.R. A theory of pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement. in Classical Conditioning II: Current Research and Theory (eds. Black, A.H. & Prokasy, W.F.) (Appleton-Century-Crofts, New York, 1972).

  65. Sutton, R.S. & Barto, A.G. Toward a modern theory of adaptive networks: expectation and prediction. Psychol. Rev. 88, 135–170 (1981).

    Article  CAS  PubMed  Google Scholar 

  66. Pearce, J.M. & Hall, G. A model for Pavlovian learning: variations in the effectiveness of conditioned but not of unconditioned stimuli. Psychol. Rev. 87, 532–552 (1980).

    Article  CAS  PubMed  Google Scholar 

  67. Belova, M.A., Paton, J.J., Morrison, S.E. & Salzman, C.D. Expectation modulates neural responses to pleasant and aversive stimuli in primate amygdala. Neuron 55, 970–984 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Klavir, O., Genud-Gabai, R. & Paz, R. Functional connectivity between amygdala and cingulate cortex for adaptive aversive learning. Neuron 80, 1290–1300 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. McHugh, S.B. et al. Aversive prediction error signals in the amygdala. J. Neurosci. 34, 9024–9033 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schoenbaum, G., Chiba, A.A. & Gallagher, M. Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning. J. Neurosci. 19, 1876–1884 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shabel, S.J., Schairer, W., Donahue, R.J., Powell, V. & Janak, P.H. Similar neural activity during fear and disgust in the rat basolateral amygdala. PLoS ONE 6, e27797 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Roesch, M.R., Calu, D.J., Esber, G.R. & Schoenbaum, G. Neural correlates of variations in event processing during learning in basolateral amygdala. J. Neurosci. 30, 2464–2471 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Roy, M. et al. Representation of aversive prediction errors in the human periaqueductal gray. Nat. Neurosci. 17, 1607–1612 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bolles, R.C. & Fanselow, M.S. A perceptual-defensive-recuperative model of fear and pain. Behav. Brain Sci. 3, 291–323 (1980).

    Article  Google Scholar 

  76. McNally, G.P. & Cole, S. Opioid receptors in the midbrain periaqueductal gray regulate prediction errors during pavlovian fear conditioning. Behav. Neurosci. 120, 313–323 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Helmstetter, F.J. & Tershner, S.A. Lesions of the periaqueductal gray and rostral ventromedial medulla disrupt antinociceptive but not cardiovascular aversive conditional responses. J. Neurosci. 14, 7099–7108 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fanselow, M.S. Pavlovian conditioning, negative feedback and blocking: mechanisms that regulate association formation. Neuron 20, 625–627 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Furlong, T.M., Cole, S., Hamlin, A.S. & McNally, G.P. The role of prefrontal cortex in predictive fear learning. Behav. Neurosci. 124, 574–586 (2010).

    Article  PubMed  Google Scholar 

  80. Johansen, J.P., Hamanaka, H., Diaz-Mataix, L. & LeDoux, J.E. Hebbian and neuromodulatory mechanisms act synergistically to instruct associative memory formation. Soc. Neurosci. Abstr. 914.15 (2010).

  81. Lima, S.Q., Hromadka, T., Znamenskiy, P. & Zador, A.M. PINP: a new method of tagging neuronal populations for identification during in vivo electrophysiological recording. PLoS ONE 4, e6099 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Courtin, J. et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Senn, V. et al. Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81, 428–437 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Pezze, M.A. & Feldon, J. Mesolimbic dopaminergic pathways in fear conditioning. Prog. Neurobiol. 74, 301–320 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Sara, S.J. The locus coeruleus and noradrenergic modulation of cognition. Nat. Rev. Neurosci. 10, 211–223 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Bissière, S., Humeau, Y. & Luthi, A. Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nat. Neurosci. 6, 587–592 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Grace, A.A. & Rosenkranz, J.A. Regulation of conditioned responses of basolateral amygdala neurons. Physiol. Behav. 77, 489–493 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Tully, K., Li, Y., Tsvetkov, E. & Bolshakov, V.Y. Norepinephrine enables the induction of associative long-term potentiation at thalamo-amygdala synapses. Proc. Natl. Acad. Sci. USA 104, 14146–14150 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Heidbreder, C.A. & Groenewegen, H.J. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci. Biobehav. Rev. 27, 555–579 (2003).

