CoChat
Sign Up
Cited by 467Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP

Open access
Lisman, John, Grace, Anthony A., Duzel, Emrah·2011·Trends in Neurosciences
DOI 10.1016/j.tins.2011.07.006PMC PMC3183413
Open this paper in CoChat — free account

Abstract

According to the Hebb rule, the change in the strength of a synapse depends only on the local interaction of presynaptic and postsynaptic events. Studies at many types of synapses indicate that the early phase of long-term potentiation (LTP) has Hebbian properties. However, it is now clear that the Hebb rule does not account for late LTP; this requires an additional signal that is non-local. For novel information and motivational events such as rewards, this signal at hippocampal CA1 synapses is mediated by the neuromodulator, dopamine. In this Review, we discuss recent experimental findings that support the view that this “neoHebbian” framework can account for memory behavior in a variety of learning situations.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes a neoHebbian framework in which Hebbian early LTP at hippocampal CA1 synapses is supplemented by a third, non-local dopamine signal required for late LTP and stable episodic memory. It synthesizes rodent and human evidence that novelty, reward, and aversive/motivational events trigger dopamine release that selectively stabilizes memory at long delays and can enhance temporally nearby weak memories via a synaptic tag-and-capture “penumbra.”

Key findings

  • Late LTP in CA1 requires D1 dopamine receptor signaling: D1 antagonists, D1 receptor deletion, or dopamine depletion block late LTP, while early LTP is less affected. In a rodent one-trial reward-location memory task, intrahippocampal D1/D5 antagonist SCH23390 before encoding impaired memory at 24 hours but not at 30 minutes.
  • Dopamine neurons burst in response to reward, novelty, and aversive stimuli; bursts last about 200–500 msec, have interspike intervals <100 msec, and generally contain about 3–5 spikes, with up to 50% of dopamine neurons silent at baseline. In mice, 89% of VTA dopaminergic neurons responded with activation to a conditioned reward, the majority showed suppression to fearful events, and 25% responded with excitation to both positive and fearful events.
  • Human fMRI studies show SN/VTA activation by reward, novelty, and aversive events. Reward prospect improved long-term episodic memory, with enhancement greater at late timepoints (3 weeks vs. 20 minutes) and consistently after 24-hour retention intervals.
  • Novelty can create a behavioral “penumbra”: in rodents, a single reward-location exposure normally forgotten within hours persisted for at least 24 hours if preceded or followed within 30 minutes by novelty exploration; in humans, novel scenes presented 5 minutes before pre-familiarized words increased later recollection, with a stronger effect at 24 hours than at 30 minutes.

Methods

  • Review article; no new experimental data are reported.
  • Synthesizes electrophysiological, pharmacological, genetic, and behavioral studies in rodents, plus human fMRI, PET, and electrophysiological findings.
  • Main analysis is a narrative integration of evidence around dopamine-dependent late LTP, dopamine neuron firing properties, and the synaptic tag-and-capture model.

Limitations

  • The paper states that more human studies are needed, especially on dopaminergic manipulations and long-term memory; selective D1/D5 compounds are not readily available for healthy humans, and fMRI cannot distinguish SN/VTA subregions or tonic versus bursting modes. It also notes unresolved questions about the duration of hippocampal dopamine signals, penumbra properties, and the relative consolidation of rewarding versus aversive events in humans.
  • Evident from the text: as a review, it does not use a systematic search or meta-analytic method, and some proposed circuitry—such as perirhinal cortical information generating phasic dopamine responses—is explicitly described as needing experimental testing.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tins.2011.07.006

Cites

145 of 145 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 121 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Stable synaptic modification requires a third signal dependent on a systems-level computation, in addition to the two-factor Hebbian process.

    “We term this “neoHebbian” to indicate that in addition to the 2-factor Hebbian process, stable synaptic modification requires a third signal dependent on a systems level computation.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Dopamine enhances protein synthesis within dendrites of hippocampal neurons.

