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Lost in translation: how to upgrade fear memory research

Molecular Psychiatry volume 23, pages 2122–2132 (2018)Cite this article

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Abstract

We address some of the current limitations of translational research in fear memory and suggest alternatives that might help to overcome them. Appropriate fear responses are adaptive, but disruption of healthy fear memory circuits can lead to anxiety and fear-based disorders. Stress is one of the main environmental factors that can disrupt memory circuits and constitutes as a key factor in the etiopathology of these psychiatric conditions. Current therapies for anxiety and fear-based disorders have limited success rate, revealing a clear need for an improved understanding of their neurobiological basis. Although animal models are excellent for dissecting fear memory circuits and have driven tremendous advances in the field, translation of these findings into the clinic has been limited so far. Animal models of stress-induced pathological fear combined with powerful cutting-edge techniques would help to improve the translational value of preclinical studies. We also encourage combining animal and human research, including psychiatric patients in order to find new pharmacological targets with real therapeutic potential that will improve the extrapolation of the findings. Finally, we highlight novel neuroimaging approaches that improve our understanding of anxiety and fear-based disorders.

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References

  1. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21:169–84.

    PubMed  PubMed Central  Google Scholar 

  2. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21:655–79.

    CAS  PubMed  Google Scholar 

  3. Kanwar A, Malik S, Prokop LJ, Sim LA, Feldstein D, Wang Z, et al. The association between anxiety disorders and suicidal behaviors: a systematic review and meta-analysis. Depress Anxiety. 2013;30:917–29.

    PubMed  Google Scholar 

  4. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B. Group C study, et al. Econ Cost brain Disord Eur Eur J Neurol. 2012;19:155–62.

    CAS  Google Scholar 

  5. Bandelow B, Michaelis S. Epidemiology of anxiety disorders in the 21st century. Dialog- Clin Neurosci. 2015;17:327–35.

    Google Scholar 

  6. Farb DH, Ratner MH. Targeting the modulation of neural circuitry for the treatment of anxiety disorders. Pharmacol Rev. 2014;66:1002–32.

    CAS  PubMed  Google Scholar 

  7. Clark DM. Anxiety disorders: why they persist and how to treat them. Behav Res Ther. 1999;37:S5–27.

    PubMed  Google Scholar 

  8. Kindt M. A behavioural neuroscience perspective on the aetiology and treatment of anxiety disorders. Behav Res Ther. 2014;62:24–36.

    PubMed  Google Scholar 

  9. Wermter A-K, Laucht M, Schimmelmann BG, Banaschewski T, Banaschweski T, Sonuga-Barke EJS, et al.From nature versus nurture, via nature and nurture, to gene x environment interaction in mental disorders. Eur Child Adolesc Psychiatry. 2010;19:199–210.

    PubMed  Google Scholar 

  10. Plumb TN, Cullen PK, Minor TR. Parameters of hormetic stress and resilience to trauma in rats. Stress. 2015;18:88–95.

    PubMed  Google Scholar 

  11. Pêgo JM, Sousa JC, Almeida OFX, Sousa N. Stress and the neuroendocrinology of anxiety disorders. Curr Top Behav Neurosci. 2010;2:97–117.

    PubMed  Google Scholar 

  12. McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79:16–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Roozendaal B, McEwen BS, Chattarji S, Stress, memory and the amygdala. Nat Rev Neurosci. 2009;10:423–33.

    CAS  PubMed  Google Scholar 

  14. Kendler KS. Genetic epidemiology in psychiatry. Taking both genes and environment seriously. Arch Gen Psychiatry. 1995;52:895–9.

    CAS  PubMed  Google Scholar 

  15. Franklin TB, Saab BJ, Mansuy IM. Neural mechanisms of stress resilience and vulnerability. Neuron. 2012;75:747–61.

    CAS  PubMed  Google Scholar 

  16. Macphail EM. Cognitive function in mammals: the evolutionary perspective. Brain Res Cogn Brain Res. 1996;3:279–90.

    CAS  PubMed  Google Scholar 

  17. Anderson DJ, Adolphs R. A framework for studying emotions across species. Cell. 2014;157:187–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci. 2012;35:24–35.

    CAS  PubMed  Google Scholar 

  19. Lüthi A, Lüscher C. Pathological circuit function underlying addiction and anxiety disorders. Nat Neurosci. 2014;17:1635–43.

    PubMed  Google Scholar 

  20. Maeng LY, Milad MR. Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones. Horm Behav. 2015;76:106–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Altemus M, Sarvaiya N, Neill Epperson C. Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol. 2014;35:320–30.

