, Volume 236, Issue 1, pp 133–142 | Cite as

Neuroepigenetic mechanisms underlying fear extinction: emerging concepts

  • Paul R. MarshallEmail author
  • Timothy W. Bredy


An understanding of how memory is acquired and how it can be modified in fear-related anxiety disorders, with the enhancement of failing memories on one side and a reduction or elimination of traumatic memories on the other, is a key unmet challenge in the fields of neuroscience and neuropsychiatry. The latter process depends on an important form of learning called fear extinction, where a previously acquired fear-related memory is decoupled from its ability to control behaviour through repeated non-reinforced exposure to the original fear-inducing cue. Although simple in description, fear extinction relies on a complex pattern of brain region and cell-type specific processes, some of which are unique to this form of learning and, for better or worse, contribute to the inherent instability of fear extinction memory. Here, we explore an emerging layer of biology that may compliment and enrich the synapse-centric perspective of fear extinction. As opposed to the more classically defined role of protein synthesis in the formation of fear extinction memory, a neuroepigenetic view of the experience-dependent gene expression involves an appreciation of dynamic changes in the state of the entire cell: from a transient change in plasticity at the level of the synapse, to potentially more persistent long-term effects within the nucleus. A deeper understanding of neuroepigenetic mechanisms and how they influence the formation and maintenance of fear extinction memory has the potential to enable the development of more effective treatment approaches for fear-related neuropsychiatric conditions.


Neuroepigenetics Extinction Learning Epitranscriptomics Memory Epigenetics DNA modification DNA structure Histone modification RNA modification RNA editing 



The authors would also like to thank Ms. Rowan Tweedale for helpful editing of the manuscript.

Funding information

The authors gratefully acknowledge grant support from the NIH (5R01MH105398-TWB) and the Australian Research Council (SR120300015-TWB).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdou K, Shehata M, Choko K, Nishizono H, Matsuo M, Muramatsu S, Inokuchi K (2018) Synapse-specific representation of the identity of overlapping memory engrams. Science (80) 360:1227–1231Google Scholar
  2. Adli M (2018) The CRISPR tool kit for genome editing and beyond. Nat Commun 9:1911PubMedPubMedCentralGoogle Scholar
  3. An B, Kim J, Park K, Lee S, Song S, Choi S (2017) Amount of fear extinction changes its underlying mechanisms. elife 6Google Scholar
  4. Anuar ND (2018) Using TALENs to knockout H2A.Lap1 function in mice. Aust Natl Univ. PhD thesis:1–274Google Scholar
  5. Ashapkin VV, Romanov GA, Tushmalova NA, Vanyushin BF (1982) Selective DNA synthesis in the rate brain induced by. Learning 48:355–362Google Scholar
  6. Attardo A, Fitzgerald JE, Schnitzer MJ (2015) Impermanence of dendritic spines in live adult CA1 hippocampus. Nature 523:592–596PubMedPubMedCentralGoogle Scholar
  7. Auber A, Tedesco V, Jones CE, Monfils MH, Chiamulera C (2013) Post-retrieval extinction as reconsolidation interference: methodological issues or boundary conditions? Psychopharmacology 226:631–647PubMedPubMedCentralGoogle Scholar
  8. Bahari-Javan S, Maddalena A, Kerimoglu C, Wittnam J, Held T, Bahr M, Burkhardt S, Delalle I, Kugler S, Fischer A, Sananbenesi F (2012) HDAC1 regulates fear extinction in mice. J Neurosci 32:5062–5073PubMedGoogle Scholar
  9. Baker-Andresen D, Ratnu VS, Bredy TW (2013) Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation. Trends Neurosci 36:3–13PubMedGoogle Scholar
