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Cited by 328Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchMemory Processes and Influences

The right time to learn: Mechanisms and optimization of spaced learning

Open access
Smolen, Paul, Zhang, Yili, Byrne, John H.·2016·Nature Reviews Neuroscience
DOI 10.1038/nrn.2015.18PMC PMC5126970
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Abstract

For many types of learning, spaced training, which involves repeated long inter-trial intervals, leads to more robust memory formation than does massed training, which involves short or no intervals. Several cognitive theories have been proposed to explain this superiority, but only recently have data begun to delineate the underlying cellular and molecular mechanisms of spaced training, and we review these theories and data here. Computational models of the implicated signalling cascades have predicted that spaced training with irregular inter-trial intervals can enhance learning. This strategy of using models to predict optimal spaced training protocols, combined with pharmacotherapy, suggests novel ways to rescue impaired synaptic plasticity and learning.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes cognitive theories and molecular/cellular evidence for why spaced training produces stronger memory than massed training, emphasizing refractory/priming processes, kinase and transcription dynamics, and computational optimization. It argues that models of signaling cascades can predict irregular spaced protocols and drug combinations that enhance or rescue synaptic plasticity, though many mechanisms remain incompletely validated.

Key findings

  • Spaced training is superior to massed training across many forms of learning and species. In *Aplysia*, five spaced 5-HT pulses (5 minutes each, 20-minute inter-stimulus interval) robustly elicit long-term facilitation lasting more than 24 hours, whereas continuous 5-HT over 25 minutes fails; four spaced electrical stimuli with 30-minute intervals yield long-term sensitization lasting more than 24 hours, with weak residual sensitization at 4 days, and daily repetition for 4 days yields stronger sensitization lasting more than 1 week.
  • Hippocampal LTP studies show that theta-burst stimuli at 10- or 40-minute intervals did not cumulatively increase LTP, but intervals of 60 or 90 minutes did; a refractory period of ~60 minutes is associated with priming and spine remodeling, and integrin receptor replacement over ~40–60 minutes is hypothesized to underlie this refractory period.
  • Optimal intervals are system-specific: in *Aplysia*, maximal long-term sensitization occurred with a 45-minute inter-stimulus interval, not 15 or 60 minutes; in mice, 60-minute intervals enhanced object recognition learning and ERK1/2 signaling in wild-type and fragile X syndrome model mice, whereas 20- or 120-minute intervals did not.
  • A computational model simulated 10,000 protocols of five trials with intervals of 0–45 minutes; the predicted irregular “enhanced” protocol produced greater LTF and LTS than the standard 20-minute-interval protocol. Extended models predicted rescue protocols after CBP or CREB1 knockdown, and a drug-modeling study found no single-drug effect fully rescued LTP in a Rubinstein–Taybi syndrome model, but two paired-drug effects did, with additive synergism.

Methods

  • Narrative review, not a primary experimental study; it integrates traditional learning theories (encoding variability, study-phase retrieval, deficient-processing/consolidation) with molecular and cellular findings.
  • Evidence is drawn from cited studies across humans, *Aplysia*, *Drosophila*, bees, rodents, non-human primates, hippocampal slices, and cell cultures, plus computational models of PKA, ERK/MAPK, CREB/C/EBP, CBP, LTP, and LTF.
  • Main analysis is qualitative synthesis and discussion of model predictions and empirical validations; no systematic review or meta-analytic methods are stated.

Limitations

  • Stated: some aspects of the spacing effect cannot be explained by current models; future models are likely incomplete owing to gaps in knowledge and uncertainties in biochemical parameters such as enzyme activities or protein concentrations.
  • Stated: some proposed mechanisms lack empirical validation (for example, the dCREB2 isoform phosphorylation competition hypothesis); network-level data are needed to assess encoding variability and study-phase retrieval theories; few studies delineate both minimum and maximum effective intervals for a given system.
  • Evident: as a review, it presents no new primary data and does not report a systematic search or risk-of-bias assessment; suggestions about clinical and educational benefits are forward-looking.

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

Integrity signals

Registry

Crossref · 10.1038/nrn.2015.18

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 171 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Spaced training leads to improved memory in invertebrates such as Aplysia californica, Drosophila melanogaster and bees, and in rodents and non-human primates.

    “Spaced training also leads to improved memory in invertebrates, such as the mollusk Aplysia californica11–14, Drosophila melanogaster15,16 and bees17, and in rodents18,19 and non-human primates20,21.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [11] Philips, G. T., Kopec, A. M. & Carew, T. J. Pattern and predictability in memory formation: from molecular mechanisms to clinical relevance. Neurobiol. Learn. Mem. 105, 117–124 (2013). source

      Not checked in the free run.