    “Dopamine enhances protein synthesis within dendrites of hippocampal neurons [85].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Smith WB 2005 Dopaminergic stimulation of local protein synthesis enhances surface expression of GluR1 and synaptic transmission in hippocampal neurons Neuron 45 765 779 15748851 source

      Not checked in the free run.

  • Premisecitation

    LTP is specific to the synapses at which the Hebb rule is met.

    “The ability to induce LTP at single visualizable synaptic connections by 2-photon uncaging of glutamate has directly confirmed the synapse specificity of LTP [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Matsuzaki M 2004 Structural basis of long-term potentiation in single dendritic spines Nature 429 761 766 15190253 PMC4158816 source

      Not checked in the free run.

  • Premisecitation

    Hippocampal late LTP is blocked when ERK1/2 activation is blocked by a dominant-negative mutation of MEK1.

    “Hippocampal late LTP is blocked when ERK1/2 activation is blocked by a dominant-negative mutation of MEK1, the kinase that directly phosphorylates ERK1/2 [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Kelleher RJ 3rd 2004 Translational control by MAPK signaling in long-term synaptic plasticity and memory Cell 116 467 479 15016380 source

      Not checked in the free run.

  • Premisecitation

    Genetic or pharmacological interference with NMDARs or CaMKII strongly interferes with memory formation.

    “Experiments show that genetic or pharmacological interference with NMDARs or CaMKII strongly interferes with memory formation [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Lisman J 2002 The molecular basis of CaMKII function in synaptic and behavioural memory Nature reviews 3 175 190 11994750 source

      Not checked in the free run.

  • May combine two claims. 45
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Premisenone given

    The Hebb rule does not account for late LTP; late LTP requires an additional non-local signal.

    “However, it is now clear that the Hebb rule does not account for late LTP; this requires an additional signal that is non-local.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Opening of the NMDA receptor is Hebbian: the channel opens only if there is both presynaptic glutamate release and strong postsynaptic depolarization.

    “The opening of the NMDAR is Hebbian: the channel opens only if there is both presynaptic glutamate release and strong postsynaptic depolarization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In primates, novel stimuli can trigger burst firing of dopamine cells, which habituates as stimuli become familiar.

    “In primates, novel stimuli can trigger burst firing of dopamine cells which habituates as stimuli become familiar [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Ljungberg T 1992 Responses of monkey dopamine neurons during learning of behavioral reactions J Neurophysiol 67 145 163 1552316 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Preventing strong depolarization by injecting negative current prevents the induction of LTP.

    “Furthermore, preventing strong depolarization by injecting negative current prevents the induction of LTP [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Malinow R Miller JP 1986 Postsynaptic hyperpolarization during conditioning reversibly blocks induction of long-term potentiation Nature 320 529 530 3008000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo events involve NMDAR-dependent processes triggered by hippocampal replay, whereas Hebbian NMDAR-dependent processes in the slice occur only during the initial induction of LTP.

    “Whereas the Hebbian NMDAR-dependent processes in the slice occur only during the initial induction of LTP, events in vivo also involve NMDAR-dependent processes triggered by hippocampal replay processes [142].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Shimizu E 2000 NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation Science (New York, N Y 290 1170 1174 11073458

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Novelty-related activation of the SN/VTA has a long (about 30 minutes) penumbra that affects memory for unrelated information.

    “the observation that novelty-related activation of the SN/VTA has a long (ca. 30 minutes) penumbra that affects memory for unrelated information (e.g. exposure to novel scenes can affect memory for words) [74]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Fenker DB 2008 Novel scenes improve recollection and recall of words J Cogn Neurosci 20 1250 1265 18284351

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dopamine antagonists would produce a weak reduction of memory at short times after learning but a strong reduction at later times.

    “Based on these results, one would predict that dopamine antagonists would produce a weak reduction of memory at short times after learning but would produce a strong reduction at later times.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dopamine antagonists applied during LTP induced by multiple tetani have a strongly time-dependent effect: the first phase of LTP is not strongly affected, but potentiation measured an hour after induction is strongly attenuated.

