Manipulating Hippocampus-Dependent Memories: To Enhance, Delete or Incept?



Memory manipulation has advanced substantially in recent years to a range of new methods available to researchers. These methods include optogenetics, transcranial stimulation, deep brain stimulation, pharmacological agents and cued reactivation of memories during sleep. Here we review and evaluate findings from these methods in relation to manipulations of hippocampus-dependent memories. In doing so we shed light on the different ways in which memories can be erased, enhanced or implanted.


Deep Brain Stimulation Ventral Tegmental Area Fear Conditioning Memory Consolidation Local Field Potential 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Anderson MC, Ochsner KN, Kuhl B, Cooper J, Robertson E, Gabrieli SW, Glover GH, Gabrieli JDE (2004) Neural systems underlying the suppression of unwanted memories. Science 303(5655):232–235CrossRefPubMedGoogle Scholar
  2. Antony JW, Gobel EW, O’Hare JK, Reber PJ, Paller KA (2012) Cued memory reactivation during sleep influences skill learning. Nat Neurosci 15(8):1114–1116CrossRefPubMedPubMedCentralGoogle Scholar
  3. Arzi A, Shedlesky L, Ben-Shaul M, Nasser K, Oksenberg A, Hairston IS, Sobel N (2012) Humans can learn new information during sleep. Nat Neurosci 15(10):1460–1465CrossRefPubMedGoogle Scholar
  4. Barnes DC, Wilson DA (2014) Slow-wave sleep-imposed replay modulates both strength and precision of memory. J Neurosci 34(15):5134–5142CrossRefPubMedPubMedCentralGoogle Scholar
  5. Baxendale S (2004) Memories aren’t made of this: amnesia at the movies. Br Med J 329(7480):1480CrossRefGoogle Scholar
  6. Bendor D, Wilson MA (2012) Biasing the content of hippocampal replay during sleep. Nat Neurosci 15:1439–1444CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bliss TVP, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407):31–39CrossRefPubMedGoogle Scholar
  8. Brunet A, Ashbaugh AR, Saumier D, Pitman RK, Nelson M, Tremblay J, Roullet P, Birmes P (2011) Does reconsolidation occur in humans: a reply. Front Behav Neurosci 5:74CrossRefPubMedPubMedCentralGoogle Scholar
  9. Buzsaki G (2009) Rhythms of the brain. Oxford University Press, OxfordGoogle Scholar
  10. Buzsáki G, Anastassiou CA, Koch C (2012) The origin of extracellular fields and currents—EEG, ECoG, LFP and spikes. Nat Rev Neurosci 13(6):407–420CrossRefPubMedPubMedCentralGoogle Scholar
  11. De Bitencourt RM, Pamplona FA, Takahashi RN (2013) A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: potential extinction enhancers. Neuropharmacology 64:389–395CrossRefPubMedGoogle Scholar
  12. De Kleine RA, Rothbaum BO, van Minnen A (2013) Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review. Eur J Psychotraumatol:4. doi: 10.3402/ejpt.v4i0.21626
  13. de Lavilléon G, Lacroix MM, Rondi-Reig L, Benchenane K (2015) Explicit memory creation during sleep demonstrates a causal role of place cells in navigation. Nat Neurosci 18(4):493–495CrossRefPubMedGoogle Scholar
  14. Diekelmann S, Born J (2010) The memory function of sleep. Nat Rev Neurosci 11(2):114–126PubMedGoogle Scholar
  15. Diekelmann S, Büchel C, Born J, Rasch B (2011) Labile or stable: opposing consequences for memory when reactivated during waking and sleep. Nat Neurosci 14(3):381–386CrossRefPubMedGoogle Scholar
  16. Dudai Y (2004) The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol 55:51–86CrossRefPubMedGoogle Scholar
  17. Eichenbaum H (2004) Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44:109–120CrossRefPubMedGoogle Scholar
  18. Ego-Stengel V, Wilson MA (2010) Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 20(1):1–10PubMedPubMedCentralGoogle Scholar
  19. File SE, Fluck E, Fernandes C (1999) Beneficial effects of glycine (bioglycin) on memory and attention in young and middle-aged adults. J Clin Psychopharmacol 19:506–512CrossRefPubMedGoogle Scholar
  20. Frankland PW, Bontempi B (2005) The organization of recent and remote memories. Nat Rev Neurosci 6:119–130CrossRefPubMedGoogle Scholar
  21. Frankland PW, Köhler S, Josselyn SA (2013) Hippocampal neurogenesis and forgetting. Trends Cogn Sci 36(9):497–503Google Scholar