    • cites [12] Philips, G. T., Ye, X., Kopec, A. M. & Carew, T. J. MAPK establishes a molecular context that defines effective training patterns for long-term memory formation. J. Neurosci. 33, 7565–7573 (2013). This work characterized the dynamics of MAPK and its activation of C/EBP, a transcription factor that is important for long-term memory formation, identifying the response of MAPK within a specific time window as essential for generating an optimal inter-trial interval. source

      Not checked in the free run.

    • cites [13] Wainwright, M. L., Zhang, H., Byrne, J. H. & Cleary, L. J. Localized neuronal outgrowth induced by long-term sensitization training in Aplysia. J. Neurosci. 22, 4132–4141 (2002). source

      Not checked in the free run.

    • cites [14] Mauelshagen, J., Sherff, C. M. & Carew, T. J. Differential induction of long-term synaptic facilitation by spaced and massed applications of serotonin at sensory neuron synapses of Aplysia californica. Learn. Mem. 5, 246–256 (1998). source

      Not checked in the free run.

    • cites [15] Beck, C. D., Schroeder, B. & Davis, R. L. Learning performance of normal and mutant Drosophila after repeated conditioning trials with discrete stimuli. J. Neurosci. 20, 2944–2953 (2000). source

      Not checked in the free run.

    • cites [16] Pagani, M. R., Oishi, K., Gelb, B. D. & Zhong, Y. The phosphatase SHP2 regulates the spacing effect for long-term memory induction. Cell 139, 186–198 (2009). source

      Not checked in the free run.

    • cites [17] Menzel, R., Manz, G., Menzel, R. & Greggers, U. Massed and spaced learning in honeybees: the role of CS, US, the intertrial interval, and the test interval. Learn. Mem. 8, 198–208 (2001). source

      Not checked in the free run.

  • Premisecitation

    In rat fear conditioning, spaced extinction trials are more effective than massed trials at establishing new memories.

    “in rat fear conditioning spaced extinction trials are more effective than massed trials at establishing new memories22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Urcelay, G. P., Wheeler, D. S. & Miller, R. R. Spacing extinction trials alleviates renewal and spontaneous recovery. Learn. Behav. 37, 60–73 (2009). source

      Not checked in the free run.

  • Premisecitation

    Spaced training, which involves repeated long inter-trial intervals, leads to more robust memory formation than massed training, which involves short or no intervals, for many types of learning.

    “For many types of learning, spaced training, which involves repeated long inter-trial intervals, leads to more robust memory formation than does massed training, which involves short or no intervals.”
    • Also stated in: § Abstract · boosted
      “Such training has been known since the seminal work of Ebbinghaus to be superior to training that includes short inter-trial intervals (massed training or massed learning) in terms of its ability to promote memory formation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites REF. 1

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  • Premisecitation

    Subsequent spaced trains of theta-burst stimuli, with intervals of 60 minutes or more between trains, were needed for optimal reinforcement of LTP in rat hippocampal slices.

    “subsequent spaced trains of theta-burst stimuli, with intervals of 60 minutes or more between the trains, were needed for optimal reinforcement of LTP46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Cao, G. & Harris, K. M. Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice. J. Neurophysiol. 112, 1916–1924 (2014). source

      Not checked in the free run.

  • Interpretationreasoning

    In massed training, trials would come too close together to initiate separate rounds of transcription.

    “In massed training, the trials would come too close together to initiate separate rounds of transcription.”
    Quote in the paperSubstantial claim
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Premisecitation

    Spaced learning is more effective than massed learning for facts, concepts and lists, skill and motor learning, classroom education including science and vocabulary learning, and generalization of conceptual knowledge in children.

    “For example, spaced learning is more effective than massed learning for facts, concepts and lists2–4, skill learning and motor learning5,6, in classroom education (including science learning and vocabulary learning)7–9, and in generalization of conceptual knowledge in children10.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [2] Cepeda, N. J., Pashler, H., Vul, E., Wixted, J. T. & Rohrer, D. Distributed practice in verbal recall tasks: a review and quantitative synthesis. Psychol. Bull. 132, 354–380 (2006). This extensive review and meta-analysis delineates the comprehensive body of knowledge describing human spaced and massed verbal learning, as well as theories posited to explain the superiority of spaced training over massed training in terms of inducing long-term memory formation. source

      Not checked in the free run.

    • cites [3] Godbole, N. R., Delaney, P. F. & Verkoeijen, P. P. The spacing effect in immediate and delayed free recall. Memory 22, 462–469 (2014). source

      Not checked in the free run.