    “Early experiments revealed that dopamine antagonists applied during the LTP induced by multiple tetani (generally 100Hz for 1s) had an effect that was strongly time dependent [7]. Whereas the first phase of LTP was not strongly affected, the potentiation measured an hour after induction was strongly attenuated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Frey U 1990 Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices Brain research 522 69 75 1977494

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Early work showed that dopamine agonists alone could produce potentiation.

    “Another quandary was posed by early work showing that dopamine agonists alone could produce potentiation [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Huang YY Kandel ER 1995 D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus Proceedings of the National Academy of Sciences of the United States of America 92 2446 2450 7708662 PMC42234

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premiseown data

    Early LTP is completely unaffected by dopamine antagonist.

    “Results such as those shown in Fig. 1 (top traces) suggest that early LTP is completely unaffected by dopamine antagonist.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Late LTP is blocked by D1 antagonists and by genetic deletion of D1 receptors.

    “Late LTP is blocked by D1 antagonists [14] (Fig. 1A) and by genetic deletion of D1 receptors (Fig. 1C) [15, 16].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] O’Carroll CM Morris RG 2004 Heterosynaptic co-activation of glutamatergic and dopaminergic afferents is required to induce persistent long-term potentiation Neuropharmacology 47 324 332 15275821

      Not checked in the free run.

    • cites [15] Matthies H 1997 Dopamine D1-deficient mutant mice do not express the late phase of hippocampal long-term potentiation Neuroreport 8 3533 3535 9427321

      Not checked in the free run.

    • cites [16] Granado N 2008 D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-Induced arc and zif268 expression in the hippocampus Cereb Cortex 18 1 12 17395606

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In freely behaving mice, VTA dopaminergic neurons can exhibit responses to different valences; 89% respond with activation to a conditioned reward, they also respond to fearful events with the majority showing suppression, and 25% respond with excitation to both positive and fearful events.

    “Thus, although 89% of VTA dopaminergic neurons respond with activation to a conditioned reward, they also respond to fearful events, with the majority of the neurons showing suppression. Interestingly, 25% respond with excitation to both positive and fearful events [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Wang DV Tsien JZ 2011 Convergent processing of both positive and negative motivational signals by the VTA dopamine neuronal populations PloS one 6 e17047 21347237 PMC3039659 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Late LTP is dependent on protein synthesis, whereas early LTP is not.

    “LTP at these later times (termed late LTP) is dependent on protein synthesis, whereas the LTP at early times is not [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Frey U 1993 Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons Science (New York, N Y 260 1661 1664 8389057 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dopamine neurons can fire in response to unexpected aversive outcomes and cues predicting punishments.

    “It is now well-established that dopamine neurons can also fire in response to unexpected aversive outcomes and cues predicting punishments [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Bromberg-Martin ES 2010 Dopamine in motivational control: rewarding, aversive, and alerting Neuron 68 815 834 21144997 PMC3032992 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both early and late LTP are dopamine-dependent, but late LTP has a stronger dependence.

    “Thus, both early and late LTP are dopamine-dependent, but late LTP has a stronger dependence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Depletion of dopamine selectively blocks late LTP, and this block can be reversed by a D1 agonist.

    “Furthermore, depletion of dopamine selectively blocks late LTP [18], a block that can be reversed by a D1 agonist (Fig. 1D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Yang HW 2002 Change in bi-directional plasticity at CA1 synapses in hippocampal slices taken from 6-hydroxydopamine-treated rats: the role of endogenous norepinephrine The European journal of neuroscience 16 1117 1128 12383241

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This one-trial memory for novel associations is critically dependent on the hippocampus and on glutamatergic neurotransmission during encoding.

    “This one-trial memory for novel associations is critically dependent on the hippocampus and on glutamatergic neurotransmission during encoding [25, 26].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Tse D 2007 Schemas and memory consolidation Science (New York, N Y 316 76 82 17412951 source

      Not checked in the free run.