    PubMed  PubMed Central  Google Scholar 

  22. Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, et al. A key role for orexin in panic anxiety. Nat Med. 2010;16:111–5.

    CAS  PubMed  Google Scholar 

  23. Brandão ML, Zanoveli JM, Ruiz-Martinez RC, Oliveira LC, Landeira-Fernandez J. Different patterns of freezing behavior organized in the periaqueductal gray of rats: Association with different types of anxiety. Behav Brain Res. 2008;188:1–13.

    PubMed  Google Scholar 

  24. Santos M, D’Amico D, Spadoni O, Amador-Arjona A, Stork O, Dierssen M. Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model. J Neurosci. 2013;33:15259–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hefner K, Whittle N, Juhasz J, Norcross M, Karlsson R-M, Saksida LM, et al. Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain. J Neurosci. 2008;28:8074–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Craske MG, Stein MB, Eley TC, Milad MR, Holmes A, Rapee RM, et al. Anxiety disorders. Nat Rev Dis Prim. 2017;3:17024

    PubMed  Google Scholar 

  27. Sawamura T, Klengel T, Armario A, Jovanovic T, Norrholm SD, Ressler KJ, et al. Dexamethasone treatment leads to enhanced fear extinction and dynamic Fkbp5 regulation in amygdala. Neuropsychopharmacology. 2016;41:832–46.

    CAS  PubMed  Google Scholar 

  28. Andero R, Dias BG, Ressler KJ. A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation. Neuron. 2014;83:444–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Izquierdo A, Wellman CL, Holmes A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci. 2006;26:5733–8.

    CAS  PubMed  Google Scholar 

  30. Takahashi T, Morinobu S, Iwamoto Y, Yamawaki S. Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats. Psychopharmacol (Berl). 2006;189:165–73.

    CAS  Google Scholar 

  31. Baratta MV, Christianson JP, Gomez DM, Zarza CM, Amat J, Masini CV, et al. Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear. Neuroscience. 2007;146:1495–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Maren S. Neurobiology of pavlovian fear conditioning. Annu Rev Neurosci. 2001;24:897–931.

    CAS  PubMed  Google Scholar 

  33. Maren S, Quirk GJ. Neuronal signalling of fear memory. Nat Rev Neurosci. 2004;5:844–52.

    CAS  PubMed  Google Scholar 

  34. Pape H-C, Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev. 2010;90:419–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Belzung C, Turiault M, Griebel G. Optogenetics to study the circuits of fear- and depression-like behaviors: a critical analysis. Pharmacol Biochem Behav. 2014;122:144–57.

    CAS  PubMed  Google Scholar 

  36. Dejean C, Courtin J, Rozeske RR, Bonnet MC, Dousset V, Michelet T, et al. Neuronal circuits for fear expression and recovery: Recent advances and potential therapeutic strategies. Biol Psychiatry. 2015;78:298–306.

    PubMed  Google Scholar 

  37. Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci. 2015;18:1213–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sternson SM, Roth BL. Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci. 2014;37:387–407.

    CAS  PubMed  Google Scholar 

  39. LeDoux J. The amygdala. Curr Biol. 2007;17:R868–74.

    CAS  PubMed  Google Scholar 

  40. Gafford GM, Ressler KJ. Mouse models of fear-related disorders: Cell-type-specific manipulations in amygdala. Neuroscience. 2016;321:108–20.

    CAS  PubMed  Google Scholar 

  41. Sparta DR, Jennings JH, Ung RL, Stuber GD. Optogenetic strategies to investigate neural circuitry engaged by stress. Behav Brain Res. 2013;255:19–25.

    PubMed  PubMed Central  Google Scholar 

  42. Ciocchi S, Herry C, Grenier F, Wolff SBE, Letzkus JJ, Vlachos I, et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature. 2010;468:277–82.

    CAS  PubMed  Google Scholar 

  43. Roth BL. DREADDs for neuroscientists. Neuron. 2016;89:683–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. McCullough KM, Choi D, Guo J, Zimmerman K, Walton J, Rainnie DG, et al. Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala. Nat Commun. 2016;7:13149

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Rask-Andersen M, Almén MS, Schiöth HB. Trends in the exploitation of novel drug targets. Nat Rev Drug Discov. 2011;10:579–90.

    CAS  PubMed  Google Scholar 

  46. Zhu H, Roth BL. DREADD: a chemogenetic GPCR signaling platform. Int J Neuropsychopharmacol. 2014;18:pyu007.

    PubMed  PubMed Central  Google Scholar 

  47. Baratta MV, Kodandaramaiah SB, Monahan PE, Yao J, Weber MD, Lin P-A, et al. Stress enables reinforcement-elicited serotonergic consolidation of fear memory. Biol Psychiatry. 2016;79:814–22.

