, Volume 236, Issue 7, pp 2039–2048 | Cite as

Individual variability in the recall of fear extinction is associated with phosphorylation of mitogen-activated protein kinase in the infralimbic cortex

  • Amanda S. Russo
  • Jessica Lee
  • Ryan G. ParsonsEmail author
Original Investigation



Although most individuals will be exposed to trauma at some point, only a small portion of individuals develops posttraumatic stress disorder (PTSD), suggesting there are factors which render some individuals particularly susceptible to the development of this disorder. One cardinal feature of PTSD is the failure to extinguish fear responses to cues that once signaled danger. Rodent studies of fear learning and extinction have provided insight into the neural mechanisms underlying extinction; however, most of these studies have focused on mechanisms involved in typical responses and fewer have identified mechanisms that distinguish animals that extinguish well versus those that do not extinguish their fear responses. Investigation of individual differences in fear extinction might help us better understand the susceptibility to and development of PTSD.


In order to understand the neural mechanisms underlying such variation, we assessed phosphorylated mitogen-activated protein kinase (P-MAPK) levels in infralimbic cortex (IL), basolateral amygdala (BLA), and dorsal hippocampus in subsets of rats which exhibited good or poor recall of extinction.


We found a relationship between extinction recall and P-MAPK in the IL such that rats which had good extinction recall had higher levels of P-MAPK than those which had poor extinction recall. We also found that rats which had good extinction recall had higher levels of P-MAPK in the dorsal hippocampus than control rats.


Our findings suggest that individual differences in the recall of extinction learning can be explained by altered cell signaling in the IL.


Fear conditioning Fear memory extinction Infralimbic cortex Mitogen-activated protein kinase Posttraumatic stress disorder 


Author contributions

ASR and RGP were responsible for the study design. ASR, JL, and RGP performed the experiments and analyzed data. All authors have critically reviewed the content and approved the final version submitted for publication.