    • cites [26] Bethus I 2010 Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates J Neurosci 30 1610 1618 20130171 PMC6633999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dopamine responses conform with a signed prediction error; they increase for better than expected outcomes and decrease for worse than expected outcomes.

    “In reinforcement learning, dopamine responses conform with a signed prediction error; they increase for better than expected (reward) outcomes and decrease for worse than expected (aversive) outcomes [43].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Schultz W 2007 Multiple dopamine functions at different time courses Annual review of neuroscience 30 259 288 17600522 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Reward-related SN/VTA activation improves memory for the rewarded stimulus, but not for non-rewarded stimuli given in close temporal proximity.

    “Reward-related SN/VTA activation improves memory for the rewarded stimulus, but not for the non-rewarded stimuli given in close temporal proximity [57]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Wittmann B 2011 Behavioural specifications of reward-associated long-term memory enhancement in humans Learning and Memory 18 296 300 21502336 PMC3465832

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Dopamine by itself does not produce potentiation; rather, it acts as a permissive signal for late-phase LTP induced by an NMDAR-dependent process.

    “Thus, it is now clear that dopamine by itself does not produce potentiation; rather, it acts as a permissive signal for the late-phase LTP induced by a NMDAR-dependent process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In monkeys, a substantial fraction of dopamine neurons in the dorsolateral SN/VTA are responsive to conditioned cues predicting aversive events, whereas those in the more ventromedial portions are inhibited by aversive stimuli.

    “In monkeys, a substantial fraction of dopamine neurons in the dorsolateral SN/VTA are responsive to conditioned cues predicting aversive events; in contrast, those in the more ventromedial portions of the SN/VTA are inhibited by aversive stimuli [97]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Matsumoto M Hikosaka O 2009 Two types of dopamine neuron distinctly convey positive and negative motivational signals Nature 459 837 841 19448610 PMC2739096 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The potentiation produced by dopamine agonists depended on the action of test pulses given during agonist application, and activation of NMDARs by the test pulses was required.

    “However, it was subsequently shown that this potentiation depended on the action of test pulses given during agonist application and that activation of NMDARs by the test pulses was required [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Navakkode S 2007 Synergistic requirements for the induction of dopaminergic D1/D5-receptor-mediated LTP in hippocampal slices of rat CA1 in vitro Neuropharmacology 52 1547 1554 17433377

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo recordings show that CA3/CA1 synapses are strengthened over time during trace eyeblink conditioning, but this strengthening is greatly reduced in D1 receptor knockout mice or after reducing D1 receptors by virally delivered siRNA.

    “In vivo recordings show that CA3/CA1 synapses are strengthened over time during trace eyeblink conditioning but that this strengthening is greatly reduced either in D1 receptor knockout mice or after reducing D1 receptors by virally delivered siRNA [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Granado N 2008 D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-Induced arc and zif268 expression in the hippocampus Cereb Cortex 18 1 12 17395606

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intrahippocampal infusion of the D1/D5 dopaminergic antagonist SCH23390 just before encoding causes impaired memory for the new reward-location association measured 24 hours later, but has no effect on early memory measured at 30 minutes.

    “Intrahippocampal infusion of the D1/D5 dopaminergic antagonist SCH23390 just before encoding causes impaired memory for the new reward-location association measured 24 hours later, but has no effect on early memory measured at 30 minutes [26]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Bethus I 2010 Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates J Neurosci 30 1610 1618 20130171 PMC6633999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Some cells in the SN and VTA are GABAergic or glutamatergic, and others release both glutamate and dopamine.

    “Although the SN and VTA are known as dopaminergic regions, some cells in these regions are GABAergic or glutamatergic, and others release both glutamate and dopamine [31, 32].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Nair-Roberts RG 2008 Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat Neuroscience 152 1024 1031 18355970 PMC2575227

      Not checked in the free run.

    • cites [32] Hnasko TS 2010 Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo Neuron 65 643 656 20223200 PMC2846457 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The tonic firing mode of dopamine cells is driven by intrinsic pacemaker conductances.