    • cites [4] Raman, M. et al. Teaching in small portions dispersed over time enhances long-term knowledge retention. Med. Teach. 32, 250–255 (2010). source

      Not checked in the free run.

    • cites [5] Donovan, J. J. & Radosevich, D. J. A meta-analytic review of the distribution of practice effect. J. Appl. Psychol. 84, 795–805 (1999). source

      Not checked in the free run.

    • cites [6] Shea, C. H., Lai, Q., Black, C. & Park, J. H. Spacing practice sessions across days benefits the learning of motor skills. Hum. Mov. Sci. 19, 737–760 (2000). source

      Not checked in the free run.

    • cites [7] Gluckman, M., Vlach, H. A. & Sandhofer, C. M. Spacing simultaneously promotes multiple forms of learning in children's science curriculum. Appl. Cognit. Psychol. 28, 266–273 (2014). source

      Not checked in the free run.

    • cites [8] McDaniel, M. A. & Callender, A. A. in Learning and Memory: A Comprehensive Reference Vol. 2 (ed. Roediger, H. L.) 819–844 (Academic Press, 2008). source

      Not checked in the free run.

    • cites [9] Sobel, H. S., Cepeda, N. J. & Kapler, I. V. Spacing effects in real-world classroom vocabulary learning. Appl. Cognit. Psychol. 25, 763–767 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Learning is implemented, at least in part, by changes in synaptic strength (synaptic plasticity).

    “There is now agreement that learning is implemented, at least in part, by changes in synaptic strength (synaptic plasticity).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Nabavi, S. et al. Engineering a memory with LTD and LTP. Nature 511, 348–352 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The first theta-burst stimulus initiates priming at all synaptic contacts of the stimulated afferents but only initiates consolidation and strengthening at a subset of contacts.

    “Instead, they suggest that the first theta-burst stimulus initiates priming at all synaptic contacts of the stimulated afferents but only initiates consolidation and strengthening at a subset of contacts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LTP that persists for several hours or more requires translation and transcription, which is reliant on transcription factors such as CREB.

    “LTP that persists for several hours or more requires translation and transcription50,51, which is reliant on key transcription factors such as cyclic AMP-responsive element (CRE)-binding protein (CREB)52.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] Nguyen, P. V., Abel, T. & Kandel, E. R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107 (1994). source

      Not checked in the free run.

    • cites [51] Scharf, M. T. et al. Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training. J. Neurophysiol. 87, 2770–2777 (2002). source

      Not checked in the free run.

    • cites [52] Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1249–1254 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Each theta-burst stimulus led to actin filament polymerization in spines, which is important for stabilization of LTP.

    “Each theta-burst stimulus led to actin filament polymerization in spines, which is known to be important for the stabilization of LTP49.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Rex, C. S. et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol. 186, 85–97 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Spines that undergo priming but not consolidation exhibit a refractory period of about 60 minutes, suggesting that priming takes time to complete.

    “Spines that undergo priming but not consolidation exhibit a refractory period of ~60 minutes, suggesting that priming takes time to complete (FIG. 2a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Drosophila melanogaster olfactory learning, each spaced training trial generated a distinct wave of MAPK activity, whereas massed training trials were too close together to generate distinct waves.

    “In an olfactory learning protocol, each spaced training trial generated a distinct wave of MAPK activity, whereas massed training trials were too close together to generate distinct waves.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Pagani, M. R., Oishi, K., Gelb, B. D. & Zhong, Y. The phosphatase SHP2 regulates the spacing effect for long-term memory induction. Cell 139, 186–198 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Computational simulations have supported the plausibility of a mechanism based on differential phosphorylation of dCREB2 isoforms, but it has not been validated empirically.

    “Computational simulations have supported the plausibility of this mechanism65, but it has not been validated empirically.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Smolen, P., Baxter, D. A. & Byrne, J. H. Frequency selectivity, multistability, and oscillations emerge from models of genetic regulatory systems. Am. J. Physiol. 274, C531–C542 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Protein phosphatase 1 (PP1) appeared necessary for this spacing effect, because PP1 inhibition allowed the shorter interval to activate CREB.

    “Protein phosphatase 1 (PP1) appeared to be necessary for this spacing effect, because PP1 inhibition allowed the shorter interval to activate CREB.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Genoux, D. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–974 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Following either a single 5-HT pulse or a single electric shock, MAPK activation peaked at or near 45 minutes post-trial; thus, a 45-minute interval might optimally reinforce the effects of MAPK.

