Korean Journal of Biological Psychiatry (생물정신의학)

The Korean Society of Biological Psychiatry (대한생물정신의학회)
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Neural Circuit and Mechanism of Fear Conditioning

공포 조건화 학습의 신경회로와 기전

  • Choi, Kwang-Yeon (Neural Circuit and Behavior Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2011.04.14
  • Accepted : 2011.04.28
  • Published : 2011.05.31
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Abstract

Pavlovian fear conditioning has been extensively studied for the understanding of neurobiological basis of memory and emotion. Pavlovian fear conditioning is an associative memory which forms when conditioned stimulus (CS) is paired with unconditioned stimulus (US) once or repeatedly. This behavioral model is also important for the understanding of anxiety disorders such as posttraumatic stress disorder. Here we describe the neural circuitry involved in fear conditioning and the molecular mechanisms underlying fear memory formation. During consolidation some memories fade out but other memories become stable and concrete. Emotion plays an important role in determining which memories will survive. Memory becomes unstable and editable again immediately after retrieval. It opens the possibility for us of modulating the established fear memory. It provides us with very efficient tools to improve the efficacy of cognitive-behavior therapy and other exposure-based therapy treating anxiety disorders.

Keywords

References

  1. Horgan J. The undiscovered mind. 1st ed: Free Press;1999. p.45.
  2. Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005; 48:175-187. https://doi.org/10.1016/j.neuron.2005.09.025
  3. Raybuck JD, Lattal KM. Double dissociation of amygdala and hippocampal contributions to trace and delay fear conditioning. PLoS One 2011;6:e15982. https://doi.org/10.1371/journal.pone.0015982
  4. LaBar KS, LeDoux JE, Spencer DD, Phelps EA. Impaired fear conditioning following unilateral temporal lobectomy in humans. J Neurosci 1995;15:6846-6855.
  5. Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 1995; 269:1115-1118. https://doi.org/10.1126/science.7652558
  6. Maren S. Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 2001;24:897-931. https://doi.org/10.1146/annurev.neuro.24.1.897
  7. Li XF, Stutzmann GE, LeDoux JE. 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 1996;3:229-242. https://doi.org/10.1101/lm.3.2-3.229
  8. Quirk GJ, Armony JL, LeDoux JE. Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 1997;19:613-624. https://doi.org/10.1016/S0896-6273(00)80375-X
  9. Quirk GJ, Repa C, LeDoux JE. Fear conditioning enhances shortlatency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 1995;15:1029-1039. https://doi.org/10.1016/0896-6273(95)90092-6
  10. Sacco T, Sacchetti B. Role of secondary sensory cortices in emotional memory storage and retrieval in rats. Science 2010;329:649-656. https://doi.org/10.1126/science.1183165
  11. Romanski LM, Clugnet MC, Bordi F, LeDoux JE. Somatosensory and auditory convergence in the lateral nucleus of the amygdala. Behav Neurosci 1993;107:444-450. https://doi.org/10.1037/0735-7044.107.3.444
  12. LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J Neurosci 1990;10:1062-1069.
  13. Miserendino MJ, Sananes CB, Melia KR, Davis M. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 1990;345:716-718. https://doi.org/10.1038/345716a0
  14. LeDoux JE, Iwata J, Cicchetti P, Reis DJ. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci 1988;8:2517-2529.
  15. Van de Kar LD, Piechowski RA, Rittenhouse PA, Gray TS. Amygdaloid lesions: differential effect on conditioned stress and immobilization- induced increases in corticosterone and renin secretion. Neuroendocrinology 1991;54:89-95. https://doi.org/10.1159/000125856
  16. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992;106:274-285. https://doi.org/10.1037/0735-7044.106.2.274
  17. Phillips RG, LeDoux JE. Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learn Mem 1994;1:34-44.
  18. Maren S, Anagnostaras SG, Fanselow MS. The startled seahorse: is the hippocampus necessary for contextual fear conditioning? Trends Cogn Sci 1998;2:39-42. https://doi.org/10.1016/S1364-6613(98)01123-1
  19. Maren S, Fanselow MS. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J Neurosci 1995;15:7548-7564.