This work was supported by startup funds from Stony Brook University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P (1998) The 1996 Detroit area survey of trauma. Arch Gen Psychiatry 55(7):626–632. CrossRefGoogle Scholar
  2. Burgos-Robles A, Vidal-Gonzalez I, Santini E, Quirk GJ (2007) Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53(6):871–880. CrossRefGoogle Scholar
  3. Bush DE, Sotres-Bayon F, LeDoux JE (2007) Individual differences in fear: isolating fear reactivity and fear recovery phenotypes. J Trauma Stress: Off Publ Int Soc Trauma Stress Stud 20(4):413–422.
  4. Chang CH, Berke JD, Maren S (2010) Single-unit activity in the medial prefrontal cortex during immediate and delayed extinction of fear in rats. PLoS One 5(8):e11971. CrossRefGoogle Scholar
  5. Corcoran KA, Maren S (2001) Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J Neurosci 21(5):1720–1726. CrossRefGoogle Scholar
  6. Corcoran KA, Maren S (2004) Factors regulating the effects of hippocampal inactivation on renewal of conditional fear after extinction. Learn Mem 11(5):598–603.
  7. Davis M (2006) Neural systems involved in fear and anxiety measured with fear-potentiated startle. Am Psychol 61(8):741–756. CrossRefGoogle Scholar
  8. Davis M, Myers KM (2002) The role of glutamate and gamma-aminobutyric acid in fear extinction: clinical implications for exposure therapy. Biol Psychiatry 52(10):998–1007.
  9. Do-Monte FH, Manzano-Nieves G, Quiñones-Laracuente K, Ramos-Medina L, Quirk GJ (2015a) Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci 35(8):3607–3615. CrossRefGoogle Scholar
  10. Do-Monte FH, Quinones-Laracuente K, Quirk GJ (2015b) A temporal shift in the circuits mediating retrieval of fear memory. Nature 519(7544):460–463. CrossRefGoogle Scholar
  11. Fitzgerald PJ, Seemann JR, Maren S (2014) Can fear extinction be enhanced? A review of pharmacological and behavioral findings. Brain Res Bull 105:46–60. CrossRefGoogle Scholar
  12. Foa EB, Kozak MJ (1986) Emotional processing of fear: exposure to corrective information. Psychol Bull 99(1):20–35 CrossRefGoogle Scholar
  13. Gafford GM, Parsons RG, Helmstetter FJ (2013) Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory. Hippocampus 23(9):842–847. CrossRefGoogle Scholar
  14. Garcia R, Chang CH, Maren S (2006) Electrolytic lesions of the medial prefrontal cortex do not interfere with long-term memory of extinction of conditioned fear. Learn Mem 13(1):14–17. CrossRefGoogle Scholar
  15. Hefner K, Whittle N, Juhasz J, Norcross M, Karlsson R-M, Saksida LM, Holmes A (2008) Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain. J Neurosci 28(32):8074–8085. CrossRefGoogle Scholar
  16. Herry C, Mons N (2004) Resistance to extinction is associated with impaired immediate early gene induction in medial prefrontal cortex and amygdala. Eur J Neurosci 20(3):781–790. CrossRefGoogle Scholar
  17. Herry C, Trifilieff P, Micheau J, Lüthi A, Mons N (2006) Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala. Eur J Neurosci 24(1):261–269. CrossRefGoogle Scholar
  18. Holmes A, Singewald N (2013) Individual differences in recovery from traumatic fear. Trends Neurosci 36(1):23–31. CrossRefGoogle Scholar
  19. Holmes A, Fitzgerald PJ, MacPherson KP, DeBrouse L, Colacicco G, Flynn S, Masneuf S, Pleil KE, Li C, Macrinkiewcz CA, Kash TL, Gunduz-Cinar O, Camp M (2012) Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat Neurosci 15(10):1359–1361. CrossRefGoogle Scholar
  20. Hugues S, Garcia R (2007) Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory. Learn Mem 14(8):520–524. CrossRefGoogle Scholar
  21. Hugues S, Deschaux O, Garcia R (2004) Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear. Learn Mem 11(5):540–543. CrossRefGoogle Scholar
  22. Hugues S, Chessel A, Lena I, Marsault R, Garcia R (2006) Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation. Synapse 60(4):280–287. CrossRefGoogle Scholar
  23. Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M., & Nelson, C.B. (1995). Posttraumatic stress disorder in the National Comorbidity Survey Arch Gen Psychiatry, 52(12), 48–1060. doi:
  24. Kim JH, Hamlin AS, Richardson R (2009) Fear extinction across development: the involvement of the medial prefrontal cortex as assessed by temporary inactivation and immunohistochemistry. J Neurosci 29(35):10802–10808. CrossRefGoogle Scholar
  25. Kim HS, Cho HY, Augustine GJ, Han JH (2016) Selective control of fear expression by optogenetic manipulation of infralimbic cortex after extinction. Neuropsychopharmacology 41(5):1261–1273. CrossRefGoogle Scholar
  26. King G, Scott E, Graham BM, Richardson R (2017) Individual differences in fear extinction and anxiety-like behavior. Learn Mem 24(5):182–190. CrossRefGoogle Scholar
  27. Knapska E, Maren S (2009) Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. Learn Mem 16(8):486–493. CrossRefGoogle Scholar
  28. Knapska E, Macias M, Mikosz M, Nowak A, Owczarek D, Wawrzyniak M, Pieprzyk M, Cymerman IA, Werka T, Sheng M, Maren S, Jaworski J, Kaczmarek L (2012) Functional anatomy of neural circuits regulating fear and extinction. Proc Natl Acad Sci 109(42):17093–17098. CrossRefGoogle Scholar
