CoChat
Sign Up
Cited by 90Memory and Neural MechanismsMemory Processes and InfluencesNeuroscience and Neuropharmacology Research

New learning and unlearning: strangers or accomplices in threat memory attenuation?

Open access
Clem, Roger L., Schiller, Daniela·2016·Trends in Neurosciences
DOI 10.1016/j.tins.2016.03.003PMC PMC4972342
Open this paper in CoChat — free account

Abstract

To achieve greatest efficacy, therapies for attenuating fear and anxiety should preclude the re-emergence of emotional responses. Of relevance to this aim, preclinical models of threat memory reduction are considered to engage one of two discrete neural processes: either establishment of a new behavioral response that competes with, and thereby temporarily interferes with the expression of, threat memory (new learning) or one that modifies and thereby disrupts threat memory (unlearning). We contend that a strict dichotomy of new learning and unlearning does not provide a compelling explanation for current data. Instead, we suggest that the evidence warrants consideration of alternative models that assume cooperation rather than competition between formation of new cellular traces and the modification of preexisting ones.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.tins.2016.03.003

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • It is possible that the original memory also undergoes some modification, if only to reflect that the CS is now ambiguous, or to incorporate the representation of other cues or contexts that may allow the appropriate response to the CS to be disambiguated.

    “it is possible that the original memory also undergoes some modification, if only to reflect that the CS is now ambiguous, or to incorporate the representation of other cues or contexts that may allow the appropriate response to the CS to be disambiguated (Clem and Schiller, 2016).”

    From Retrieval-Dependent Mechanisms Affecting Emotional Memory Persistence: Reconsolidation, Extinction, and the Space in Between (2020) · cites this paper as Clem and Schiller, 2016

    The ‘Considering the alternative: a mixed model’ section proposes that the original threat-memory trace may be partially altered, and the ‘Discrimination on the basis of biochemical mechanisms’ section describes a proposed integration of new safety information into memory during reconsolidation. The paper also describes context-dependent encoding of inhibitory CS associations, but does not say that the original memory is modified to represent the CS as ambiguous or to incorporate cues that disambiguate it. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 94 · Cited by 90