    “Following either a single 5-HT pulse or a single electric shock, MAPK activation peaked at or near 45 minutes post-trial12,66; thus, a 45-minute interval might optimally reinforce the effects of MAPK.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Philips, G. T., Ye, X., Kopec, A. M. & Carew, T. J. MAPK establishes a molecular context that defines effective training patterns for long-term memory formation. J. Neurosci. 33, 7565–7573 (2013). This work characterized the dynamics of MAPK and its activation of C/EBP, a transcription factor that is important for long-term memory formation, identifying the response of MAPK within a specific time window as essential for generating an optimal inter-trial interval. source

      Not checked in the free run.

    • cites [66] Philips, G. T., Tzvetkova, E. I. & Carew, T. J. Transient mitogen-activated protein kinase activation is confined to a narrow temporal window required for the induction of two-trial long term memory in Aplysia. J. Neurosci. 27, 13701–13705 (2007). source

      Not checked in the free run.

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

    Premisecitation

    Two isoforms of Drosophila melanogaster CREB - dCREB2-a and dCREB2-r - can activate and repress transcription, respectively.

    “Two isoforms of D. melanogaster CREB — dCREB2-a and dCREB2-r — can activate and repress transcription, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Yin, J. C., Del Vecchio, M., Zhou, H. & Tully, T. CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81, 107–115 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Aplysia californica, when two electric shocks were given to induce LTS, maximal LTS was produced when the inter-stimulus interval was 45 minutes; LTS was not produced with intervals of 15 or 60 minutes.

    “In experiments with A. californica, when two electric shocks were given to induce LTS, maximal LTS was produced when the inter-stimulus interval was 45 minutes. LTS was not produced with intervals of 15 or 60 minutes66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Philips, G. T., Tzvetkova, E. I. & Carew, T. J. Transient mitogen-activated protein kinase activation is confined to a narrow temporal window required for the induction of two-trial long term memory in Aplysia. J. Neurosci. 27, 13701–13705 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo, four spaced electrical stimuli with 30-minute intervals yielded LTS lasting more than 24 hours, with weak residual LTS detectable at 4 days, and repetition once per day for 4 days yielded much stronger LTS lasting more than 1 week.

    “In vivo, four spaced electrical stimuli (with 30 minutes intervals between the stimuli) yielded LTS that lasted for more than 24 hours, with weak residual LTS being detectable at 4 days post-training, and repetition of this spaced protocol once per day for 4 days yielded much stronger LTS that lasted for more than 1 week13,57,58.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Wainwright, M. L., Zhang, H., Byrne, J. H. & Cleary, L. J. Localized neuronal outgrowth induced by long-term sensitization training in Aplysia. J. Neurosci. 22, 4132–4141 (2002). source

      Not checked in the free run.

    • cites [57] Frost, W. N., Castellucci, V., Hawkins, R. D. & Kandel, E. R. Monosynaptic connections made by the sensory neurons of the gill- and siphon-withdrawal reflex in Aplysia participate in the storage of long-term memory for sensitization. Proc. Natl Acad. Sci. USA 82, 8266–8269 (1985). source

      Not checked in the free run.

    • cites [58] Pinsker, H. M., Hening, W. A., Carew, T. J. & Kandel, E. R. Long-term sensitization of a defensive withdrawal reflex in Aplysia. Science 182, 1039–1042 (1973). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, object recognition trials separated by 15 minutes produced marked phosphorylation and activation of CREB in the hippocampus and cortex, but trials separated by 5 minutes did not.

    “One study in mice61 found marked phosphorylation and activation of CREB in the hippocampus and the cortex when object recognition trials were separated by an interval of 15 minutes but not by an interval of 5 minutes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Genoux, D. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–974 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following inhibitory avoidance training in rats, late peaks in BDNF expression and C/EBP expression occur at about 12 hours post-training, and inhibiting BDNF action at this time blocks memory maintenance.

    “Following inhibitory avoidance training in rats, late peaks in brain-derived neurotrophic factor (BDNF) expression and in C/EBP expression occur at ~12 hours post-training, and inhibiting BDNF action at this time blocks memory maintenance59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Beckinschtein, P. et al. Persistence of long-term memory storage requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Neuron 53, 261–277 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PKC acts to downregulate PKA, and PKA activation is necessary for LTF; thus LTF is suppressed, in part, by stronger PKC activation during massed training.

    “It is known that PKC acts to downregulate protein kinase A (PKA) and that PKA activation is necessary for LTF; thus, these data delineate crosstalk between signalling pathways such that LTF is suppressed, in part, by stronger PKC activation during massed training.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a hippocampal slice preparation, 5-10-minute intervals between tetani were ideal for induction of LTP, and they produced similar levels of LTP, with longer or shorter intervals yielding both less LTP and less ERK1/2 activation.