    Article  PubMed  Google Scholar 

  90. LeDoux, J.E., Iwata, J., Cicchetti, P. & Reis, D.J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Petrovich, G.D. & Swanson, L.W. Projections from the lateral part of the central amygdalar nucleus to the postulated fear conditioning circuit. Brain Res. 763, 247–254 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Ciocchi, S. et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468, 277–282 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Haubensak, W. et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468, 270–276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Viviani, D. et al. Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333, 104–107 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Penzo, M.A., Robert, V. & Li, B. Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala. J. Neurosci. 34, 2432–2437 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pi, H.J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Klavir, O., Genud-Gabai, R. & Paz, R. Low-frequency stimulation depresses the primate anterior-cingulate-cortex and prevents spontaneous recovery of aversive memories. J. Neurosci. 32, 8589–8597 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Maroun, M., Kavushansky, A., Holmes, A., Wellman, C. & Motanis, H. Enhanced extinction of aversive memories by high-frequency stimulation of the rat infralimbic cortex. PLoS ONE 7, e35853 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Likhtik, E., Pelletier, J.G., Paz, R. & Pare, D. Prefrontal control of the amygdala. J. Neurosci. 25, 7429–7437 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Livneh, U. & Paz, R. Amygdala-prefrontal synchronization underlies resistance to extinction of aversive memories. Neuron 75, 133–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Burgos-Robles, A., Vidal-Gonzalez, I. & Quirk, G.J. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. J. Neurosci. 29, 8474–8482 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Buzsáki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Markram, H., Lubke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Kayser, C., Montemurro, M.A., Logothetis, N.K. & Panzeri, S. Spike-phase coding boosts and stabilizes information carried by spatial and temporal spike patterns. Neuron 61, 597–608 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Likhtik, E., Stujenske, J.M., Topiwala, M.A., Harris, A.Z. & Gordon, J.A. Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat. Neurosci. 17, 106–113 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Huxter, J., Burgess, N. & O'Keefe, J. Independent rate and temporal coding in hippocampal pyramidal cells. Nature 425, 828–832 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Huxter, J.R., Senior, T.J., Allen, K. & Csicsvari, J. Theta phase-specific codes for two-dimensional position, trajectory and heading in the hippocampus. Nat. Neurosci. 11, 587–594 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Benchenane, K. et al. Coherent theta oscillations and reorganization of spike timing in the hippocampal- prefrontal network upon learning. Neuron 66, 921–936 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Pastalkova, E., Itskov, V., Amarasingham, A. & Buzsaki, G. Internally generated cell assembly sequences in the rat hippocampus. Science 321, 1322–1327 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Popa, D., Duvarci, S., Popescu, A.T., Lena, C. & Pare, D. Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep. Proc. Natl. Acad. Sci. USA 107, 6516–6519 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Ascoli, G.A. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Lovett-Barron, M. et al. Regulation of neuronal input transformations by tunable dendritic inhibition. Nat. Neurosci. 15, 423–430 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Massi, L. et al. Temporal dynamics of parvalbumin-expressing axo-axonic and basket cells in the rat medial prefrontal cortex in vivo. J. Neurosci. 32, 16496–16502 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Baeg, E.H. et al. Fast spiking and regular spiking neural correlates of fear conditioning in the medial prefrontal cortex of the rat. Cereb. Cortex 11, 441–451 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Carlén, M. et al. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol. Psychiatry 17, 537–548 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T.C. Bienvenu, R.R. Rozeske and J. Ormond for helpful comments on the manuscript. This work was supported by grants to C.H. from the French National Research Agency (ANR-2010-BLAN-1442-01; ANR-10-EQPX-08 OPTOPATH; LABEX BRAIN ANR 10-LABX-43), the European Research Council under the European Union's Seventh Framework Program (FP7/2007-2013)/ERC grant agreement no. 281168, the Conseil Regional d'Aquitaine, and by grants to J.P.J. from MEXT (Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS)), Strategic Research Program for Brain Sciences (11041047) and Grants-in-Aid for Scientific Research (25710003, 25116531).

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Correspondence to Cyril Herry or Joshua P Johansen.

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Herry, C., Johansen, J. Encoding of fear learning and memory in distributed neuronal circuits. Nat Neurosci 17, 1644–1654 (2014). https://doi.org/10.1038/nn.3869

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