  22. Garner AR, Rowland DC, Hwang SY, Baumgaertel K, Roth BL, Kentros C, Mayford M (2012) Generation of a Synthetic Memory Trace. Science 335(6075):1513–1516CrossRefPubMedPubMedCentralGoogle Scholar
  23. Girardeau G, Benchenane K, Wiener SI, Buzsáki G, Zugaro MB (2009) Selective suppression of hippocampal ripples impairs spatial memory. Nat Neurosci 12(10):1222–1223CrossRefPubMedGoogle Scholar
  24. Graham BM, Richardson R (2011) Intraamygdala infusion of fibroblast growth factor 2 enhances extinction and reduces renewal and reinstatement in adult rats. J Neurosci 31(40):14151–14157CrossRefPubMedGoogle Scholar
  25. Groes (2016) Memory in the twenty-first century new critical perspectives from the arts, humanities, and sciences. Palgrave MacMillan, BasingstokeGoogle Scholar
  26. Halassa MM, Siegle JH, Ritt JT, Ting JT, Feng G, Moore CI (2011) Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles. Nat Neurosci 14(9):1118–1120CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM et al (2008) Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 63(1):119–123CrossRefPubMedGoogle Scholar
  28. Hardt O, Nader K, Nader L (2013) Decay happens: the role of active forgetting in memory. Trends Cogn Sci 17(3):111–120CrossRefPubMedGoogle Scholar
  29. Hauner KK, Howard JD, Zelano C, Gottfried JA (2013) Stimulus-specific enhancement of fear extinction during slow-wave sleep. Nat Neurosci 16:1553–1555CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hulbert JC, Henson RN, Anderson MC (2016) Inducing amnesia through systematic suppression. Nat Commun 7:11003CrossRefPubMedPubMedCentralGoogle Scholar
  31. Jacobs J, Miller J, Lee SA, Coffey T, Watrous AJ, Sperling MR et al (2016) Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory. Neuron 92(5):983–990. doi: 10.1016/j.neuron.2016.10.062 CrossRefPubMedGoogle Scholar
  32. Ji D, Wilson MA (2006) Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat Neurosci 10(1):100–107CrossRefPubMedGoogle Scholar
  33. Kaplan GB, Moore KA (2011) The use of cognitive enhancers in animal models of fear extinction. Pharmacol Biochem Behav 99:217–228CrossRefPubMedGoogle Scholar
  34. Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science 256(5057):675–677CrossRefPubMedGoogle Scholar
  35. Kindt M, Soeter M, Vervliet B (2009) Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci 12:256–258CrossRefPubMedGoogle Scholar
  36. Kuriyama K, Honma M, Yoshiike T, Kim Y (2013) Valproic acid but not D-cycloserine facilitates sleep-dependent offline learning of extinction and habituation of conditioned fear in humans. Neuropharmacology 64:424–431CrossRefPubMedGoogle Scholar
  37. Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R et al (2010) A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 68(4):521–534CrossRefPubMedGoogle Scholar
  38. Lee AK, Wilson MA (2002) Memory of sequential experience in the hippocampus during slow wave sleep. Neuron 36(6):1183–1194CrossRefPubMedGoogle Scholar
  39. Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C et al (2013) Prkcz null mice show normal learning and memory. Nature 493(7432):416–419CrossRefPubMedPubMedCentralGoogle Scholar
  40. Liao SM, Sandberg A (2008) The normativity of memory modification. Neuroethics 1(2):85–99CrossRefGoogle Scholar
  41. Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S (2012) Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484(7394):381–385CrossRefPubMedPubMedCentralGoogle Scholar
  42. Loftus EF, Palmer JC (1974) Reconstruction of automobile destruction: an example of the interaction between language and memory. J Verbal Learn Verbal Behav 13(5):585–589CrossRefGoogle Scholar
  43. Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44(1):5–21CrossRefPubMedGoogle Scholar
  44. Maren S (2001) Neurobiology of Pavlovian fear conditioning. Ann Rev Neurosci 24(1):897–931CrossRefPubMedGoogle Scholar
  45. Martin A, Chao LL (2001) Semantic memory and the brain: structure and processes. Curr Opin Neurobiol 11:194–201CrossRefPubMedGoogle Scholar
  46. Marshall L, Helgadóttir H, Mölle M, Born J (2006) Boosting slow oscillations during sleep potentiates memory. Nature 444(7119):610–613CrossRefPubMedGoogle Scholar
