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Durable fear memories require PSD-95

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A Corrigendum to this article was published on 31 March 2015

Abstract

Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95GK), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95GK mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories.

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References

  1. Gale GD, Anagnostaras SG, Godsil BP, Mitchell S, Nozawa T, Sage JR et al. Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of rats. J Neurosci 2004; 24: 3810–3815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Parsons RG, Ressler KJ . Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 2013; 16: 146–153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Griebel G, Holmes A . 50 Years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 2013; 12: 667–687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Auber A, Tedesco V, Jones CE, Monfils MH, Chiamulera C . Post-retrieval extinction as reconsolidation interference: methodological issues or boundary conditions? Psychopharmacology (Berl) 2013; 226: 631–647.

    Article  CAS  Google Scholar 

  5. Besnard A, Caboche J, Laroche S . Reconsolidation of memory: a decade of debate. Prog Neurobiol 2012; 99: 61–80.

    Article  PubMed  Google Scholar 

  6. Tronson NC, Taylor JR . Molecular mechanisms of memory reconsolidation. Nat Rev Neurosci 2007; 8: 262–275.

    Article  CAS  PubMed  Google Scholar 

  7. Johansen JP, Cain CK, Ostroff LE, LeDoux JE . Molecular mechanisms of fear learning and memory. Cell 2011; 147: 509–524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dudai Y . The restless engram: consolidations never end. Annu Rev Neurosci 2012; 35: 227–247.

    Article  CAS  PubMed  Google Scholar 

  9. Graff J, Joseph NF, Horn ME, Samiei A, Meng J, Seo J et al. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 2014; 156: 261–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fernandez E, Collins MO, Uren RT, Kopanitsa MV, Komiyama NH, Croning MD et al. Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins. Mol Syst Biol 2009; 5: 269.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kim E, Sheng M . PDZ domain proteins of synapses. Nat Rev Neurosci 2004; 5: 771–781.

    Article  CAS  PubMed  Google Scholar 

  12. Nelson CD, Kim MJ, Hsin H, Chen Y, Sheng M . Phosphorylation of threonine-19 of PSD-95 by GSK-3beta is required for PSD-95 mobilization and long-term depression. J Neurosci 2013; 33: 12122–12135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen X, Nelson CD, Li X, Winters CA, Azzam R, Sousa AA et al. PSD-95 is required to sustain the molecular organization of the postsynaptic density. J Neurosci 2011; 31: 6329–6338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS . PSD-95 involvement in maturation of excitatory synapses. Science 2000; 290: 1364–1368.

    CAS  PubMed  Google Scholar 

  15. Elias GM, Funke L, Stein V, Grant SG, Bredt DS, Nicoll RA . Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 2006; 52: 307–320.

    Article  CAS  PubMed  Google Scholar 

  16. Xu W, Schluter OM, Steiner P, Czervionke BL, Sabatini B, Malenka RC . Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD. Neuron 2008; 57: 248–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Opazo P, Sainlos M, Choquet D . Regulation of AMPA receptor surface diffusion by PSD-95 slots. Curr Opin Neurobiol 2011; 22: 453–460.

    Article  PubMed  CAS  Google Scholar 

  18. Beique JC, Andrade R . PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J Physiol 2003; 546: 859–867.

    Article  CAS  PubMed  Google Scholar 

  19. Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 2003; 40: 595–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sturgill JF, Steiner P, Czervionke BL, Sabatini BL . Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking. J Neurosci 2009; 29: 12845–12854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhattacharyya S, Biou V, Xu W, Schluter O, Malenka RC . A critical role for PSD-95/AKAP interactions in endocytosis of synaptic AMPA receptors. Nat Neurosci 2009; 12: 172–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Woods GF, Oh WC, Boudewyn LC, Mikula SK, Zito K . Loss of PSD-95 enrichment is not a prerequisite for spine retraction. J Neurosci 2011; 31: 12129–12138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mao SC, Chang CH, Wu CC, Orejanera MJ, Manzoni OJ, Gean PW . Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training. PLoS One 2013; 8: e59580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mao SC, Lin HC, Gean PW . Augmentation of fear extinction by D-cycloserine is blocked by proteasome inhibitors. Neuropsychopharmacology 2008; 33: 3085–3095.

    Article  CAS  PubMed  Google Scholar 

  25. Tsai NP, Wilkerson JR, Guo W, Maksimova MA, DeMartino GN, Cowan CW et al. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 2012; 151: 1581–1594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rashid AJ, Cole CJ, Josselyn SA . Emerging roles for MEF2 transcription factors in memory. Genes Brain Behav 2014; 13: 118–125.

    Article  CAS  PubMed  Google Scholar 

  27. Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998; 396: 433–439.