    “Studies performed both in vivo and in vitro show that the tonic mode is driven by intrinsic pacemaker conductances [34, 36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Grace AA Bunney BS 1983 Intracellular and extracellular electrophysiology of nigral dopaminergic neurons--1. Identification and characterization Neuroscience 10 301 315 6633863

      Not checked in the free run.

    • cites [36] Grace AA Onn SP 1989 Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro J Neurosci 9 3463 3481 2795134 PMC6569889

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of the ventral subiculum excites the nucleus accumbens, which inhibits the ventral pallidum; this reduces inhibition of dopamine cells and increases the number of tonically firing cells.

    “Activation of the ventral subiculum (an output structure of the hippocampus) excites the nucleus accumbens (Nac), which, in turn, inhibits the ventral pallidum. This reduces the inhibition of dopamine cells and thereby increases the number of tonically firing cells [38, 39].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Floresco SB 2001 Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons Journal of Neuroscience 21 4915 4922 11425919 PMC6762358

      Not checked in the free run.

    • cites [39] Floresco SB 2003 Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission Nature neuroscience 6 968 973 12897785

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Burst firing controls some downstream functions, but others may depend on how many cells are in the tonic mode.

    “These results indicate that burst firing controls some downstream functions, but others may depend on how many cells are in the tonic mode (see Boxes 3 and 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Novelty, reward stimuli and aversive stimuli are all able to activate the dopamine system in both monkeys and humans.

    “Thus, novelty, reward stimuli and aversive stimuli are all able to activate the dopamine system in both monkeys and humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The perirhinal cortex shows much stronger responses to novel items than familiar items and may form connections to the PPTg.

    “The perirhinal cortex [65], for instance, shows much stronger responses to novel items than familiar items and may form connects to the PPTg (Figure I), a structure that regulates the SN/VTA.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Xiang JZ Brown MW 1998 Differential neuronal encoding of novelty, familiarity and recency in regions of the anterior temporal lobe Neuropharmacology 37 657 676 9705004

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Classical work showed the importance of reward as a stimulus for the bursting of dopamine cells.

    “Classical work showed the importance of reward as a stimulus for the bursting of these cells [43]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Schultz W 2007 Multiple dopamine functions at different time courses Annual review of neuroscience 30 259 288 17600522 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective genetic inactivation of NMDARs in dopaminergic cells blocked burst production and prevented conditioned behavioral responses that were dependent on dopamine.

    “selective genetic inactivation of NMDARs in dopaminergic cells blocked burst production and prevented conditioned behavioral responses that were dependent on dopamine [41]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Zweifel LS 2009 Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior Proceedings of the National Academy of Sciences of the United States of America 106 7281 7288 19342487 PMC2678650 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human SN/VTA activation can also occur due to aversive events and novel stimuli.

    “Other work using fMRI has demonstrated that activation can also occur due to aversive events [53] as well as novel stimuli [54].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Guitart-Masip M 2011 Action dominates valence in anticipatory representations in the human striatum and dopaminergic midbrain Journal of Neuroscience 31 7867 7875 21613500 PMC3109549

      Not checked in the free run.

    • cites [54] Duzel E 2010 NOvelty-related motivation of anticipation and exploration by dopamine (NOMAD): implications for healthy aging Neuroscience and biobehavioral reviews 34 660 669 19715723 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Midbrain dopamine neurons consist of three largely contiguous cell groups: the retrorubral field (A8), the substantia nigra pars compacta (A9), and the ventral tegmental area (A10).

    “Midbrain dopamine neurons consist of three largely contiguous cell groups: the retrorubral field (cell group A8 in the rat nomenclature), the substantia nigra pars compacta (SNc, A9), and the ventral tegmental area (VTA, A10) [28, 29].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Dahlström A Fuxe K 1964 Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons Acta Physiol Scand 62 1 80 14229500

      Not checked in the free run.