    “One study80 found that in a hippocampal slice preparation, 5–10-minute intervals between tetani were ideal for induction of LTP, and they produced similar levels of LTP, with longer or shorter intervals yielding both less LTP and less ERK1/2 activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Ajay, S. M. & Bhalla, U. S. A role for ERKII in synaptic pattern selectivity on the time scale of minutes. Eur. J. Neurosci. 20, 2671–2680 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Training with intervals of 60 minutes, but not 20 or 120 minutes, enhanced object recognition learning in wild-type mice and in Fmr1-knockout mice, at least partly by increasing synaptic activation of ERK1 and ERK2.

    “Similarly, training with intervals of 60 minutes, but not 20 or 120 minutes, enhanced object recognition learning in wild-type mice and in a mouse model of fragile X syndrome (fragile X mental retardation 1 (Fmr1)-knockout mice), at least partly by increasing synaptic activation of extracellular signal-regulated kinase 1 (ERK1; also known as MAPK3) and ERK2 (also known as MAPK1)67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Seese, R. R., Wang, K., Yao, Y. Q., Lynch, G. & Gall, C. M. Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice. Proc. Natl Acad. Sci. USA 111, 16907–16912 (2014). source

      Not checked in the free run.

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

    Interpretationreasoning

    In that protocol, the rate-limiting process would be plausibly slower activation of an unspecified kinase or other intracellular signalling event, with a time constant near the minimum effective interval of about 40 minutes.

    “Here, the rate-limiting process would be different — plausibly slower activation of an unspecified kinase or other intracellular signalling event, with a time constant near the minimum effective interval of ~40 minutes.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Such brief intervals might allow for reinforcement of the activity of a short-lived second messenger such as cAMP that is produced by preceding trials.

    “Such brief intervals might allow for the reinforcement of the activity of a short-lived second messenger such as cAMP that is produced by preceding trials.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    For rapid honeybee olfactory learning with an effective interval of 1 minute, the rate-limiting process might be second messenger accumulation or rapid activation of a kinase.

    “For example, for rapid honeybee olfactory learning with an effective interval of 1 minute, the rate-limiting process might be second messenger accumulation or rapid activation of a kinase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    It is hypothesized that subsequent theta-burst stimuli at these synaptic contacts cannot induce spine enlargement or LTP until after this replacement has occurred, thus accounting for the refractory period of about 1 hour.

    “it is hypothesized82 that subsequent theta-burst stimuli at these synaptic contacts cannot induce spine enlargement or LTP until after this replacement has occurred, thus accounting for the refractory period of ~1 hour in order for a second theta-burst stimulus to yield additional LTP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Babayan, A. H. et al. Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. J. Neurosci. 32, 12854–12861 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Priming allows these spines to potentiate after the second stimulus, and thus constitutes a biochemical stimulus trace.

    “Priming allows these spines to potentiate after the second stimulus, and thus constitutes a biochemical stimulus trace (FIGS 1d,2a).”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    These hypothesized dynamics may be in line with deficient-processing theory, with receptor replacement being the necessary process that can only occur during spaced inter-trial intervals.

    “These hypothesized dynamics may be in line with deficient-processing theory, with receptor replacement being the necessary process that can only occur during spaced inter-trial intervals (FIG. 3).”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    For intervals longer than the maximum effective interval, the individual biochemical traces would decay and not overlap.

    “For intervals longer than the maximum, the individual biochemical traces would decay and not overlap.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: For maximum intervals, each trial or stimulus generates a separate, relatively short-lived biochemical trace, and for effective spaced learning these traces must overlap and summate, with the summed magnitude driving long-lasting synaptic potentiation.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Different theories may be more or less applicable to different memory systems.

    “Indeed, different theories may be more or less applicable to different memory systems.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    These variants have also been argued not to readily accommodate certain verbal learning observations.

    “These variants have also been argued not to readily accommodate certain verbal learning observations2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Cepeda, N. J., Pashler, H., Vul, E., Wixted, J. T. & Rohrer, D. Distributed practice in verbal recall tasks: a review and quantitative synthesis. Psychol. Bull. 132, 354–380 (2006). This extensive review and meta-analysis delineates the comprehensive body of knowledge describing human spaced and massed verbal learning, as well as theories posited to explain the superiority of spaced training over massed training in terms of inducing long-term memory formation. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    It seems plausible that repeated memory reactivations might induce further rounds of transcription of genes involved in LTP, such as C/ebp and other CREB-activated genes, supporting further consolidation of long-term memory.

    “It also seems plausible that repeated memory reactivations might induce further rounds of transcription of genes involved in LTP, such as C/ebp and other CREB-activated genes, supporting further consolidation of long-term memory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    For almost all learning paradigms, the training intervals are fixed, although in one type of spaced training paradigm, the intervals between sessions progressively lengthen.