  20. Lomo T. The discovery of long-term potentiation. Philos Trans R Soc Lond B Biol Sci 2003;358:617-620. https://doi.org/10.1098/rstb.2002.1226
  21. McKernan MG, Shinnick-Gallagher P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 1997;390: 607-611. https://doi.org/10.1038/37605
  22. Bauer EP, Schafe GE, LeDoux JE. NMDA receptors and L-type voltage- gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J Neurosci 2002;22:5239-5249.
  23. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000; 23:155-184. https://doi.org/10.1146/annurev.neuro.23.1.155
  24. Schafe GE, Nader K, Blair HT, LeDoux JE. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci 2001;24:540-546. https://doi.org/10.1016/S0166-2236(00)01969-X
  25. Horak M, Chang K, Wenthold RJ. Masking of the endoplasmic reticulum retention signals during assembly of the NMDA receptor. J Neurosci 2008;28:3500-3509. https://doi.org/10.1523/JNEUROSCI.5239-07.2008
  26. Rodrigues SM, Schafe GE, LeDoux JE. Molecular mechanisms underlying emotional learning and memory in the lateral amygdala. Neuron 2004;44:75-91. https://doi.org/10.1016/j.neuron.2004.09.014
  27. Erreger K, Geballe MT, Kristensen A, Chen PE, Hansen KB, Lee CJ, et al. Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. Mol Pharmacol 2007;72:907-920. https://doi.org/10.1124/mol.107.037333
  28. Williams K. Modulation and block of ion channels: a new biology of polyamines. Cell Signal 1997;9:1-13. https://doi.org/10.1016/S0898-6568(96)00089-7
  29. Rubin MA, Berlese DB, Stiegemeier JA, Volkweis MA, Oliveira DM, dos Santos TL, et al. Intra-amygdala administration of polyamines modulates fear conditioning in rats. J Neurosci 2004;24:2328-2334. https://doi.org/10.1523/JNEUROSCI.1622-03.2004
  30. Rodrigues SM, Schafe GE, LeDoux JE. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J Neurosci 2001;21:6889- 6896.
  31. Alagarsamy S, Sorensen SD, Conn PJ. Coordinate regulation of metabotropic glutamate receptors. Curr Opin Neurobiol 2001;11: 357-362. https://doi.org/10.1016/S0959-4388(00)00219-1
  32. Liao GY, Wagner DA, Hsu MH, Leonard JP. Evidence for direct protein kinase-C mediated modulation of N-methyl-D-aspartate receptor current. Mol Pharmacol 2001;59:960-964. https://doi.org/10.1124/mol.59.5.960
  33. Cleva RM, Olive MF. Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders. Molecules 2011;16: 2097-2106. https://doi.org/10.3390/molecules16032097
  34. Yasuda R, Sabatini BL, Svoboda K. Plasticity of calcium channels in dendritic spines. Nat Neurosci 2003;6:948-955. https://doi.org/10.1038/nn1112
  35. Barria A, Muller D, Derkach V, Griffith LC, Soderling TR. Regulatory phosphorylation of AMPA-type glutamate receptors by CaMKII during long-term potentiation. Science 1997;276:2042-2045. https://doi.org/10.1126/science.276.5321.2042
  36. Soderling TR, Chang B, Brickey D. Cellular signaling through multifunctional Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 2001;276:3719-3722. https://doi.org/10.1074/jbc.R000013200
  37. Boehm J, Kang MG, Johnson RC, Esteban J, Huganir RL, Malinow R. Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron 2006;51: 213-225. https://doi.org/10.1016/j.neuron.2006.06.013
  38. Mammen AL, Kameyama K, Roche KW, Huganir RL. Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J Biol Chem 1997;272:32528-32533. https://doi.org/10.1074/jbc.272.51.32528
  39. Roche KW, O'Brien RJ, Mammen AL, Bernhardt J, Huganir RL. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 1996;16:1179-1188. https://doi.org/10.1016/S0896-6273(00)80144-0
  40. Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci 2000;20:89-102.
  41. Ehlers MD. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 2000;28: 511-525. https://doi.org/10.1016/S0896-6273(00)00129-X
  42. Esteban JA, Shi SH, Wilson C, Nuriya M, Huganir RL, Malinow R. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat Neurosci 2003;6:136-143. https://doi.org/10.1038/nn997
  43. Adams JP, Sweatt JD. Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu Rev Pharmacol Toxicol 2002;42: 135-163. https://doi.org/10.1146/annurev.pharmtox.42.082701.145401
  44. Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB. A synaptic Ras- GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 1998;20:895-904. https://doi.org/10.1016/S0896-6273(00)80471-7