    • cites [29] Beckstead RM 1979 Efferent connections of the substantia nigra and ventral tegmental area in the rat Brain research 175 191 217 314832 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The reward-related improvement in memory should be small with short delays when early LTP is present, but large at much longer delays when late LTP is present.

    “Furthermore, this improvement should be small with short delays when early LTP is present, but large at much longer delays when late LTP is present.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More recent work has demonstrated conditions under which dopamine cells can be driven by aversive stimuli.

    “More recent work has demonstrated conditions under which dopamine cells can be driven by aversive stimuli (reviewed in [45]; see also Box 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Bromberg-Martin ES 2010 Dopamine in motivational control: rewarding, aversive, and alerting Neuron 68 815 834 21144997 PMC3032992 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dopamine has no effect on previously formed memories and is not required at the time of retrieval.

    “Dopamine has no effect on the previously formed memories and is not required at the time of retrieval [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] O’Carroll CM 2006 Dopaminergic modulation of the persistence of one-trial hippocampus-dependent memory Learning & memory (Cold Spring Harbor, N Y 13 760 769 PMC1783630 17142305

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    D1/D5 receptor-mediated effects do not strongly affect encoding or early memory, but do affect memory at later times.

    “These data demonstrate that D1/D5 receptor-mediated effects do not strongly affect encoding or early memory, but do affect memory at later times.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    In a negative prediction error, depression of dopaminergic neuron activity attenuates dopamine-mediated potentiation of the ventral subiculum while removing inhibition of the mPFC input; consequently the mPFC drives the animal to switch response strategies.

    “However, in the absence of an expected reward, or if a worse than expected outcome occurs (i.e., a negative prediction error), the consequent depression of dopaminergic neuron activity would attenuate dopamine-mediated potentiation of the ventral subiculum while at the same time removing inhibition of the mPFC input. Consequently the mPFC would drive the animal to switch response strategies [122].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Goto Y Grace AA 2008 Limbic and cortical information processing in the nucleus accumbens Trends in neurosciences 31 552 558 18786735 PMC2884964

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In a positive prediction error, the subicular input would be potentiated, causing the animal to maintain focus on the current task and allowing rewarded behaviors to be maintained.

    “In a condition in which the animal’s behavior leads to a better than expected outcome and phasic release (i.e. positive prediction error), the subicular input would be potentiated, causing the animal to maintain focus on the current task, thus allowing rewarded behaviors to be maintained.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A novel stimulus in the absence of reward can also produce burst firing of dopamine cells.

    “while subsequent studies have demonstrated that a novel stimulus (in the absence of reward) can also produce burst firing [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Ljungberg T 1992 Responses of monkey dopamine neurons during learning of behavioral reactions J Neurophysiol 67 145 163 1552316 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The lateral habenula provides SN/VTA dopamine neurons with a negative reward-prediction signal through the fasciculus retroflexus fiber bundles.

    “The lateral habenula provides SN/VTA dopamine neurons with a negative reward-prediction signal through the fasciculus retroflexus fiber bundles [[119]].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Matsumoto M Hikosaka O 2007 Lateral habenula as a source of negative reward signals in dopamine neurons Nature 447 1111 1115 17522629 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    LTP immediately produces a synapse-specific tag, and PRPs can only produce late LTP at tagged synapses.

    “Frey and Morris propose that this specificity occurs because LTP immediately produces a synapse-specific “tag” and that PRPs can only produce late LTP at tagged synapses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Frey U Morris RG 1997 Synaptic tagging and long-term potentiation [see comments] Nature 385 533 536 9020359

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The hippocampus integrates information about stimuli and their spatial location into a contextual representation and can compute various types of novel changes in these relationships.

    “The hippocampus, on the other hand, integrates information about stimuli and their spatial location into a contextual representation and can compute various types of novel changes in these relationships.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    fMRI studies confirm SN/VTA activation by associative novelty and stimulus novelty but less by other salient events such as rareness or negative emotional content.