  10. Baum M (1988) Spontaneous recovery from the effects of flooding (exposure) in animals. Behav Res Ther 26:185–186PubMedGoogle Scholar
  11. Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356PubMedPubMedCentralGoogle Scholar
  12. Bouton ME, Bolles RC (1979a) Contextual control of the extinction of conditioned fear. Learn Motiv 10:445–466Google Scholar
  13. Bouton ME, Bolles RC (1979b) Role of conditioned contextual stimuli in reinstatement of extinguished fear. J Exp Psychol Anim Behav Process 5:368–378PubMedGoogle Scholar
  14. Bredy TW, Barad M (2008) The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learn Mem 15:39–45PubMedPubMedCentralGoogle Scholar
  15. Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14:268–276PubMedPubMedCentralGoogle Scholar
  16. Cain CK, Blouin AM, Barad M (2003) Temporally massed CS presentations generate more fear extinction than spaced presentations. J Exp Psychol Anim Behav Process. 29:323–333PubMedGoogle Scholar
  17. Chen S, Cai D, Pearce K, Sun PY, Roberts AC, Glanzman DL. 2014. Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in Aplysia. :1–21Google Scholar
  18. Clem RL, Huganir RL (2010) Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science (80). 330:1108–1112PubMedCentralGoogle Scholar
  19. Clem RL, Schiller D (2016) New learning and unlearning: strangers or accomplices in threat memory attenuation? Trends Neurosci 39:340–351PubMedPubMedCentralGoogle Scholar
  20. Damez-Werno DM, Sun H, Scobie KN, Shao N, Rabkin J, Dias C, Calipari ES, Maze I, Pena CJ, Walker DM, Cahill ME, Chandra R, Gancarz A, Mouzon E, Landry JA, Cates H, Lobo MK, Dietz D, Allis CD, Guccione E, Turecki G, Defilippi P, Neve RL, Hurd YL, Shen L, Nestler EJ (2016) Histone arginine methylation in cocaine action in the nucleus accumbens. Proc Natl Acad Sci 113:9623–9628PubMedGoogle Scholar
  21. Day JJ, Sweatt JD (2010) DNA methylation and memory formation. Nat Neurosci 13:1319–1323PubMedPubMedCentralGoogle Scholar
  22. Day JJ, Sweatt JD (2011) Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory. Neurobiol Learn Mem 96:2–12PubMedGoogle Scholar
  23. Dietz DM, LaPlant Q, Watts EL, Hodes GE, Russo SJ, Feng J, Oosting RS, Vialou V, Nestler EJ (2011) Paternal transmission of stressed-induced pathologies. Biol Psychiatry 70:408–414PubMedPubMedCentralGoogle Scholar
  24. Draizen EJ, Shaytan AK, Mariño-Ramírez L, Talbert PB, Landsman D, Panchenko AR (2016) HistoneDB 2.0: a histone database with variants—an integrated resource to explore histones and their variants. Database:2016Google Scholar
  25. Dudai Y, Eisenberg M (2004) Rites of passage of the engram: reconsolidation and the lingering consolidation hypothesis. Neuron 44:93–100PubMedGoogle Scholar
  26. Eisenberg M, Kobilo T, Berman DE, Dudai Y (2003) Stability of retrieved memory: inverse correlation with trace dominance. Science (80). 301:1102–1104Google Scholar
  27. Felsenfeld G, Davies DR, Rich A (1957) Formation of a three-stranded polynucleotide molecule. J Am Chem Soc 79:2023–2024Google Scholar
  28. Fischer A (2014) Epigenetic memory: the Lamarckian brain. EMBO J 33:945–967PubMedPubMedCentralGoogle Scholar
  29. Flavell CR, Lambert EA, Winters BD, Bredy TW (2013) Mechanisms governing the reactivation-dependent destabilization of memories and their role in extinction. Front Behav Neurosci 7:214PubMedPubMedCentralGoogle Scholar
  30. Franklin TB, Russig H, Weiss IC, Grff J, Linder N, Michalon A, Vizi S, Mansuy IM (2010) Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68:408–415PubMedGoogle Scholar
  31. Gao H (2016) Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm Sin B 6:268–286PubMedPubMedCentralGoogle Scholar