Research works printed but not linked: 74

  1. [1]McGaugh JL 1966 Time-dependent processes in memory storage Science 153 1351 1358 5917768
  2. [2]Pavlov IP 1927 Conditioned Reflexes Oxford University Press
  3. [3]Bouton ME 2002 Context, ambiguity, and unlearning: sources of relapse after behavioral extinction Biological psychiatry 52 976 986 12437938
  4. [4]Myers KM Davis M 2007 Mechanisms of fear extinction Mol Psychiatry 12 120 150 17160066
  5. [5]Przybyslawski J Sara SJ 1997 Reconsolidation of memory after its reactivation Behav Brain Res 84 241 246 9079788
  6. [6]Nader K 2000 The labile nature of consolidation theory Nature reviews Neuroscience 1 216 219 11257912
  7. [8]Bentz D Schiller D 2015 Threat processing: models and mechanisms Wiley Interdiscip Rev Cogn Sci 6 427 439 26267313
  8. [9]Bouton ME 2014 Why behavior change is difficult to sustain Prev Med 68 29 36 24937649 PMC4287360
  9. [10]Rescorla RA 2004 Spontaneous recovery Learn Mem 11 501 509 15466300
  10. [11]Agren T 2014 Human reconsolidation: a reactivation and update Brain Res Bull 105 70 82 24397965
  11. [12]Dudai Y 2012 The restless engram: consolidations never end Annu Rev Neurosci 35 227 247 22443508
  12. [13]Nader K 2015 Reconsolidation and the Dynamic Nature of Memory Cold Spring Harb Perspect Biol 7 PMC4588064 26354895
  13. [14]Quirk GJ 2010 Erasing fear memories with extinction training The Journal of neuroscience: the official journal of the Society for Neuroscience 30 14993 14997 21068303 PMC3380534
  14. [15]Reichelt AC Lee JL 2013 Memory reconsolidation in aversive and appetitive settings Frontiers in behavioral neuroscience 7 118 24058336 PMC3766793
  15. [16]Schiller D Phelps EA 2011 Does reconsolidation occur in humans? Frontiers in behavioral neuroscience 5 24 21629821 PMC3099269
  16. [17]Taylor JR Torregrossa MM 2015 Pharmacological disruption of maladaptive memory Handb Exp Pharmacol 228 381 415 25977090
  17. [18]Trent S 2015 Rescue of long-term memory after reconsolidation blockade Nature communications 6 7897 PMC4532853 26238574
  18. [19]Hardt O 2009 Storage or retrieval deficit: the yin and yang of amnesia Learn Mem 16 224 230 19304892
  19. [21]Clem RL Huganir RL 2010 Calcium-permeable AMPA receptor dynamics mediate fear memory erasure Science 330 1108 1112 21030604 PMC3001394
  20. [22]Clem RL Huganir RL 2013 Norepinephrine enhances a discrete form of long-term depression during fear memory storage The Journal of neuroscience: the official journal of the Society for Neuroscience 33 11825 11832 23864672 PMC3713724
  21. [23]Kim J 2007 Amygdala depotentiation and fear extinction Proceedings of the National Academy of Sciences of the United States of America 104 20955 20960 18165656 PMC2409248
  22. [24]Lin HC 2011 GABAA receptor endocytosis in the basolateral amygdala is critical to the reinstatement of fear memory measured by fear-potentiated startle The Journal of neuroscience: the official journal of the Society for Neuroscience 31 8851 8861 21677169 PMC6622947
  23. [25]McKernan MG Shinnick-Gallagher P 1997 Fear conditioning induces a lasting potentiation of synaptic currents in vitro Nature 390 607 611 9403689
  24. [26]Namburi P 2015 A circuit mechanism for differentiating positive and negative associations Nature 520 675 678 25925480 PMC4418228
  25. [29]Zhou Y 2009 CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala Nature neuroscience 12 1438 1443 19783993 PMC2783698
  26. [30]Rumpel S 2005 Postsynaptic receptor trafficking underlying a form of associative learning Science 308 83 88 15746389
  27. [33]Penzo MA 2015 The paraventricular thalamus controls a central amygdala fear circuit Nature 519 455 459 25600269 PMC4376633
  28. [34]Nabavi S 2014 Engineering a memory with LTD and LTP Nature 511 348 352 24896183 PMC4210354
  29. [35]Cho JH 2013 Synaptic encoding of fear extinction in mPFC-amygdala circuits Neuron 80 1491 1507 24290204 PMC3872173
  30. [36]Amano T 2010 Synaptic correlates of fear extinction in the amygdala Nature neuroscience 13 489 494 20208529 PMC2847017
  31. [38]Likhtik E 2014 Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety Nature neuroscience 17 106 113 24241397 PMC4035371
  32. [39]Courtin J 2014 Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression Nature 505 92 96 24256726
  33. [40]Herry C 2008 Switching on and off fear by distinct neuronal circuits Nature 454 600 606 18615015
  34. [43]Li Y 2013 Learning and reconsolidation implicate different synaptic mechanisms Proceedings of the National Academy of Sciences of the United States of America 110 4798 4803 23487762 PMC3607055
  35. [44]Ryan TJ 2015 Memory. Engram cells retain memory under retrograde amnesia Science 348 1007 1013 26023136 PMC5583719
  36. [45]Mickley GA 2012 Acute, but not chronic, exposure to d-cycloserine facilitates extinction and modulates spontaneous recovery of a conditioned taste aversion Physiology & behavior 105 417 427 21925192 PMC3225641
  37. [46]Mao SC 2006 Extinction training in conjunction with a partial agonist of the glycine site on the NMDA receptor erases memory trace The Journal of neuroscience: the official journal of the Society for Neuroscience 26 8892 8899 16943544 PMC6675349
  38. [47]Walker DL 2002 Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats The Journal of neuroscience: the official journal of the Society for Neuroscience 22 2343 2351 11896173 PMC6758267
  39. [48]Ledgerwood L 2004 D-cycloserine and the facilitation of extinction of conditioned fear: consequences for reinstatement Behavioral neuroscience 118 505 513 15174928
  40. [50]Schiller D 2010 Preventing the return of fear in humans using reconsolidation update mechanisms Nature 463 49 53 20010606 PMC3640262
  41. [51]Kim J 2010 Reactivation of fear memory renders consolidated amygdala synapses labile The Journal of neuroscience: the official journal of the Society for Neuroscience 30 9631 9640 20631192 PMC6632454
  42. [52]Lee S 2013 GluA1 phosphorylation at serine 831 in the lateral amygdala is required for fear renewal Nature neuroscience 16 1436 1444 23974710
  43. [54]Chen S 2014 Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in Aplysia eLife 3 e03896 25402831 PMC4270066