    “Indeed, fMRI studies (for examples see Box 2 Figure 1) confirm SN/VTA activation by associative novelty [60] and stimulus novelty [61] but less by other salient events such as rareness or negative emotional content [61].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Schott BH 2004 Activation of midbrain structures by associative novelty and the formation of explicit memory in humans Learning & memory (Cold Spring Harbor, N Y 11 383 387 15254215

      Not checked in the free run.

    • cites [61] Bunzeck N Duzel E 2006 Absolute stimulus-novelty is coded by the human substantia nigra/VTA Neuron 3 369 379 16880131 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PET studies show that novelty-seeking traits are inversely associated with D2-like receptor availability in the SN/VTA region and positively correlated with white matter connectivity between the hippocampus and the ventral striatum.

    “positron emission tomography (PET) studies in humans show that novelty-seeking traits are inversely associated with D2-like receptor availability in the SN/VTA region [62] and are positively correlated with white matter connectivity between the hippocampus and the ventral striatum [63].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Zald DH 2008 Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans J Neurosci 28 14372 14378 19118170 PMC2748420

      Not checked in the free run.

    • cites [63] Cohen MX 2009 Connectivity-based segregation of the human striatum predicts personality characteristics Nature neuroscience 12 32 34 19029888

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    From the neoHebbian framework, the earlier negative result is understandable; SN/VTA activity-related enhancement of memory would be more apparent if testing is conducted after long retention intervals.

    “From the perspective of the neoHebbian framework, this negative result is understandable; i.e., the SN/VTA activity-related enhancement of memory would be more apparent if testing is conducted after long retention intervals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the perirhinal cortex, stimulus-related incoming information can be compared to stored information and a stimulus-related novelty signal is computed.

    “In the perirhinal cortex, for instance, stimulus-related incoming information can be compared to stored information and a stimulus-related novelty signal is computed [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Xiang JZ Brown MW 1998 Differential neuronal encoding of novelty, familiarity and recency in regions of the anterior temporal lobe Neuropharmacology 37 657 676 9705004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The human SN/VTA is also activated by cues that predict novel images, or by unexpected novel images that followed familiarity-predictive cues.

    “The human SN/VTA is also activated by cues that predict novel images, or by unexpected novel images that followed familiarity-predictive cues (ie. an ‘unexpected novelty’ response) [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Wittmann BC 2007 Anticipation of novelty recruits reward system and hippocampus while promoting recollection Neuroimage 38 194 202 17764976 PMC2706325

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Other properties of LTP (weak/strong; penumbra) appear also to have predictive power in explaining properties of memory.

    “Moreover, other properties of LTP (weak/strong; penumbra) appear also to have predictive power in explaining properties of memory.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In schizophrenia, enhanced activation of the hippocampal system may increase dopamine release and skew behavioral choice towards repetitive behavior.

    “In schizophrenia, the enhanced activation of the hippocampal system may increase dopamine release and skew behavioral choice towards repetitive behavior (see Box 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Box 3

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The drug-induced memory impairment is not due to an effect of dopamine on encoding, as shown by rescue of long-term memory if there is a preceding exposure to a novel environment.

    “That this drug-induced memory impairment is not due to an effect of dopamine on encoding is nicely demonstrated by the rescue of long-term memory if there is a preceding exposure to a novel environment [72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Wang SH 2010 Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory Proceedings of the National Academy of Sciences of the United States of America 107 19537 19542 20962282 PMC2984182

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parkinson's disease usually begins with loss of nigrostriatal dopamine cells in the ventral tier SNc, leaving dorsal tier projection neurons to hippocampus, ventral striatum, and cortex intact.

    “Parkinson’s disease (PD) usually begins with loss of nigrostriatal dopamine cells in the ventral tier SNc, leaving the dorsal tier projection neurons to the hippocampus, ventral striatum, and cortex intact [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Fearnley JM Lees AJ 1991 Ageing and Parkinson’s disease: substantia nigra regional selectivity Brain 114 Pt 5 2283 2301 1933245 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-term retention is not helped by simple re-exposure to recently learned material but is greatly helped by retesting even when subjects already know the answer.