  47. McClelland JL, Rogers TT (2003) The parallel distributed processing approach to semantic cognition. Nat Rev Neurosci 4(4):310–322CrossRefPubMedGoogle Scholar
  48. McNamara CG, Tejero-Cantero Á, Trouche S, Campo-Urriza N, Dupret D (2014) Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nat Neurosci 17(12):1658–1660CrossRefPubMedPubMedCentralGoogle Scholar
  49. Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420(6911):70–74CrossRefPubMedGoogle Scholar
  50. Misanin JR, Miller RR, Lewis DJ (1968) Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160:554–555CrossRefPubMedGoogle Scholar
  51. Mohamed AD, Sahakian BJ (2012) The ethics of elective psychopharmacology. Int J Neuropsychopharmacol Off Sci J Coll Int Neuropsychopharmacol CINP 15:559–571Google Scholar
  52. Moscovitch M, Nadel L, Winocur G, Gilboa A, Rosenbaum RS (2006) The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr Opin Neurobiol 16:179–190CrossRefPubMedGoogle Scholar
  53. Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406(6797):722–726CrossRefPubMedGoogle Scholar
  54. Oudiette D, Paller KA (2013) Upgrading the sleeping brain with targeted memory reactivation. Trends Cogn Sci 17(3):142–149CrossRefPubMedGoogle Scholar
  55. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC (2006) Storage of spatial information by the maintenance mechanism of LTP. Science 313(5790):1141–1144CrossRefPubMedGoogle Scholar
  56. Rabinak CA, Angstadt M, Sripada CS, Abelson JL, Liberzon I, Milad MR, Phan KL (2013) Cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology 64:396–402CrossRefPubMedGoogle Scholar
  57. Ragan CI, Bard I, Singh I (2013) What should we do about student use of cognitive enhancers? An analysis of current evidence. Neuropharmacology 64:588–595CrossRefPubMedGoogle Scholar
  58. Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL et al (2013) Creating a false memory in the Hippocampus. Science 341(6144):387–391CrossRefPubMedGoogle Scholar
  59. Rasch B, Büchel C, Gais S, Born J (2007) Odour cues during slow-wave sleep prompt declarative memory consolidation. Science 315(5817):1426–1429CrossRefPubMedGoogle Scholar
  60. Redondo RL, Kim J, Arons AL, Ramirez S, Liu X, Tonegawa S (2014) Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513(7518):426–430CrossRefPubMedPubMedCentralGoogle Scholar
  61. Ren SQ, Yan JZ, Zhang XY et al (2013) PKCλ is critical in AMPA receptor phosphorylation and synaptic incorporation during LTP. EMBO J 32(10):1365–1380CrossRefPubMedPubMedCentralGoogle Scholar
  62. Rodríguez MLC, Campos J, Forcato C, Leiguarda R, Maldonado H, Molina VA, Pedreira ME (2013) Enhancing a declarative memory in humans: the effect of clonazepam on reconsolidation. Neuropharmacology 64:432–442CrossRefPubMedGoogle Scholar
  63. Rolls A, Makam M, Kroeger D, Colas D, de Lecea L, Heller HC (2013) Sleep to forget: interference of fear memories during sleep. Mol Psychiatry 18:1166–1170CrossRefPubMedPubMedCentralGoogle Scholar
  64. Rudoy JD, Voss JL, Westerberg CE, Paller KA (2009) Strengthening individual memories by reactivating them during sleep. Science 326(5956):1079–1079CrossRefPubMedPubMedCentralGoogle Scholar
  65. Sadeh N, Verbitsky S, Dudai Y, Segal M (2015) Zeta inhibitory peptide, a candidate inhibitor of protein kinase Mζ, is excitotoxic to cultured hippocampal neurons. J Neurosci 35(36):12404–12411CrossRefPubMedGoogle Scholar
  66. Sara SJ (2010) Reactivation, retrieval, replay and reconsolidation in and out of sleep: connecting the dots. Front Behav Neurosci 4:185. doi: 10.3389/fnbeh.2010.00185 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Schiller D, Phelps EA (2011) Does reconsolidation occur in humans? Front Behav Neurosci 5:24. doi: 10.3389/fnbeh.2011.00024 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Schreiner T, Lehmann M, Rasch B (2015) Auditory feedback blocks memory benefits of cueing during sleep. Nat Commun 6:8729CrossRefPubMedPubMedCentralGoogle Scholar
  69. Serrano P, Yao Y, Sacktor TC (2005) Persistent phosphorylation by protein kinase Mζ maintains late-phase long-term potentiation. J Neurosci 25(8):1979–1984CrossRefPubMedGoogle Scholar