  44. [55]Parsons RG Davis M 2011 Temporary disruption of fear-potentiated startle following PKMzeta inhibition in the amygdala Nature neuroscience 14 295 296 21258326 PMC3080103
  45. [56]Wang ME 2015 Extinction of Learned Fear Induces Hippocampal Place Cell Remapping The Journal of neuroscience: the official journal of the Society for Neuroscience 35 9122 9136 26085635 PMC4469738
  46. [57]An B 2012 Long-term neural correlates of reversible fear learning in the lateral amygdala The Journal of neuroscience: the official journal of the Society for Neuroscience 32 16845 16856 23175837 PMC6621751
  47. [59]Frankland PW 2004 The involvement of the anterior cingulate cortex in remote contextual fear memory Science 304 881 883 15131309
  48. [60]Do-Monte FH 2015 A temporal shift in the circuits mediating retrieval of fear memory Nature 519 460 463 25600268 PMC4376623
  49. [61]Lopez J 2015 Memory retrieval requires ongoing protein synthesis and NMDA receptor activity-mediated AMPA receptor trafficking The Journal of neuroscience: the official journal of the Society for Neuroscience 35 2465 2475 25673841 PMC6605616
  50. [62]Suzuki A 2004 Memory reconsolidation and extinction have distinct temporal and biochemical signatures The Journal of neuroscience: the official journal of the Society for Neuroscience 24 4787 4795 15152039 PMC6729467
  51. [63]Lee SH 2008 Synaptic protein degradation underlies destabilization of retrieved fear memory Science 319 1253 1256 18258863
  52. [64]Pick JE 2013 Neuronal expression of the ubiquitin E3 ligase APC/C-Cdh1 during development is required for long-term potentiation, behavioral flexibility, and extinction Neurobiol Learn Mem 100 25 31 23238556 PMC3562375
  53. [65]Ben Mamou C 2006 NMDA receptors are critical for unleashing consolidated auditory fear memories Nature neuroscience 9 1237 1239 16998481
  54. [67]Suzuki A 2008 Activation of LVGCCs and CB1 receptors required for destabilization of reactivated contextual fear memories Learn Mem 15 426 433 18511694 PMC2414253
  55. [69]Kimura R 2008 Autophosphorylation of alphaCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction Learn Mem 15 837 843 18984565 PMC2632808
  56. [73]Flavell CR 2011 Behavioural memory reconsolidation of food and fear memories Nature communications 2 504 PMC3516828 22009036
  57. [75]Ma X 2012 Post-retrieval extinction training enhances or hinders the extinction of morphine-induced conditioned place preference in rats dependent on the retrieval-extinction interval Psychopharmacology 221 19 26 22048130
  58. [76]Olshavsky ME 2013 Updating appetitive memory during reconsolidation window: critical role of cue-directed behavior and amygdala central nucleus Frontiers in behavioral neuroscience 7 186 24367304 PMC3856395
  59. [77]Sartor GC Aston-Jones G 2013 Post-Retrieval Extinction Attenuates Cocaine Memories Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology PMC3957116 24257156
  60. [79]Agren T 2012 Disruption of reconsolidation erases a fear memory trace in the human amygdala Science 337 1550 1552 22997340
  61. [80]Schiller D 2013 Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement Proceedings of the National Academy of Sciences of the United States of America 110 20040 20045 24277809 PMC3864277
  62. [81]Auber A 2013 Post-retrieval extinction as reconsolidation interference: methodological issues or boundary conditions? Psychopharmacology 226 631 647 23404065 PMC3682675
  63. [83]Baker KD 2013 Memory retrieval before or after extinction reduces recovery of fear in adolescent rats Learn Mem 20 467 473 23950194
  64. [84]Tedesco V 2014 Extinction, applied after retrieval of auditory fear memory, selectively increases zinc-finger protein 268 and phosphorylated ribosomal protein S6 expression in prefrontal cortex and lateral amygdala Neurobiol Learn Mem 115 78 85 25196703
  65. [85]Antion MD 2008 Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity Learn Mem 15 29 38 18174371 PMC2170513
  66. [86]Maren S 2013 The contextual brain: implications for fear conditioning, extinction and psychopathology Nature reviews Neuroscience 14 417 428 23635870 PMC5072129
  67. [88]Jin J Maren S 2015 Fear renewal preferentially activates ventral hippocampal neurons projecting to both amygdala and prefrontal cortex in rats Sci Rep 5 8388 25669753 PMC4323647
  68. [89]Orsini CA 2011 Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction The Journal of neuroscience: the official journal of the Society for Neuroscience 31 17269 17277 22114293 PMC3241946
  69. [90]Sotres-Bayon F 2012 Gating of fear in prelimbic cortex by hippocampal and amygdala inputs Neuron 76 804 812 23177964 PMC3508462
  70. [91]Burgos-Robles A 2009 Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure The Journal of neuroscience: the official journal of the Society for Neuroscience 29 8474 8482 19571138 PMC2733220
  71. [92]Ji J Maren S 2005 Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction Learn Mem 12 270 276 15930505 PMC1142455
  72. [93]Kandel ER 2014 The molecular and systems biology of memory Cell 157 163 186 24679534
  73. [94]Herry C Johansen JP 2014 Encoding of fear learning and memory in distributed neuronal circuits Nature neuroscience 17 1644 1654 25413091
  74. [95]Johansen JP 2011 Molecular mechanisms of fear learning and memory Cell 147 509 524 22036561 PMC3215943

Authors
Clem, R. L., & Schiller, D.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Clem, Roger L.
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2016-05
Volume
39
Issue
5
Pages
340-351
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2016.03.003
PMC
PMC4972342
OpenAlex
W2337604019
Cited by
90
References
94
Citations by year
2026: 5 · 2025: 9 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 14 · 2017: 13 · 2016: 3
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (R01MH105535, R01MH105414)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
fear extinction, anxiety, new learning, unlearning, memory reconsolidation, memory modification, competition and cooperation, preclinical models
MeSH terms
Brain, Conditioning, Classical, Extinction, Psychological, Humans, Learning, Memory

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review