    “long-term retention is not helped by simple re-exposure to recently learned material but is greatly helped by retesting even when subjects already know the answer [83].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Karpicke JD Roediger HL 3rd 2008 The critical importance of retrieval for learning Science (New York, N Y 319 966 968 18276894 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single exposure to the location of a small reward is rapidly forgotten in rodents within a few hours, but persists for at least 24 hours if preceded or followed within 30 minutes by novelty exploration.

    “a single exposure to the location of a small reward is rapidly forgotten in rodents within a few hours, but persists for at least 24 hours if it is preceded or followed (within 30 minutes) by novelty exploration [72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Wang SH 2010 Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory Proceedings of the National Academy of Sciences of the United States of America 107 19537 19542 20962282 PMC2984182

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both the tag and PRPs have considerable lifetimes.

    “It appears that both the tag and the PRPs have considerable lifetimes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Stimulation of protein synthesis and induction of Hebbian plasticity do not need to be coincident; the trigger for protein synthesis can occur before or after Hebbian plasticity with intervening periods of many minutes.

    “stimulation of protein synthesis and the induction of Hebbian plasticity do not need to be coincident; indeed, the trigger for protein synthesis can occur either before or after Hebbian plasticity (with intervening periods of many minutes).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    LTP at short times is relatively insensitive to dopamine, whereas LTP with longer delays is sensitive.

    “A key insight to emerge from physiological experiments is that LTP at short times is relatively insensitive to dopamine, whereas LTP with longer delays is sensitive.”
    Quote in the paperSubstantial claim
58 of 58

  • The paper relies on this without support.

    There is relatively little work comparing the consolidation of rewarding and aversive events in humans.

    “Surprisingly, there is relatively little work comparing the consolidation of rewarding and aversive events (e.g. losses) in humans (although there is extensive work on the consolidation of emotionally negative stimuli).”

  • The paper relies on this without support.

    The conditions that lead to activation of the human dopamine system, as judged by fMRI signals, are similar to the conditions leading to activation in non-primate mammals.

    “The conditions that lead to activation of the human dopamine system, as judged by fMRI signals, are similar to the conditions leading to activation in non-primate mammals.”
2 of 2

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?

Cites

Flagged first, then by citations

1 of the 146 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Watson, J.S., trans. and ed. (1986) Cicero on Oratory and Orators (Landmarks in Rhetoric and Public Address), Southern Illinois University Press

Cited by

Sorted by citations

Related

Authors
Lisman, J., Grace, A. A., & Duzel, E.
Affiliations
  • Brandeis University (US)
  • University of Pittsburgh (US)
Corresponding author
Lisman, John
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2011-10
Volume
34
Issue
10
Pages
536-547
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2011.07.006
PMC
PMC3183413
OpenAlex
W2060322330
Semantic Scholar
2d3befef55d10b6b1538c81c9214e8c2a0fd75fc
Cited by
465
References
146
Citations by year
2026: 27 · 2025: 25 · 2024: 39 · 2023: 29 · 2022: 36 · 2021: 31 · 2020: 31 · 2019: 33 · 2018: 36 · 2017: 30 · 2016: 41 · 2015: 32 · 2014: 22 · 2013: 29 · 2012: 22
FWCI
1.96
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)
  • UCL Discovery (University College London) (submittedVersion)
  • DZNE Pub (submittedVersion, other-oa)
Funders
  • National Institutes of Health (2r01mh057440-26a1)
  • National Institute of Mental Health (MH-57440, R01-MH057440, R37MH057440)
  • National Institute on Drug Abuse (DA 15408, R01DA027807)
  • National Institute of Neurological Disorders and Stroke (R01NS027337)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
episodic memory, long-term potentiation, dopamine, hippocampal CA1, Hebbian rule, synaptic plasticity, reward, memory formation
MeSH terms
Animals, Dopamine, Neuronal Plasticity, Synapses, Long-Term Potentiation, Memory, Episodic

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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