    Article  CAS  PubMed  Google Scholar 

  28. Elkobi A, Ehrlich I, Belelovsky K, Barki-Harrington L, Rosenblum K . ERK-dependent PSD-95 induction in the gustatory cortex is necessary for taste learning, but not retrieval. Nat Neurosci 2008; 11: 1149–1151.

    Article  CAS  PubMed  Google Scholar 

  29. Nithianantharajah J, Komiyama NH, McKechanie A, Johnstone M, Blackwood DH, Clair DS et al. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat Neurosci 2013; 16: 16–24.

    Article  CAS  PubMed  Google Scholar 

  30. Irvine EE, Drinkwater L, Radwanska K, Al-Qassab H, Smith MA, O'Brien M et al. Insulin receptor substrate 2 is a negative regulator of memory formation. Learn Mem 2012; 18: 375–383.

    Article  CAS  Google Scholar 

  31. Li C, Brake WG, Romeo RD, Dunlop JC, Gordon M, Buzescu R et al. Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice. Proc Natl Acad Sci U S A 2004; 101: 2185–2190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu F, Day M, Muniz LC, Bitran D, Arias R, Revilla-Sanchez R et al. Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci 2008; 11: 334–343.

    Article  CAS  PubMed  Google Scholar 

  33. Camp MC, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson RM et al. A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol 2011; 16: 428–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nagura H, Ishikawa Y, Kobayashi K, Takao K, Tanaka T, Nishikawa K et al. Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding-deficient PSD-95 knockin mice. Mol Brain 2012; 5: 43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM et al. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 2004; 41: 625–638.

    Article  CAS  PubMed  Google Scholar 

  36. Feyder M, Karlsson RM, Mathur P, Lyman M, Bock R, Momenan R et al. Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. Am J Psychiatry 2010; 167: 1508–1517.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Crusio WE, Goldowitz D, Holmes A, Wolfer D . Standards for the publication of mouse mutant studies. Genes Brain Behav 2009; 8: 1–4.

    Article  CAS  PubMed  Google Scholar 

  38. Yang RJ, Mozhui K, Karlsson RM, Cameron HA, Williams RW, Holmes A . Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning. Neuropsychopharmacology 2008; 33: 2595–2604.

    Article  CAS  PubMed  Google Scholar 

  39. Misane I, Tovote P, Meyer M, Spiess J, Ogren SO, Stiedl O . Time-dependent involvement of the dorsal hippocampus in trace fear conditioning in mice. Hippocampus 2005; 15: 418–426.

    Article  CAS  PubMed  Google Scholar 

  40. Feyder M, Wiedholz L, Sprengel R, Holmes A . Impaired associative fear learning in mice with complete loss or haploinsufficiency of AMPA GluR1 receptors. Front Behav Neurosci 2007; 1: 4.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kinney JW, Starosta G, Holmes A, Wrenn CC, Yang RJ, Harris AP et al. Deficits in trace cued fear conditioning in galanin-treated rats and galanin-overexpressing transgenic mice. Learn Mem 2002; 9: 178–190.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bouton ME . Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol Psychiatry 2002; 52: 976–986.

    Article  PubMed  Google Scholar 

  43. Camp MC, Macpherson KP, Lederle L, Graybeal C, Gaburro S, Debrouse LM et al. Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes. Neuropsychopharmacology 2012; 37: 1534–1547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Frankland PW, O'Brien C, Ohno M, Kirkwood A, Silva AJ . Alpha-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 2001; 411: 309–313.

    Article  CAS  PubMed  Google Scholar 

  45. Kim JJ, Fanselow MS . Modality-specific retrograde amnesia of fear. Science 1992; 256: 675–677.

    Article  CAS  PubMed  Google Scholar 

  46. Whittle N, Hauschild M, Lubec G, Holmes A, Singewald N . Rescue of impaired fear extinction and normalization of cortico-amygdala circuit dysfunction in a genetic mouse model by dietary zinc restriction. J Neurosci 2010; 30: 13586–13596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hefner K, Whittle N, Juhasz J, Norcross M, Karlsson RM, Saksida LM et al. Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain. J Neurosci 2008; 28: 8074–8085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Holmes A, Fitzgerald PJ, Macpherson KP, Debrouse L, Colacicco G, Flynn SM et al. Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat Neurosci 2012; 15: 1359–1361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brigman JL, Daut RA, Wright T, Gunduz-Cinar O, Graybeal C, Davis MI et al. GluN2B in corticostriatal circuits governs choice learning and choice shifting. Nat Neurosci 2013; 16: 1101–1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DePoy L, Daut R, Brigman JL, Macpherson K, Crowley N, Gunduz-Cinar O et al. Chronic alcohol produces neuroadaptations to prime dorsal striatal learning. Proc Natl Acad Sci USA 2013; 110: 14783–14788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fitzgerald PJ, Whittle N, Flynn SM, Graybeal C, Pinard CR, Gunduz-Cinar O et al. Prefrontal single-unit firing associated with deficient extinction in mice. Neurobiol Learn Mem 2013; 113: 69–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Burgos-Robles A, Vidal-Gonzalez I, Santini E, Quirk GJ . Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 2007; 53: 871–880.