  32. Gräff J, Tsai LH (2013) Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14:97–111PubMedGoogle Scholar
  33. Gräff J, Joseph NF, Horn ME, Samiei A, Meng J, Seo J, Rei D, Bero AW, Phan TX, Wagner F, Holson E, Xu J, Sun J, Neve RL, Mach RH, Haggarty SJ, Tsai LH (2014) Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 156:261–276PubMedPubMedCentralGoogle Scholar
  34. Gupta-Agarwal S, Franklin AV, DeRamus T, Wheelock M, Davis RL, McMahon LL, Lubin FD (2012) G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 32:5440–5453PubMedPubMedCentralGoogle Scholar
  35. Gupta-Agarwal S, Jarome TJ, Fernandez J, Lubin FD (2014) NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation. Learn Mem 21:351–362PubMedPubMedCentralGoogle Scholar
  36. Hake SB, Allis CD (2006) Histone H3 variants and their potential role in indexing mammalian genomes: the “H3 barcode hypothesis”. Proc Natl Acad Sci 103:6428–6435PubMedGoogle Scholar
  37. Hayashi-Takagi A, Yagishita S, Nakamura M, Shirai F, Wu YI, Loshbaugh AL, Kuhlman B, Hahn KM, Kasai H (2015) Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature 525:333–338PubMedPubMedCentralGoogle Scholar
  38. Hemstedt TJ, Lattal KM, Wood MA (2017) Reconsolidation and extinction: using epigenetic signatures to challenge conventional wisdom. Neurobiol Learn Mem 142:55–65PubMedPubMedCentralGoogle Scholar
  39. Herry C, Ciocchi S, Senn V, Demmou L, Müller C, Lüthi A (2008) Switching on and off fear by distinct neuronal circuits. Nature 454:600–606Google Scholar
  40. Herry C, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich I, Lüthi A (2010) Neuronal circuits of fear extinction. Eur J Neurosci 31:599–612PubMedGoogle Scholar
  41. Hong J, Kim D (2017) Freezing response-independent facilitation of fear extinction memory in the prefrontal cortex. Sci Rep 7Google Scholar
  42. Ito M (1989) Long-term depression. Annu Rev Neurosci 12:85–102PubMedGoogle Scholar
  43. Itzhak Y, Anderson KL, Kelley JB, Petkov M (2012) Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice. Neurobiol Learn Mem 97:409–417PubMedPubMedCentralGoogle Scholar
  44. Jarome TJ, Perez GA, Hauser RM, Hatch KM, Lubin FD (2018) EZH2 methyltransferase activity controls Pten expression and mTOR signaling during fear memory reconsolidation. J Neurosci:0538–0518Google Scholar
  45. Jimenez JC, Su K, Goldberg AR, Luna VM, Biane JS, Ordek G, Zhou P, Ong SK, Wright MA, Zweifel L, Paninski L, Hen R, Kheirbek MA (2018) Anxiety cells in a hippocampal-hypothalamic circuit. Neuron 97:670–683.e6PubMedPubMedCentralGoogle Scholar
  46. Kida S, Josselyn SA, De Ortiz SP, Kogan JH, Chevere I, Masushige S, Silva AJ (2002) CREB required for the stability of new and reactivated fear memories. Nat Neurosci 5:348–355PubMedGoogle Scholar
  47. Kim J, Kwon J-T, Kim H-S, Han J-H (2013) CREB and neuronal selection for memory trace. Front Neural Circuits 7Google Scholar
  48. Lai CSW, Adler A, Gan W-B (2018) Fear extinction reverses dendritic spine formation induced by fear conditioning in the mouse auditory cortex. Proc Natl Acad Sci:201801504Google Scholar
  49. Lashley K (1950) In search of the engram. Exp Biol Symp No 4 Physiol Mech Anim Behav:454–482Google Scholar
  50. Lechner HA, Squire LR (1999) 100 years of consolidation—remembering Müller and Pilzecker. Learn Mem (Cold Spring Harb NY)Google Scholar
  51. Lee JLC, Everitt BJ, Thomas KL (2004) Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science (80- ) 304:839–843Google Scholar
  52. Li X, Wei W, Ratnu VS, Bredy TW (2013) On the potential role of active DNA demethylation in establishing epigenetic states associated with neural plasticity and memory. Neurobiol Learn Mem 105:125–132PubMedGoogle Scholar