  29. Lebrón K, Milad MR, Quirk GJ (2004) Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. Learn Mem 11(5):544–548. CrossRefGoogle Scholar
  30. Lu KT, Walker DL, Davis M (2001) Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J Neurosci 21(16):RC162. CrossRefGoogle Scholar
  31. Marek R, Jin J, Goode TD, Giustino TF, Wang Q, Acca Holehonnur R, Ploski JE, Fitzgerald PJ, Lynagh T, Lynch JW, Maren S, Sah P (2018) Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nat Neurosci 21(3):384–392. CrossRefGoogle Scholar
  32. Maren S, Chang CH (2006) Recent fear is resistant to extinction. Proc Natl Acad Sci 103(47):18020–18025. CrossRefGoogle Scholar
  33. Maren S, Phan KL, Liberzon I (2013) The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14(6):417–428. CrossRefGoogle Scholar
  34. Milad MRR, Quirk GJJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420(6911):70–74. CrossRefGoogle Scholar
  35. Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129–151. CrossRefGoogle Scholar
  36. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK (2008) Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res 42(7):515–520. CrossRefGoogle Scholar
  37. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan NA, Handwerger K, Orr SP, Rauch SL (2009) Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 66(12):1075–1082. CrossRefGoogle Scholar
  38. Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12(2):49–150. CrossRefGoogle Scholar
  39. Orsini CA, Kim JH, Knapska E, Maren S (2011) Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction. J Neurosci 31(47):17269–17277. CrossRefGoogle Scholar
  40. Parsons RG, Ressler KJ (2013) Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16(2):146–153. CrossRefGoogle Scholar
  41. Parsons RG, Gafford GM, Helmstetter FJ (2010) Regulation of extinction-related plasticity by opioid receptors in the ventrolateral periaqueductal gray matter. Front Behav Neurosci 4:44. Google Scholar
  42. Pavlov IP (1927) Conditional reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford Univ. Press, Oxford, EnglandGoogle Scholar
  43. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ (2010) Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328(5983):1288–1290. CrossRefGoogle Scholar
  44. Quirk GJ (2002) Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery. Learn Mem 9(6):402–407. CrossRefGoogle Scholar
  45. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and r retrieval. Neuropsychopharmacology 33(1):56–72. CrossRefGoogle Scholar
  46. Quirk GJ, Russo GK, Barron JL, Lebron K (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20(16):6225–6231. CrossRefGoogle Scholar
  47. Rescorla RA (2004) Spontaneous recovery. Learn Mem 11(5):501–509.
  48. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhances as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61(11):1136-1144. CrossRefGoogle Scholar
  49. Rothbaum BO, Davis M (2003) Applying learning principles to the treatment of post-trauma reactions. Ann N Y Acad Sci 1008(1):112-121. CrossRefGoogle Scholar
  50. Russo AS, Parsons RG (2017) Acoustic startle response in rats predicts inter-individual variation in fear extinction. Neurobiol Learn Mem 139:157-164. CrossRefGoogle Scholar
  51. Sharko AC, Fadel JR, Kaigler KF, Wilson MA (2017) Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction. Physiol Behav 178:93-102. CrossRefGoogle Scholar
  52. Shumake J, Furgeson-Moreira S, Monfils MH (2014) Predictability and heritability of individual differences in fear learning. Anim Cogn 17(5):1207-1221. CrossRefGoogle Scholar
  53. Sierra-Mercado D Jr, Corcoran KA, Lebrón-Milad K, Quirk GJ (2006) Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. Eur J Neurosci 24(6):1751-1758. CrossRefGoogle Scholar
  54. Sotres-Bayon F, Sierra-Mercado D, Pardilla-Delgado E, Quirk GJ (2012) Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76(4):804-812. CrossRefGoogle Scholar
  55. Swanson, L.W. (2004) Brain maps: structure of the rat brain, 3rd edition.Google Scholar
  56. Szapiro G, Vianna MRM, McGaugh JL, Medina JH, Izquierdo I (2003) The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear. Hippocampus 13(1):53-58. CrossRefGoogle Scholar
  57. Tronson NC, Schrick C, Guzman YF, Huh KH, Srivastava DP, Penzes P, Guedea AL, Gao C, Radulovic J (2009) Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear. J Neurosci 29(11):3387-3394. CrossRefGoogle Scholar
  58. Wang Q, Jin J, Maren S (2016) Renewal of extinguished fear activates ventral hippocampal neurons projecting to the prelimbic and infralimbic cortices in rats. Neurobiol Learn Mem 134:38-43. CrossRefGoogle Scholar
  59. Wiltgen BJ, Zhou M, Cai Y, Balaji J, Karlsson MG, Parivash SN, Li W, Silva AJ (2010) The hippocampus plays a selective role in the retrieval of detailed contextual memories. Curr Biol 20(15):1336-1344. CrossRefGoogle Scholar
  60. Yehuda R, LeDoux J (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56(1):19-32. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychologyStony Brook UniversityStony BrookUSA

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