    “For almost all learning paradigms, the training intervals are fixed, although in one type of spaced training paradigm, the intervals between sessions progressively lengthen2,84.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Cepeda, N. J., Pashler, H., Vul, E., Wixted, J. T. & Rohrer, D. Distributed practice in verbal recall tasks: a review and quantitative synthesis. Psychol. Bull. 132, 354–380 (2006). This extensive review and meta-analysis delineates the comprehensive body of knowledge describing human spaced and massed verbal learning, as well as theories posited to explain the superiority of spaced training over massed training in terms of inducing long-term memory formation. source

      Not checked in the free run.

    • cites [84] Karpicke, J. D. & Roediger, H. L. Is expanding retrieval a superior method for learning text materials? Mem. Cognit. 38, 116–124 (2010). source

      Not checked in the free run.

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

    Interpretationreasoning

    Subsequent trials delivered at times that coincide with kinase activity peaks might optimally reinforce learning.

    “For example, subsequent trials that are delivered at times that coincide with kinase activity peaks might optimally reinforce learning.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    The standard protocol yielded an intermediate peak value of inducer and was predicted to have an intermediate effectiveness.

    “This standard protocol yielded an intermediate peak value of inducer and was predicted to have an intermediate effectiveness (FIG. 4c).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Zhang, Y. et al. Computational design of enhanced learning protocols. Nat. Neurosci. 15, 294–297 (2012). This study found that computational models describing long-term synaptic strengthening can successfully predict optimal spaced training protocols, with irregular inter-trial intervals, that enhance learning. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Models of biochemical cascades that underlie memory formation can be used in simulations to rapidly test the effectiveness of different training protocols.

    “One approach is to develop models of the biochemical cascades that underlie memory formation and use simulations to rapidly test the effectiveness of different training protocols85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Zhang, Y. et al. Computational design of enhanced learning protocols. Nat. Neurosci. 15, 294–297 (2012). This study found that computational models describing long-term synaptic strengthening can successfully predict optimal spaced training protocols, with irregular inter-trial intervals, that enhance learning. source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In response to each 5-HT pulse, PKA activity increases rapidly and decays rapidly.

    “In response to each 5-HT pulse, PKA activity increases rapidly and decays rapidly (FIG. 4c).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Philips, G. T., Kopec, A. M. & Carew, T. J. Pattern and predictability in memory formation: from molecular mechanisms to clinical relevance. Neurobiol. Learn. Mem. 105, 117–124 (2013). source

      Not checked in the free run.

    • cites [12] Philips, G. T., Ye, X., Kopec, A. M. & Carew, T. J. MAPK establishes a molecular context that defines effective training patterns for long-term memory formation. J. Neurosci. 33, 7565–7573 (2013). This work characterized the dynamics of MAPK and its activation of C/EBP, a transcription factor that is important for long-term memory formation, identifying the response of MAPK within a specific time window as essential for generating an optimal inter-trial interval. source

      Not checked in the free run.

    • cites [92] Müller, U. & Carew, T. J. Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21, 1423–1434 (1998). source

      Not checked in the free run.

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

    Premisecitation

    The 'standard' protocol (five 5-minute pulses of 5-HT, with uniform inter-stimulus intervals of 20 minutes) has been commonly used to induce LTF in empirical studies for ~30 years.

    “The protocol termed the ‘standard’ protocol (five 5-minute pulses of 5-HT, with uniform inter-stimulus intervals of 20 minutes) (FIG. 4b) has been commonly used to induce LTF in empirical studies for ~30 years91.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Montarolo, P. G. et al. A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science 234, 1249–1254 (1986). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Each signalling cascade in these models displays a characteristic activity time course; thus, some irregular sequence of intervals would be predicted to maximize the induction of LTP.

    “Each signalling cascade in these models displays a characteristic activity time course; thus, it is likely some irregular sequence of intervals would be predicted to maximize the induction of LTP.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent study took a first step by modelling LTP induction and transcriptional regulation by CREB, and simulating the effects of drugs on LTP by altering the parameters of the model.

    “A recent study104 took a first step by modelling LTP induction and transcriptional regulation by CREB, and simulating the effects of drugs on LTP by altering the parameters of the model.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Smolen, P., Baxter, D. A. & Byrne, J. H. Simulations suggest pharmacological methods for rescuing long-term potentiation. J. Theor. Biol. 360, 243–250 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cbp+/− mice show impaired LTP and long-term memory.

    “Cbp+/− mice show impaired LTP and long-term memory95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MAPK activity rises and decays more slowly, not peaking until ~45 minutes after a pulse.