    Article  CAS  PubMed  Google Scholar 

  53. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K . Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 2005; 8: 1263–1268.

    Article  CAS  PubMed  Google Scholar 

  54. McClure C, Cole KL, Wulff P, Klugmann M, Murray AJ . Production and titering of recombinant adeno-associated viral vectors. J Vis Exp 2011; 57: e3348.

    Google Scholar 

  55. During MJ, Young D, Baer K, Lawlor P, Klugmann M . Development and optimization of adeno-associated virus vector transfer into the central nervous system. Methods Mol Med 2003; 76: 221–236.

    CAS  PubMed  Google Scholar 

  56. Choi VW, Asokan A, Haberman RA, Samulski RJ . Production of recombinant adeno-associated viral vectors. Curr Protoc Hum Genet 2007; 53: 1–21.

    Google Scholar 

  57. Schluter OM, Xu W, Malenka RC . Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron 2006; 51: 99–111.

    Article  CAS  PubMed  Google Scholar 

  58. Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL . Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS ONE 2008; 3: e1997.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Horner CH, Arbuthnott E . Methods of estimation of spine density—are spines evenly distributed throughout the dendritic field? J Anat 1991; 177: 179–184.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Raybuck JD, Lattal KM . Bridging the interval: theory and neurobiology of trace conditioning. Behav Processes 2013; 101: 103–111.

    Article  PubMed  Google Scholar 

  61. Frankland PW, Ding HK, Takahashi E, Suzuki A, Kida S, Silva AJ . Stability of recent and remote contextual fear memory. Learn Mem 2006; 13: 451–457.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Milekic MH, Alberini CM . Temporally graded requirement for protein synthesis following memory reactivation. Neuron 2002; 36: 521–525.

    Article  CAS  PubMed  Google Scholar 

  63. Sacco T, Sacchetti B . Role of secondary sensory cortices in emotional memory storage and retrieval in rats. Science 2010; 329: 649–656.

    Article  CAS  PubMed  Google Scholar 

  64. Frankland PW, Bontempi B . The organization of recent and remote memories. Nat Rev Neurosci 2005; 6: 119–130.

    Article  CAS  PubMed  Google Scholar 

  65. Takehara K, Kawahara S, Kirino Y . Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J Neurosci 2003; 23: 9897–9905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Maviel T, Durkin TP, Menzaghi F, Bontempi B . Sites of neocortical reorganization critical for remote spatial memory. Science 2004; 305: 96–99.

    Article  CAS  PubMed  Google Scholar 

  67. Teixeira CM, Pomedli SR, Maei HR, Kee N, Frankland PW . Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J Neurosci 2006; 26: 7555–7564.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ding HK, Teixeira CM, Frankland PW . Inactivation of the anterior cingulate cortex blocks expression of remote, but not recent, conditioned taste aversion memory. Learn Mem 2008; 15: 290–293.

    Article  PubMed  Google Scholar 

  69. Goshen I, Brodsky M, Prakash R, Wallace J, Gradinaru V, Ramakrishnan C et al. Dynamics of retrieval strategies for remote memories. Cell 2011; 147: 678–689.

    Article  CAS  PubMed  Google Scholar 

  70. Bontempi B, Laurent-Demir C, Destrade C, Jaffard R . Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 1999; 400: 671–675.

    Article  CAS  PubMed  Google Scholar 

  71. Takashima A, Petersson KM, Rutters F, Tendolkar I, Jensen O, Zwarts MJ et al. Declarative memory consolidation in humans: a prospective functional magnetic resonance imaging study. Proc Natl Acad Sci USA 2006; 103: 756–761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Holahan MR, Routtenberg A . Post-translational synaptic protein modification as substrate for long-lasting, remote memory: an initial test. Hippocampus 2007; 17: 93–97.

    Article  CAS  PubMed  Google Scholar 

  73. Quinn JJ, Ma QD, Tinsley MR, Koch C, Fanselow MS . Inverse temporal contributions of the dorsal hippocampus and medial prefrontal cortex to the expression of long-term fear memories. Learn Mem 2008; 15: 368–372.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Koya E, Uejima JL, Wihbey KA, Bossert JM, Hope BT, Shaham Y . Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology 2009; 56: 177–185.