    PubMed  Google Scholar 

  48. Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Mol Psychiatry. 2014;19:1284–94.

    CAS  PubMed  Google Scholar 

  49. Gillespie CF, Phifer J, Bradley B, Ressler KJ. Risk and resilience: Genetic and environmental influences on development of the stress response. Depress Anxiety. 2009;26:984–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sharma S, Powers A, Bradley B, Ressler KJ. Gene × environment determinants of stress- and anxiety-related disorders. Annu Rev Psychol. 2016;67:239–61.

    PubMed  Google Scholar 

  51. Yin H, Kauffman KJ, Anderson DG. Delivery technologies for genome editing. Nat Rev Drug Discov. 2017;16:387–99. https://doi.org/10.1038/nrd.2016.280.

    Article  CAS  PubMed  Google Scholar 

  52. Walters BJ, Azam AB, Gillon CJ, Josselyn SA, Zovkic IB. Advanced in vivo use of CRISPR/Cas9 and anti-sense DNA inhibition for gene manipulation in the brain. Front Genet. 2016;6:362.

    PubMed  PubMed Central  Google Scholar 

  53. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science.2013;339:819–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lee HB, Sundberg BN, Sigafoos AN, Clark KJ. Genome engineering with TALE and CRISPR systems in neuroscience. Front Genet. 2016;7:47.

    PubMed  PubMed Central  Google Scholar 

  55. Sheerin CM, Lind MJ, Bountress KE, Nugent NR, Amstadter AB. The genetics and epigenetics of PTSD: overview, recent advances, and future directions. Curr Opin Psychol. 2017;14:5–11.

    PubMed  PubMed Central  Google Scholar 

  56. Smoller JW. The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology. 2016;41:297–319.

    CAS  Google Scholar 

  57. Hamel EJO, Grewe BF, Parker JG, Schnitzer MJ. Cellular level brain imaging in behaving mammals: An engineering approach. Neuron. 2015;86:140–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Buzsáki G. Large-scale recording of neuronal ensembles. Nat Neurosci. 2004;7:446–51.

    PubMed  Google Scholar 

  59. Grewe BF, Helmchen F. Optical probing of neuronal ensemble activity. Curr Opin Neurobiol. 2009;19:520–9.

    CAS  PubMed  Google Scholar 

  60. Grewe BF, Gründemann J, Kitch LJ, Lecoq JA, Parker JG, Marshall JD, et al. Neural ensemble dynamics underlying a long-term associative memory. Nature. 2017;543:670–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold K-H, Haass C, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science. 2008;321:1686–9.

    CAS  PubMed  Google Scholar 

  62. Reznichenko L, Cheng Q, Nizar K, Gratiy SL, Saisan PA, Rockenstein EM, et al. In vivo alterations in calcium buffering capacity in transgenic mouse model of synucleinopathy. J Neurosci. 2012;32:9992–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Walker DL, Ressler KJ, Lu K-T, Davis M. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci. 2002;22:2343–51.

    CAS  PubMed  Google Scholar 

  64. Yamamoto S, Morinobu S, Fuchikami M, Kurata A, Kozuru T, Yamawaki S. Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology. 2008;33:2108–16.

    CAS  PubMed  Google Scholar 

  65. Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, et al. A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. Am J Psychiatry. 2014;171:640–8.

    PubMed  PubMed Central  Google Scholar 

  66. de Kleine RA, Hendriks G-J, Kusters WJC, Broekman TG, van Minnen A. A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol Psychiatry. 2012;71:962–8.

    PubMed  Google Scholar 

  67. 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;61:1136–44.

    PubMed  Google Scholar 

  68. Mataix-Cols D, Fernández de la Cruz L, Monzani B, Rosenfield D, Andersson E, Pérez-Vigil A, et al. D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: A systematic review and meta-analysis. JAMA Psychiatry. 2017;74:501–10. https://doi.org/10.1001/jamapsychiatry.2016.3955.

    Article  PubMed  Google Scholar 

  69. Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, et al. Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med. 2013;5:188ra73

    PubMed  PubMed Central  Google Scholar 

  70. Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B, et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry. 2013;18:813–23.

    CAS  PubMed  Google Scholar 

  71. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327:863–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bach DR, Tzovara A, Vunder J. Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline. Mol Psychiatry. 2017. https://doi.org/10.1038/mp.2017.65.

    PubMed  PubMed Central  Google Scholar 

  73. Brown TE, Wilson AR, Cocking DL, Sorg BA. Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory. Neurobiol Learn Mem. 2009;91:66–72.