    “MAPK activity rises and decays more slowly, not peaking until ~45 minutes after a pulse.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Philips, G. T., Kopec, A. M. & Carew, T. J. Pattern and predictability in memory formation: from molecular mechanisms to clinical relevance. Neurobiol. Learn. Mem. 105, 117–124 (2013). source

      Not checked in the free run.

    • cites [12] Philips, G. T., Ye, X., Kopec, A. M. & Carew, T. J. MAPK establishes a molecular context that defines effective training patterns for long-term memory formation. J. Neurosci. 33, 7565–7573 (2013). This work characterized the dynamics of MAPK and its activation of C/EBP, a transcription factor that is important for long-term memory formation, identifying the response of MAPK within a specific time window as essential for generating an optimal inter-trial interval. source

      Not checked in the free run.

    • cites [92] Müller, U. & Carew, T. J. Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21, 1423–1434 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The last pulse activates PKA, so that a PKA peak is approximately coincident with peak MAPK activation, maximizing inducer and the predicted LTF.

    “This last pulse activates PKA, so that a PKA peak is approximately coincident with peak MAPK activation, maximizing inducer and the predicted LTF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mutations that decrease CBP activity cause Rubinstein-Taybi syndrome (RTS), which is associated with intellectual disability and learning deficits.

    “Mutations that decrease CBP activity cause a human genetic disorder termed Rubinstein–Taybi syndrome (RTS)94, which is associated with intellectual disability and learning deficits”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Park, E. et al. Epigenetic mechanisms of Rubinstein–Taybi syndrome. Neuromolecular Med. 16, 16–24 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    LTP impairment seen in a mouse model of RTS was first simulated.

    “LTP impairment seen in a mouse model of RTS95 was first simulated.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004). source

      Not checked in the free run.

    • cites [104] Smolen, P., Baxter, D. A. & Byrne, J. H. Simulations suggest pharmacological methods for rescuing long-term potentiation. J. Theor. Biol. 360, 243–250 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These manipulations lack the cellular precision that is necessary to demonstrate conclusively that reactivation of a particular assembly of neurons is essential for the persistence of long-term memory.

    “Although encouraging, these manipulations lack the cellular precision that is necessary to demonstrate conclusively that reactivation of a particular assembly of neurons is essential for the persistence of long-term memory.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Similar blocking effects were obtained by the indiscriminate activation of neurons that overexpressed CREB.

    “Similar blocking effects were obtained by the indiscriminate activation of neurons that overexpressed CREB.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Hsiang, H. L. et al. Manipulating a “cocaine engram” in mice. J. Neurosci. 34, 14115–14127 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Enhancing normal learning by judicious pharmacotherapy has recently received attention.

    “Indeed, enhancing normal learning by judicious pharmacotherapy has recently received attention111”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Lynch, G., Cox, C. D. & Gall, C. M. Pharmacological enhancement of memory or cognition in normal subjects. Front. Syst. Neurosci. 8, 90 (2014). source

      Not checked in the free run.

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

    Premisecitation

    The second pair corresponded to a PDE inhibitor paired with a deacetylase inhibitor.

    “The second pair corresponded to a PDE inhibitor paired with a deacetylase inhibitor.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Smolen, P., Baxter, D. A. & Byrne, J. H. Simulations suggest pharmacological methods for rescuing long-term potentiation. J. Theor. Biol. 360, 243–250 (2014). source

      Not checked in the free run.

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

    Interpretationreasoning

    For the temporal range of minutes versus hours, it is plausible that a longer trace lifetime corresponds, at least in part, to increased activation of transcription by the longer training intervals.

    “For the temporal range of minutes versus hours, it is plausible that a longer trace lifetime corresponds, at least in part, to increased activation of transcription by the longer training intervals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    This explanation may not suffice when comparing training intervals of ~1 day versus many days.

    “However, this explanation may not suffice when comparing training intervals of ~1 day versus many days.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In model development, data from several preparation types and species commonly need to be used to estimate different parameters.

    “In model development, data from several preparation types (for example, cell cultures and slices) and species (for example, primates and rodents) commonly need to be used to estimate different parameters86,88.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999). source

      Not checked in the free run.

    • cites [88] Smolen, P., Baxter, D. A. & Byrne, J. H. A model of the roles of essential kinases in the induction and expression of late long-term potentiation. Biophys. J. 90, 2760–2775 (2006). source

      Not checked in the free run.

48 of 48

  • The authors state this as an assumption.

    In Landauer's model, the state of a neural circuit following the first learning trial is such that a second reinforcing trial soon after will not markedly increase the consolidation of the learning trace resulting from the first trial.