  53. Li X, Wei W, Zhao Q-Y, Widagdo J, Baker-Andresen D, Flavell CR, D’Alessio A, Zhang Y, Bredy TW (2014) Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci 111:7120–7125PubMedGoogle Scholar
  54. Li X, Wei W, Lin Q, Magnan C, Emami M, Wearick-Silva LE, Viola T, Marshall P, Grassi-Oliveira R, Nainar S et al (2016) The formation of extinction memory requires the accumulation of N6-methyl-2-deoxyadenosine in DNA. BioRxivGoogle Scholar
  55. Li X, Marshall PR, Leighton LJ, Zajaczkowski EL (2018) The DNA repair associated protein Gadd45g regulates the temporal coding of immediate early gene expression and is required for the consolidation of associative fear memory. BioRxivGoogle Scholar
  56. Lin Q, Wei W, Coelho CM, Li X, Baker-Andresen D, Dudley K, Ratnu VS, Boskovic Z, Kobor MS, Sun YE, Bredy TW (2011) The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory. Nat Neurosci 14:1115–1117PubMedGoogle Scholar
  57. Liu C, Sun X, Wang Z, Le Q, Liu P, Jiang C, Wang F, Ma L (2017) Retrieval-induced upregulation of Tet3 in pyramidal neurons of the dorsal Hippocampus mediates cocaine-associated memory reconsolidation. Int J NeuropsychopharmacolGoogle Scholar
  58. Machnicka MA, Milanowska K, Osman Oglou O, Purta E, Kurkowska M, Olchowik A, Januszewski W, Kalinowski S, Dunin-Horkawicz S, Rother KM, Helm M, Bujnicki JM, Grosjean H (2013) MODOMICS: a database of RNA modification pathways—2013 update. Nucleic Acids Res 41:D262–D267PubMedGoogle Scholar
  59. Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao P-C, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH (2015) Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161:1592–1605PubMedPubMedCentralGoogle Scholar
  60. Malvaez M, McQuown SC, Rogge GA, Astarabadi M, Jacques V, Carreiro S, Rusche JR, Wood MA (2013) HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci 110:2647–2652PubMedGoogle Scholar
  61. Marek R, Jin J, Goode TD, Giustino TF, Wang Q, Acca GM, 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 21:384–392PubMedPubMedCentralGoogle Scholar
  62. Marshall P, Bredy TW (2016) Cognitive neuroepigenetics: the next evolution in our understanding of the molecular mechanisms underlying learning and memory? NPJ Sci Learn 1:16014PubMedPubMedCentralGoogle Scholar
  63. Mattick JS, Mehler MF (2008) RNA editing, DNA recoding and the evolution of human cognition. Trends Neurosci 31:227–233PubMedGoogle Scholar
  64. Maze I, Wenderski W, Noh KM, Bagot RC, Tzavaras N, Purushothaman I, Elsässer SJ, Guo Y, Ionete C, Hurd YL, Tamminga CA, Halene T, Farrelly L, Soshnev AA, Wen D, Rafii S, Birtwistle MR, Akbarian S, Buchholz BA, Blitzer RD, Nestler EJ, Yuan ZF, Garcia BA, Shen L, Molina H, Allis CD (2015) Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87:77–94PubMedPubMedCentralGoogle Scholar
  65. McGaugh JL (2000) Memory—a century of consolidation. Science 287:248–251PubMedPubMedCentralGoogle Scholar
  66. Milad MRR, Quirk GJJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74Google Scholar
  67. Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869PubMedGoogle Scholar
  68. Misanin JR, Miller RR, Lewis DJ (1968) Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science (80- ) 160:554–555Google Scholar
  69. Mladenova D, Barry G, Konen LM, Pineda SS, Guennewig B, Avesson L, Zinn R, Schonrock N, Bitar M, Jonkhout N, Crumlish L, Kaczorowski DC, Gong A, Pinese M, Franco GR, Walkley CR, Vissel B, Mattick JS (2018) Adar3 is involved in learning and memory in mice. Front Neurosci 12Google Scholar
  70. Morris MJ, Mahgoub M, Na ES, Pranav H, Monteggia LM (2013) Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. J Neurosci 33:6401–6411PubMedPubMedCentralGoogle Scholar