    Article  CAS  PubMed  Google Scholar 

  75. Takehara-Nishiuchi K, McNaughton BL . Spontaneous changes of neocortical code for associative memory during consolidation. Science 2008; 322: 960–963.

    Article  CAS  PubMed  Google Scholar 

  76. Kim JJ, Clark RE, Thompson RF . Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses. Behav Neurosci 1995; 109: 195–203.

    Article  CAS  PubMed  Google Scholar 

  77. Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ . The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 2004; 304: 881–883.

    Article  CAS  PubMed  Google Scholar 

  78. Euston DR, Gruber AJ, McNaughton BL . The role of medial prefrontal cortex in memory and decision making. Neuron 2012; 76: 1057–1070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Knapska E, Macias M, Mikosz M, Nowak A, Owczarek D, Wawrzyniak M et al. Functional anatomy of neural circuits regulating fear and extinction. Proc Natl Acad Sci USA 2012; 109: 17093–17098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Harvey CD, Svoboda K . Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 2007; 450: 1195–1200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Steiner P, Higley MJ, Xu W, Czervionke BL, Malenka RC, Sabatini BL . Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. Neuron 2008; 60: 788–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Prange O, Murphy TH . Modular transport of postsynaptic density-95 clusters and association with stable spine precursors during early development of cortical neurons. J Neurosci 2001; 21: 9325–9333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Meyer D, Bonhoeffer T, Scheuss V . Balance and stability of synaptic structures during synaptic plasticity. Neuron 2014; 82: 430–443.

    Article  CAS  PubMed  Google Scholar 

  84. Vetere G, Restivo L, Cole CJ, Ross PJ, Ammassari-Teule M, Josselyn SA et al. Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory. Proc Natl Acad Sci USA 2011; 108: 8456–8460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Restivo L, Vetere G, Bontempi B, Ammassari-Teule M . The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex. J Neurosci 2009; 29: 8206–8214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Milad MR, Quirk GJ . Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 2002; 420: 70–74.

    CAS  PubMed  Google Scholar 

  87. Wilber AA, Walker AG, Southwood CJ, Farrell MR, Lin GL, Rebec GV et al. Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction. Neuroscience 2011; 174: 115–131.

    Article  CAS  PubMed  Google Scholar 

  88. Sederberg PB, Kahana MJ, Howard MW, Donner EJ, Madsen JR . Theta and gamma oscillations during encoding predict subsequent recall. J Neurosci 2003; 23: 10809–10814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Headley DB, Weinberger NM . Fear conditioning enhances gamma oscillations and their entrainment of neurons representing the conditioned stimulus. J Neurosci 2013; 33: 5705–5717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Courtin J, Karalis N, Gonzalez-Campo C, Wurtz H, Herry C . Persistence of amygdala gamma oscillations during extinction learning predicts spontaneous fear recovery. Neurobiol Learn Mem 2013; 113: 82–89.

    Article  PubMed  Google Scholar 

  91. Lesting J, Narayanan RT, Kluge C, Sangha S, Seidenbecher T, Pape HC . Patterns of coupled theta activity in amygdala-hippocampal-prefrontal cortical circuits during fear extinction. PLoS One 2011; 6: e21714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 2014; 505: 92–96.

    Article  CAS  PubMed  Google Scholar 

  93. Lesburgueres E, Gobbo OL, Alaux-Cantin S, Hambucken A, Trifilieff P, Bontempi B . Early tagging of cortical networks is required for the formation of enduring associative memory. Science 2011; 331: 924–928.

    Article  CAS  PubMed  Google Scholar 

  94. Zelikowsky M, Bissiere S, Fanselow MS . Contextual fear memories formed in the absence of the dorsal hippocampus decay across time. J Neurosci 2012; 32: 3393–3397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Poulos AM, Li V, Sterlace SS, Tokushige F, Ponnusamy R, Fanselow MS . Persistence of fear memory across time requires the basolateral amygdala complex. Proc Natl Acad Sci USA 2009; 106: 11737–11741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are very grateful to Katie Kaugars for technical assistance. Research supported by NIAAA Intramural Research Program (AH), the Austrian Science Fund (FWF): P22931-B18 and Sonderforschungsbereich (SFB F4410-B19; NS), NIH MH080310 JPB foundation (WX) and a Simons Seed Grant at MIT (WX).

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Correspondence to A Holmes.

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Fitzgerald, P., Pinard, C., Camp, M. et al. Durable fear memories require PSD-95. Mol Psychiatry 20, 901–912 (2015). https://doi.org/10.1038/mp.2014.161

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