  45. Lin CH, Yeh SH, Lin CH, Lu KT, Leu TH, Chang WC, et al. A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 2001;31:841-851. https://doi.org/10.1016/S0896-6273(01)00433-0
  46. Wang JQ, Tang Q, Parelkar NK, Liu Z, Samdani S, Choe ES, et al. Glutamate signaling to Ras-MAPK in striatal neurons: mechanisms for inducible gene expression and plasticity. Mol Neurobiol 2004; 29:1-14. https://doi.org/10.1385/MN:29:1:01
  47. Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci 2000;20:8177-8187.
  48. Alberini CM, Ghirardi M, Huang YY, Nguyen PV, Kandel ER. A molecular switch for the consolidation of long-term memory: cAMPinducible gene expression. Ann N Y Acad Sci 1995;758:261-286. https://doi.org/10.1111/j.1749-6632.1995.tb24833.x
  49. Kandel ER. Genes, synapses, and long-term memory. J Cell Physiol 1997;173:124-125. https://doi.org/10.1002/(SICI)1097-4652(199711)173:2<124::AID-JCP6>3.0.CO;2-P
  50. Dudai Y. Molecular bases of long-term memories: a question of persistence. Curr Opin Neurobiol 2002;12:211-216. https://doi.org/10.1016/S0959-4388(02)00305-7
  51. Lamprecht R, LeDoux J. Structural plasticity and memory. Nat Rev Neurosci 2004;5:45-54. https://doi.org/10.1038/nrn1301
  52. Bouton ME. Context and behavioral processes in extinction. Learn Mem 2004;11:485-494. https://doi.org/10.1101/lm.78804
  53. Repa JC, Muller J, Apergis J, Desrochers TM, Zhou Y, LeDoux JE. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat Neurosci 2001;4:724-731. https://doi.org/10.1038/89512
  54. Sotres-Bayon F, Bush DE, LeDoux JE. Acquisition of fear extinction requires activation of NR2B-containing NMDA receptors in the lateral amygdala. Neuropsychopharmacology 2007;32:1929-1940. https://doi.org/10.1038/sj.npp.1301316
  55. Lin CH, Yeh SH, Lu HY, Gean PW. The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. J Neurosci 2003;23:8310- 8317.
  56. Morgan MA, Romanski LM, LeDoux JE. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett 1993;163:109-113. https://doi.org/10.1016/0304-3940(93)90241-C
  57. Milad MR, Vidal-Gonzalez I, Quirk GJ. Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner. Behav Neurosci 2004;118:389-394. https://doi.org/10.1037/0735-7044.118.2.389
  58. Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 2000;20:6225-6231.
  59. Rosenkranz JA, Moore H, Grace AA. The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J Neurosci 2003;23:11054-11064.
  60. Pare D, Quirk GJ, Ledoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol 2004;92:1-9. https://doi.org/10.1152/jn.00153.2004
  61. Corcoran KA, Maren S. Factors regulating the effects of hippocampal inactivation on renewal of conditional fear after extinction. Learn Mem 2004;11:598-603. https://doi.org/10.1101/lm.78704
  62. Wilson A, Brooks DC, Bouton ME. The role of the rat hippocampal system in several effects of context in extinction. Behav Neurosci 1995;109:828-836. https://doi.org/10.1037/0735-7044.109.5.828
  63. Corcoran KA, Desmond TJ, Frey KA, Maren S. Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction. J Neurosci 2005;25:8978-8987. https://doi.org/10.1523/JNEUROSCI.2246-05.2005
  64. Hartley CA, Phelps EA. Changing fear: the neurocircuitry of emotion regulation. Neuropsychopharmacology 2010;35:136-146. https://doi.org/10.1038/npp.2009.121
  65. Hood WF, Compton RP, Monahan JB. D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett 1989;98:91-95. https://doi.org/10.1016/0304-3940(89)90379-0
  66. Watson GB, Bolanowski MA, Baganoff MP, Deppeler CL, Lanthorn TH. D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes. Brain Res 1990;510:158-160. https://doi.org/10.1016/0006-8993(90)90745-W
  67. Hofmann SG, Pollack MH, Otto MW. Augmentation treatment of psychotherapy for anxiety disorders with D-cycloserine. CNS Drug Rev 2006;12:208-217. https://doi.org/10.1111/j.1527-3458.2006.00208.x
  68. van Berckel BN, Hijman R, van der Linden JA, Westenberg HG, van Ree JM, Kahn RS. Efficacy and tolerance of D-cycloserine in drugfree schizophrenic patients. Biol Psychiatry 1996;40:1298-1300. https://doi.org/10.1016/S0006-3223(96)00311-3
  69. D'Souza DC, Gil R, Cassello K, Morrissey K, Abi-Saab D, White J, et al. IV glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans. Biol Psychiatry 2000;47:450-462. https://doi.org/10.1016/S0006-3223(99)00133-X