  71. Müller GE, Pilzecker A (1900) Experimentelle Beiträge zur Lehre vom Gedächtnis. Z Psychol Ergänzungsband 1:1–300Google Scholar
  72. Murphy CP, Li X, Maurer V, Oberhauser M, Gstir R, Wearick-Silva LE, Viola TW, Schafferer S, Grassi-Oliveira R, Whittle N, Hüttenhofer A, Bredy TW, Singewald N (2017) MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice. Biol Psychiatry 81:979–989PubMedGoogle Scholar
  73. Myers KM (2006) Different mechanisms of fear extinction dependent on length of time since fear acquisition. Learn Mem 13:216–223PubMedPubMedCentralGoogle Scholar
  74. Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, Malinow R (2014) Engineering a memory with LTD and LTP. Nature 511:348–352PubMedPubMedCentralGoogle Scholar
  75. Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726PubMedGoogle Scholar
  76. Nainar S, Marshall PR, Tyler CR, Spitale RC, Bredy TW (2016) Evolving insights into RNA modifications and their functional diversity in the brain. Nat Neurosci 19:1292–1298PubMedPubMedCentralGoogle Scholar
  77. Naylor LH, Clark EM (1990) D(TG)n·d(CA)nsequences upstream of the rat prolactin gene form z-DNA and inhibit gene transcription. Nucleic Acids Res 18:1595–1601PubMedPubMedCentralGoogle Scholar
  78. Pavlov IP (1927) Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford Univ Press, p xv-430Google Scholar
  79. Pohl FM (1987) Hysteretic behaviour of a Z-DNA-antibody complex. Biophys Chem 26:385–390PubMedGoogle Scholar
  80. Poo M m, Pignatelli M, Ryan TJ, Tonegawa S, Bonhoeffer T, Martin KC, Rudenko A, Tsai LH, Tsien RW, Fishell G et al (2016) What is memory? The present state of the engram. BMC Biol 14:1–18Google Scholar
  81. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72PubMedGoogle Scholar
  82. Ratnu VS, Wei W, Bredy TW (2014) Activation-induced cytidine deaminase regulates activity-dependent BDNF expression in post-mitotic cortical neurons. Eur J Neurosci 40(7):3032–3039PubMedGoogle Scholar
  83. Rescorla RA, Heth CD (1975) Reinstatement of fear to an extinguished conditioned stimulus. J Exp Psychol Anim Behav Process 104:88–96Google Scholar
  84. Rice JC, Allis CD (2001) Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr Opin Cell Biol 13:263–273PubMedGoogle Scholar
  85. Rodgers AB, Morgan CP, Leu NA, Bale TL (2015) Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci 112:13699–13704PubMedGoogle Scholar
  86. Rountree MR, Selker EU (1997) DNA methylation inhibits elongation but not initiation of transcription in Neurospora crassa. Genes Dev 11:2383–2395PubMedPubMedCentralGoogle Scholar
  87. Rudenko A, Dawlaty M, Seo J, Cheng A, Meng J, Le T, Faull K, Jaenisch R, Tsai LH (2013) Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79:1109–1122PubMedPubMedCentralGoogle Scholar
  88. Russ AP, Friedel C, Grez M, von Melchner H (1996) Self-deleting retrovirus vectors for gene therapy. J Virol 70:4927–4932PubMedPubMedCentralGoogle Scholar
  89. Santoro SW, Dulac C (2012) The activity-dependent histone variant H2BE modulates the life span of olfactory neurons. elife 2012Google Scholar
  90. Saucier D, Cain DP (1995) Spatial learning without NMDA receptor-dependent long-term potentiation. Nature 378:186–189PubMedPubMedCentralGoogle Scholar
  91. Schmitt M, Matthies H (1979) Biochemical studies on histones of the central nervous system. III. Incorporation of [14C]-acetate into the histones of different rat brain regions during a learning experiment. Acta Biol Med Ger 38:683–689PubMedGoogle Scholar
  92. Siddiqui-Jain A, Grand CL, Bearss DJ, Hurley LH (2002) Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci 99:11593–11598PubMedGoogle Scholar