  70. Shema R, Sacktor TC, Dudai Y (2007) Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ. Science 317(5840):951CrossRefPubMedGoogle Scholar
  71. Shema R, Haramati S, Ron S, Hazvi S, Chen A, Sacktor TC, Dudai Y (2011) Enhancement of consolidated long-term memory by overexpression of protein kinase Mζ in the neocortex. Science 331(6021):1207–1210CrossRefPubMedGoogle Scholar
  72. Siapas AG, Wilson MA (1998) Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron 21(5):1123–1128CrossRefPubMedGoogle Scholar
  73. Sirota A, Csicsvari J, Buhl D, Buzsáki G (2003) Communication between neocortex and hippocampus during sleep in rodents. Proc Natl Acad Sci U S A 100(4):2065–2069CrossRefPubMedPubMedCentralGoogle Scholar
  74. Spiers HJ (2012) Hippocampal formation. In: Ramachandran VS (ed) The encyclopedia of human behaviour, vol 2. Academic Press, New York, pp 297–304CrossRefGoogle Scholar
  75. Spiers HJ, Bendor D (2014) Enhance, delete, incept: manipulating hippocampus-dependent memories. Brain Res Bull 105:2–7CrossRefPubMedPubMedCentralGoogle Scholar
  76. Squire LR, Alvarez P (1995) Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 5:169–177CrossRefPubMedGoogle Scholar
  77. Squire LR, Stark CEL, Clark RE (2004) The medial temporal lobe. Annu Rev Neurosci 27:279–306CrossRefPubMedGoogle Scholar
  78. Steckler T, Risbrough V (2012) Pharmacological treatment of PTSD–established and new approaches. Neuropharmacology 62(2):617–627CrossRefPubMedGoogle Scholar
  79. Steriade M, McCormick DA, Sejnowski TJ (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262(5134):679–685CrossRefPubMedGoogle Scholar
  80. Stickgold R, Walker MP (2013) Sleep-dependent memory triage: evolving generalization through selective processing. Nat Neurosci 16(2):139–145CrossRefPubMedGoogle Scholar
  81. Suthana N, Haneef Z, Stern J, Mukamel R, Behnke E, Knowlton B, Fried I (2012) Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med 366(6):502–510CrossRefPubMedPubMedCentralGoogle Scholar
  82. Thompson SA, Graham KS, Williams G, Patterson K, Kapur N, Hodges JR (2004) Dissociating person-specific from general semantic knowledge: roles of the left and right temporal lobes. Neuropsychologia 42(3):359–370CrossRefPubMedGoogle Scholar
  83. Tsokas P, Hsieh C, Yao Y, Lesburguères E et al (2016) Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice. Elife 5. doi: 10.7554/eLife.14846
  84. Uncapher MR, Boyd-Meredith JT, Chow TE, Rissman J, Wagner AD (2015) Goal-directed modulation of neural memory patterns: implications for fMRI-based memory detection. J Neurosci 35(22):8531–8545CrossRefPubMedGoogle Scholar
  85. Varela C, Weiss S, Meyer R, Halassa M, Biedenkapp J, Wilson MA, Goosens KA, Bendor D (2016) Tracking the time-dependent role of the hippocampus in memory recall using DREADDs. PLoS One 11(5):e0154374CrossRefPubMedPubMedCentralGoogle Scholar
  86. Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL (2013) PKM-(ζ) is not required for hippocampal synaptic plasticity, learning and memory. Nature 493(7432):420–423CrossRefPubMedGoogle Scholar
  87. Wang JX, Rogers LM, Gross EZ, Ryals AR, Mehmet DE, Brandstatt KL, Hermiller MA, Voss JL (2014) Targeted enhancement of the cortical-hippocampal brain networks and associative memory. Science 346(6200):1054–1057CrossRefGoogle Scholar
  88. Wang JX, Voss JL (2015) Long-lasting enhancements of memory and hippocampal-cortical functional connectivity following multiple-day targeted noninvasive stimulation. Hippocampus 25(8):877–883CrossRefPubMedPubMedCentralGoogle Scholar
  89. Wilson MA, McNaughton BL (1994) Reactivation of hippocampal ensemble memories during sleep. Science 265(5172):676–679CrossRefPubMedGoogle Scholar
  90. Zhang G, Ásgeirsdóttir HN, Cohen SJ, Munchow AH, Barrera MP, Stackman RW (2013) Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64:403–413CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Institute of Behavioural Neuroscience, Department of Experimental Psychology, Division of Psychology and Language SciencesUniversity College LondonLondonUK

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