    CAS  PubMed  Google Scholar 

  74. Arloth J, Bogdan R, Weber P, Frishman G, Menke A, Wagner KV, et al. Genetic differences in the immediate transcriptome response to stress predict risk-related brain function and psychiatric disorders. Neuron. 2015;86:1189–202.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Lonsdorf TB, Menz MM, Andreatta M, Fullana MA, Golkar A, Haaker J, et al. Don’t fear ‘fear conditioning’: Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neurosci Biobehav Rev. 2017;77:247–85. https://doi.org/10.1016/j.neubiorev.2017.02.026.

    Article  PubMed  Google Scholar 

  76. Korn CW, Staib M, Tzovara A, Castegnetti G, Bach DR. A pupil size response model to assess fear learning. Psychophysiology. 2017;54:330–43.

    PubMed  Google Scholar 

  77. Leuchs L, Schneider M, Czisch M, Spoormaker VI. Neural correlates of pupil dilation during human fear learning. Neuroimage. 2017;147:186–97.

    PubMed  Google Scholar 

  78. McGinley MJ, David SV, McCormick DA. Cortical membrane potential signature of optimal states for sensory signal detection. Neuron. 2015;87:179–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Amadi U, Lim SH, Liu E, Baratta MV, Goosens KA. Hippocampal Processing of ambiguity enhances fear memory. Psychol Sci. 2017;28:143–61.

    PubMed  Google Scholar 

  80. Herry C, Bach DR, Esposito F, Di Salle F, Perrig WJ, Scheffler K, et al. Processing of temporal unpredictability in human and animal amygdala. J Neurosci. 2007;27:5958–66.

    CAS  PubMed  Google Scholar 

  81. Belova MA, Paton JJ, Morrison SE, Salzman CD, Braus DF, Buchel C, et al. Expectation modulates neural responses to pleasant and aversive stimuli in primate amygdala. Neuron. 2007;55:970–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Grillon C, Lissek S, Rabin S, McDowell D, Dvir S, Pine DS. Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am J Psychiatry. 2008;165:898–904.

    PubMed  PubMed Central  Google Scholar 

  83. Holaway RM, Heimberg RG, Coles ME. A comparison of intolerance of uncertainty in analogue obsessive-compulsive disorder and generalized anxiety disorder. J Anxiety Disord. 2006;20:158–74.

    PubMed  Google Scholar 

  84. Dugas MJ, Gagnon F, Ladouceur R, Freeston MH. Generalized anxiety disorder: a preliminary test of a conceptual model. Behav Res Ther. 1998;36:215–26.

    CAS  PubMed  Google Scholar 

  85. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron. 1998;20:937–45.

    CAS  PubMed  Google Scholar 

  86. Sehlmeyer C, Schöning S, Zwitserlood P, Pfleiderer B, Kircher T, Arolt V, et al. Human fear conditioning and extinction in neuroimaging: A systematic review. PLoS ONE. 2009;4:e5865

    PubMed  PubMed Central  Google Scholar 

  87. Quirici MB, da Rocha AJ. Teaching neuroimages: lipoid proteinosis (Urbach-Wiethe disease): typical findings in this rare genodermatosis. Neurology. 2013;80:e93.

    PubMed  Google Scholar 

  88. 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;269:1115–8.

    CAS  PubMed  Google Scholar 

  89. Feinstein JS, Adolphs R, Damasio A, Tranel D, Naumann E, Bartussek D, et al. The human amygdala and the induction and experience of fear. Curr Biol. 2011;21:34–8.

    CAS  PubMed  Google Scholar 

  90. Fullana MA, Harrison BJ, Soriano-Mas C, Vervliet B, Cardoner N, Àvila-Parcet A, et al. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Mol Psychiatry. 2016;21:500–8.

    CAS  PubMed  Google Scholar 

  91. Harrison B, Albajes-Eizagirre A, Soriano-Mas C, Vervliet B, Cardoner N, Benet O, et al. 14. Fear extinction in the human brain: Four meta-analyses of fMRI studies. Biol Psychiatry. 2017;81:S6–7.

    Google Scholar 

  92. Bach DR, Weiskopf N, Dolan RJ. A stable sparse fear memory trace in human amygdala. J Neurosci. 2011;31:9383–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Boubela RN, Kalcher K, Huf W, Seidel E-M, Derntl B, Pezawas L, et al. fMRI measurements of amygdala activation are confounded by stimulus correlated signal fluctuation in nearby veins draining distant brain regions. Sci Rep. 2015;5:10499

    PubMed  PubMed Central  Google Scholar 

  94. Ochsner KN, Silvers JA, Buhle JT. Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion. Ann N Y Acad Sci. 2012;1251:E1–24.