    “First, the state of a neural circuit following the first learning trial is such that a second reinforcing trial soon after will not markedly increase the consolidation of the learning trace resulting from the first trial (FIG. 1a).”

  • The authors state this as an assumption.

    In Landauer's model, the probability that the second trial can successfully reinforce the first trial declines with time.

    “The second assumption is that the probability that the second trial can successfully reinforce the first trial declines with time (FIG. 1e).”

  • The authors state this as an assumption.

    For maximum intervals, each trial or stimulus generates a separate, relatively short-lived biochemical trace, and for effective spaced learning these traces must overlap and summate, with the summed magnitude driving long-lasting synaptic potentiation.

    “For maximum intervals, a reasonable qualitative assumption is that each trial or stimulus generates a separate, relatively short-lived biochemical trace and that, for effective spaced learning, these traces must overlap and summate, with the summed magnitude driving long-lasting synaptic potentiation.”

  • The authors state this as an assumption.

    Reactivations of a memory reactivate some of the same neurons and synapses that were activated in the original learning sessions.

    “To more strongly connect this variant of deficient-processing theory to recent cellular and molecular data, one must also assume that reactivations of a memory reactivate some of the same neurons and synapses that were activated in the original learning sessions.”

  • The authors state this as an assumption.

    The necessity of PKA and ERK activation for LTF can be represented by a variable 'inducer' whose value is proportional to the product of PKA and MAPK activities.

    “In the model (FIG. 4a), the necessity of PKA and ERK activation for LTF was simply represented with a variable termed ‘inducer’. The value of inducer was proportional to the product of PKA and MAPK activities.”

  • The authors state this as an assumption.

    The amount of LTF and LTS increases with an increase in the peak value of inducer.

    “The amount of LTF and LTS was predicted to increase with an increase in the peak value of inducer.”

  • The authors state this as an assumption.

    Greater peak levels of phosphorylated C/EBP (pC/EBP) predict greater LTF.

    “In simulations of the effects of different spaced protocols, greater peak levels of phosphorylated C/EBP (pC/EBP) were taken to predict greater LTF.”

  • The authors state this as an assumption.

    The magnitude of LTP induction can be represented by an increase in a synaptic weight variable.

    “In this model, the magnitude of LTP induction was represented by an increase in a synaptic weight variable.”

  • The authors state this as an assumption.

    Parameter changes in the model correspond to plausible single-drug effects.

    “Then, starting from this simulation, the parameters were altered in ways corresponding to plausible single-drug effects.”

  • The authors state this as an assumption.

    Parameter changes in the model correspond to plausible paired-drug effects.

    “Thus, pairs of parameter changes were considered, corresponding to plausible paired-drug effects.”

  • The paper relies on this without support.

    CBP is an acetyltransferase and essential co-activator for several transcription factors, including pCREB.

    “CREB-binding protein (CBP) is an acetyltransferase and essential co-activator for several transcription factors, including phosphorylated CREB (pCREB).”
11 of 11

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?

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • A 40-minute interval is described as both ineffective and approximately the minimum effective interval

    Minor

    The paper reports that theta-burst stimuli at 40-minute intervals did not cumulatively increase LTP, but later describes approximately 40 minutes as the minimum effective interval for the same spaced-LTP protocol.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hintzman, D. L. in Theories in Cognitive Psychology: The Loyola Symposium (ed. Solso, R. L.) 77–90 (Erlbaum, 1974).

Cited by

Sorted by citations

Related

Authors
Smolen, P., Zhang, Y., & Byrne, J. H.
Corresponding author
Byrne, John H.
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2016-01-25
Volume
17
Issue
2
Pages
77-88
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/nrn.2015.18
PMC
PMC5126970
OpenAlex
W2263535855
Semantic Scholar
404e422d84d8c64e750bca5ce6d0eadc4d000953
Cited by
326
References
110
Citations by year
2026: 32 · 2025: 52 · 2024: 51 · 2023: 39 · 2022: 36 · 2021: 32 · 2020: 29 · 2019: 15 · 2018: 13 · 2017: 22 · 2016: 5
FWCI
1.94
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • arXiv (Cornell University) (submittedVersion)
  • arXiv (Cornell University)
Funders
National Institute of Neurological Disorders and Stroke (NS073974, NS019895, R01NS019895, R01NS073974, R37NS019895)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
Keywords
spaced learning, massed training, intertrial interval, memory formation, synaptic plasticity, learning theory, signaling pathways, computational models of learning
MeSH terms
Animals, Computer Simulation, Humans, Learning, Models, Biological, Neuronal Plasticity, Time Factors, Signal Transduction, Memory, Long-Term

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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.

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