  70. Guastella AJ, Richardson R, Lovibond PF, Rapee RM, Gaston JE, Mitchell P, et al. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry 2008;63:544-549. https://doi.org/10.1016/j.biopsych.2007.11.011
  71. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004;61:1136-1144. https://doi.org/10.1001/archpsyc.61.11.1136
  72. Siegmund A, Golfels F, Finck C, Halisch A, Rath D, Plag J, et al. d- Cycloserine does not improve but might slightly speed up the outcome of in-vivo exposure therapy in patients with severe agoraphobia and panic disorder in a randomized double blind clinical trial. J Psychiatr Res 2011.
  73. Norberg MM, Krystal JH, Tolin DF. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 2008;63:1118-1126. https://doi.org/10.1016/j.biopsych.2008.01.012
  74. Cukor J, Spitalnick J, Difede J, Rizzo A, Rothbaum BO. Emerging treatments for PTSD. Clin Psychol Rev 2009;29:715-726. https://doi.org/10.1016/j.cpr.2009.09.001
  75. Heresco-Levy U, Kremer I, Javitt DC, Goichman R, Reshef A, Blanaru M, et al. Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol 2002; 5:301-307. https://doi.org/10.1017/S1461145702003061
  76. Yamamoto S, Morinobu S, Iwamoto Y, Ueda Y, Takei S, Fujita Y, et al. Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder. J Psychiatr Res 2010;44: 1069-1074. https://doi.org/10.1016/j.jpsychires.2010.03.013
  77. Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 2006;60:369-375. https://doi.org/10.1016/j.biopsych.2006.03.084
  78. Bourtchouladze R, Abel T, Berman N, Gordon R, Lapidus K, Kandel ER. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem 1998;5:365-374.
  79. Schafe GE, Nadel NV, Sullivan GM, Harris A, LeDoux JE. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem 1999; 6:97-110.
  80. Schafe GE, LeDoux JE. Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 2000;20:RC96.
  81. Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 2000;406:722-726. https://doi.org/10.1038/35021052
  82. Duvarci S, Nader K. Characterization of fear memory reconsolidation. J Neurosci 2004;24:9269-9275. https://doi.org/10.1523/JNEUROSCI.2971-04.2004
  83. Doyere V, Debiec J, Monfils MH, Schafe GE, LeDoux JE. Synapsespecific reconsolidation of distinct fear memories in the lateral amygdala. Nat Neurosci 2007;10:414-416. https://doi.org/10.1038/nn1871
  84. Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 2009;324:951-955. https://doi.org/10.1126/science.1167975
  85. Cooper SH. Alexander's corrective emotional experience: an objectivist turn in psychoanalytic authority and technique. Psychoanal Q 2007;76:1085-1102.
  86. Hu H, Real E, Takamiya K, Kang MG, Ledoux J, Huganir RL, et al. Emotion enhances learning via norepinephrine regulation of AMPA- receptor trafficking. Cell 2007;131:160-173. https://doi.org/10.1016/j.cell.2007.09.017
  87. Debiec J, Bush DE, LeDoux JE. Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats--a possible mechanism for the persistence of traumatic memories in PTSD. Depress Anxiety 2011;28:186-193. doi: 10.1002/da.20803.
  88. Pitman RK, Delahanty DL. Conceptually driven pharmacologic approaches to acute trauma. CNS Spectr 2005;10:99-106. https://doi.org/10.1017/S109285290001943X
  89. Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 2002;51:189-192. https://doi.org/10.1016/S0006-3223(01)01279-3
  90. Sharp S, Thomas C, Rosenberg L, Rosenberg M, Meyer W 3rd. Propranolol does not reduce risk for acute stress disorder in pediatric burn trauma. J Trauma 2010;68:193-197. https://doi.org/10.1097/TA.0b013e3181a8b326
  91. McGhee LL, Maani CV, Garza TH, Desocio PA, Gaylord KM, Black IH. The effect of propranolol on posttraumatic stress disorder in burned service members. J Burn Care Res 2009;30:92-97. https://doi.org/10.1097/BCR.0b013e3181921f51
  92. Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci 2009; 12:256-258. https://doi.org/10.1038/nn.2271
  93. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res 2008;42:503-506. https://doi.org/10.1016/j.jpsychires.2007.05.006
  94. Aravanis AM, Wang LP, Zhang F, Meltzer LA, Mogri MZ, Schneider MB, et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 2007;4:S143-S156. https://doi.org/10.1088/1741-2560/4/3/S02