    PubMed  PubMed Central  Google Scholar 

  95. Gross JJ. Antecedent- and response-focused emotion regulation: Divergent consequences for experience, expression, and physiology. J Pers Soc Psychol. 1998;74:224–37.

    CAS  PubMed  Google Scholar 

  96. Aldao A, Nolen-Hoeksema S, Schweizer S. Emotion-regulation strategies across psychopathology: A meta-analytic review. Clin Psychol Rev. 2010;30:217–37.

    PubMed  Google Scholar 

  97. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88.

    PubMed  PubMed Central  Google Scholar 

  98. Picó-Pérez M, Radua J, Steward T, Menchón JM, Soriano-Mas C. Emotion regulation in mood and anxiety disorders: A meta-analysis of fMRI cognitive reappraisal studies. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79:96–104.

    PubMed  Google Scholar 

  99. Taylor SF, Liberzon I. Neural correlates of emotion regulation in psychopathology. Trends Cogn Sci. 2007;11:413–8.

    PubMed  Google Scholar 

  100. Goldin PR, Ziv M, Jazaieri H, Hahn K, Heimberg R, Gross JJ. Impact of cognitive behavioral therapy for social anxiety disorder on the neural dynamics of cognitive reappraisal of negative self-beliefs: randomized clinical trial. JAMA Psychiatry. 2013;70:1048–56.

    PubMed  PubMed Central  Google Scholar 

  101. Woo C-W, Chang LJ, Lindquist MA, Wager TD. Building better biomarkers: brain models in translational neuroimaging. Nat Neurosci. 2017;20:365–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Koizumi A, Amano K, Cortese A, Shibata K, Yoshida W, Seymour B, et al. Fear reduction without fear through reinforcement of neural activity that bypasses conscious exposure. Nat Hum Behav. 2016;1:6

    Google Scholar 

  103. Redondo RL, Kim J, Arons AL, Ramirez S, Liu X, Tonegawa S. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature. 2014;513:426–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Paunović N. Prolonged exposure counterconditioning as a treatment for chronic posttraumatic stress disorder. J Anxiety Disord. 2003;17:479–99.

    PubMed  Google Scholar 

  105. Correia SS, McGrath AG, Lee A, Graybiel AM, Goosens KA. Amygdala-ventral striatum circuit activation decreases long-term fear. Elife. 2016; 5. https://doi.org/10.7554/eLife.12669.

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Acknowledgements

RA is supported by a NARSAD Young Investigator Grant #22434, Ramón y Cajal program RYC2014-15784, RETOS-MINECO SAF2016-76565-R and FEDER funds. MAF is supported by a PERIS contract from the Departament de Salud of Generalitat de (SLT002/16/00490). CSM is supported by a Miguel Servet contract from the Carlos III Health Institute (CPII16/00048). MAF and CSM are supported by grants (PI16/00144 and PI16/00889) from the Carlos III Health Institute and FEDER funds -a way to build Europe-. AF is supported by a Juan de la Cierva contract from the Spanish government's Economy and Competitiveness Ministry (FJCI-2016-29888). We would like to thank Nicole Gouws for proofreading the manuscript.

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Authors and Affiliations

  1. Institut de Neurociènces, Universitat Autònoma de Barcelona, Bellaterra, Spain

    África Flores & Raül Andero

  2. FIDMAG Germanes Hospitalàries–CIBERSAM, Sant Boi de Llobregat, Barcelona, Spain

    Miquel À. Fullana

  3. Department of Psychiatry, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Miquel À. Fullana

  4. Department of Psychiatry, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain

    Carles Soriano-Mas

  5. CIBERSAM-G17, Barcelona, Spain

    Carles Soriano-Mas

  6. Department of Psychobiology and Methodology in Health Sciences, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Carles Soriano-Mas

  7. CIBERSAM, Corporació Sanitaria Parc Taulí, Sabadell, Spain

    Raül Andero

  8. Department of Psychobiology and Methodology in Health Sciences, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Raül Andero

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  1. África Flores
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Correspondence to Raül Andero.

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RA declares intellectual property of the patent PCT/US2015/037629 “Methods of managing conditioned fear with neurokinin receptor antagonists”. The remaining authors declare that they have no conflict of interest.

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Flores, Á., Fullana, M.À., Soriano-Mas, C. et al. Lost in translation: how to upgrade fear memory research. Mol Psychiatry 23, 2122–2132 (2018). https://doi.org/10.1038/s41380-017-0006-0

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