  93. Silva AJ, Kogan JH, Frankland PW, Kida S (1998) Creb and memory. Annu Rev Neurosci 21:127–148Google Scholar
  94. Stafford JM, Lattal KM (2011) Is an epigenetic switch the key to persistent extinction? Neurobiol Learn Mem 96:35–40PubMedPubMedCentralGoogle Scholar
  95. Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM (2012) Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 72:25–33PubMedPubMedCentralGoogle Scholar
  96. Stefanelli G, Azam AB, Walters BJ, Brimble MA, Gettens CP, Bouchard-Cannon P, Cheng HYM, Davidoff AM, Narkaj K, Day JJ, Kennedy AJ, Zovkic IB (2018) Learning and age-related changes in genome-wide H2A.Z binding in the mouse Hippocampus. Cell Rep 22:1124–1131PubMedPubMedCentralGoogle Scholar
  97. Subramanian V, Fields PA, Boyer LA (2015) H2A.Z: a molecular rheostat for transcriptional control. F1000Prime Rep 7Google Scholar
  98. Swank MW, Sweatt JD (2001) Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning. J Neurosci 21:3383–3391PubMedGoogle Scholar
  99. Tovote P, Fadok JP, Lüthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331PubMedGoogle Scholar
  100. Vanyushin BF, Ashapkin V V (2017) History and Modern View on DNA Modifications in the Brain. In: DNA Modif Brain. [place unknown]; p. 1–25Google Scholar
  101. Walters BJ, Mercaldo V, Gillon CJ, Yip M, Neve RL, Boyce FM, Frankland PW, Josselyn SA (2017) The role of the RNA demethylase FTO (fat mass and obesity-associated) and mRNA methylation in hippocampal memory formation. Neuropsychopharmacology 42:1502–1510PubMedPubMedCentralGoogle Scholar
  102. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C (2015) N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161:1388–1399PubMedPubMedCentralGoogle Scholar
  103. Watson JD, Crick FHC (1953) Molecular structure of nucleic acids. Nature 171:737–738PubMedGoogle Scholar
  104. Webb WM, Sanchez RG, Perez G, Butler AA, Hauser RM, Rich MC, O’Bierne AL, Jarome TJ, Lubin FD (2017) Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory. Neurobiol Learn Mem 142:66–78PubMedGoogle Scholar
  105. Wei W, Coelho CM, Li X, Marek R, Yan S, Anderson S, Meyers D, Mukherjee C, Sbardella G, Castellano S, Milite C, Rotili D, Mai A, Cole PA, Sah P, Kobor MS, Bredy TW (2012) p300/CBP-associated factor selectively regulates the extinction of conditioned fear. J Neurosci 32:11930–11941PubMedPubMedCentralGoogle Scholar
  106. Whittle N, Singewald N (2014) HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochem Soc Trans 42:569–581PubMedPubMedCentralGoogle Scholar
  107. Widagdo XJ, Zhao XQ, Kempen XM, Tan XMC, Ratnu VS, Wei W, Leighton L, Spadaro PA, Edson J, Anggono XV, Bredy XTW (2016) Experience-dependent accumulation of N 6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. J Neurosci 36:6771–6777PubMedPubMedCentralGoogle Scholar
  108. Wright A, Vissel B (2012) The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain. Front Mol Neurosci 5Google Scholar
  109. Yu J, Chen M, Huang H, Zhu J, Song H, Zhu J, Park J, Ji SJ (2018) Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res 46:1412–1423PubMedGoogle Scholar
  110. Zhao W-N, Malinin N, Yang F-C, Staknis D, Gekakis N, Maier B, Reischl S, Kramer A, Weitz CJ, Sun M et al (2014) Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation. PLoS One 9:690–699Google Scholar
  111. Zovkic IB, Paulukaitis BS, Day JJ, Etikala DM, Sweatt JD (2014) Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515:582–586PubMedPubMedCentralGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cognitive Neuroepigenetics Laboratory, Queensland Brain InstituteThe University of QueenslandBrisbaneAustralia

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