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Cited by 80Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurobiology and Insect Physiology Research

Computational design of enhanced learning protocols

Open access
Zhang, Yili, Liu, Rong-Yu, Heberton, George A, Smolen, Paul, Baxter, Douglas A, Cleary, Leonard J, Byrne, John H·2012·Nature Neuroscience
DOI 10.1038/nn.2990PMC PMC3267874
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Abstract

Learning and memory are influenced by the temporal pattern of training stimuli. However, the mechanisms that determine the effectiveness of a particular training protocol are not well understood. We tested the hypothesis that the efficacy of a protocol is determined in part by interactions among biochemical cascades that underlie learning and memory. Previous findings suggest that the protein kinase A (PKA) and extracellular signal–regulated kinase (ERK) cascades are necessary to induce long-term synaptic facilitation (LTF) in Aplysia, a neuronal correlate of memory. We developed a computational model of the PKA and ERK cascades and used it to identify a training protocol that maximized PKA and ERK interactions. In vitro studies confirmed that the protocol enhanced LTF. Moreover, the protocol enhanced the levels of phosphorylation of the transcription factor CREB1. Behavioral training confirmed that long-term memory also was enhanced by the protocol. These results illustrate the feasibility of using computational models to design training protocols that improve memory.

AI snapshot

Written from the paper’s full text.

TL;DR

A computational model of PKA/ERK interactions was used to design a non-uniform 5-HT training protocol that maximized their predicted overlap, and the protocol enhanced long-term synaptic facilitation, CREB1 phosphorylation, and long-term sensitization in Aplysia. The results support using models of biochemical cascades to design training protocols that improve memory.

Key findings

  • The model identified an “Enhanced” protocol with 5-min 5-HT pulses separated by ISIs of 10, 10, 5, and 30 min; its predicted peak inducer level was ~50% higher than the Standard protocol (five 5-min pulses, uniform 20-min ISIs).
  • In sensorimotor co-cultures, both protocols induced LTF 1 day after treatment versus vehicle controls (Standard: q2 = 4.49, n = 10, p < 0.003; Enhanced: q3 = 7.57, n = 11, p < 0.001), but only the Enhanced protocol persisted to day 5 (q2 = 3.41, n = 9, p < 0.02); Enhanced LTF was greater than Standard at all time points (day 1: q2 = 3.18, p < 0.03; day 2: q2 = 2.89, p < 0.05; day 5: q3 = 3.73, p < 0.03).
  • The Enhanced protocol produced higher CREB1 phosphorylation than the Standard protocol immediately (q2 = 6.94, n = 4, p < 0.001) and 18 h after treatment (q2 = 3.69, n = 7, p < 0.02).
  • In behavioral LTS, both protocols induced sensitization at 1 day (Standard: q2 = 3.12, n = 12, p < 0.04; Enhanced: q3 = 4.13, n = 14, p < 0.02), but only the Enhanced protocol persisted for at least 5 days (q3 = 5.48, n = 9, p < 0.001).

Methods

  • A simplified mathematical model represented dynamic PKA and ERK activation, with an “inducer” term proportional to the product of PKA and ERK activities; 9,999 alternative protocols were simulated using five 5-min 5-HT stimuli with ISIs chosen as multiples of 5 min from 5–50 min.
  • In vitro electrophysiology used Aplysia sensorimotor co-cultures assigned to Standard, Enhanced, or vehicle Control groups; EPSPs were measured before treatment and 1, 2, and 5 days after treatment. CREB1 phosphorylation was measured in sensory neuron cultures at 0 h and 18 h after Standard, Enhanced, or vehicle treatment.
  • Behavioral long-term sensitization was tested in behaving animals 1 day and 5 days after training. Statistical analyses used two-way ANOVA with Student-Newman-Keuls post hoc tests; detailed methods are available online.

Limitations

  • The paper states the model was limited to the initial induction of LTM and relatively brief training sessions (e.g., 1.5 h), and it did not include slower processes such as changes in CREB1 and CREB2 synthesis, postsynaptic protein kinase C, local protein synthesis near the synapse, or sensorin synthesis.
  • The paper states the model did not account for differences in the time course and magnitude of LTF versus LTS, which may involve nonlinear transformation of LTF into motor neuron activity and plasticity at other circuit loci.
  • The paper notes it remains important to determine whether the computational approach applies to other memory systems and ultimately to human cognition; the text also makes evident that the full experimental methods are not included in the provided article body.

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

Integrity signals

Registry

Crossref · 10.1038/nn.2990

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Compared to the Standard protocol, the Enhanced protocol induced significantly higher levels of CREB1 phosphorylation 18 h after treatment (q2 = 3.69, n = 7, p < 0.02).

    “Pair-wise comparisons (SNK tests) indicated that compared to the Standard protocol, the Enhanced protocol induced significantly higher levels of CREB1 phosphorylation immediately (q2 = 6.94, n = 4, p < 0.001), and 18 h after treatment (q2 = 3.69, n = 7, p < 0.02).”
    Quote in the paperSubstantial claim
  • Findingown data

    Two-way ANOVA indicated significant differences among the three training groups in long-term sensitization (F2,82 = 11.77, p < 0.001).

    “Statistical analyses (two-way ANOVA) indicated significant differences among the three training groups (F2,82 = 11.77, p < 0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    The Standard protocol induced long-term sensitization that lasted 1 day (q2 = 3.12, n = 12, p < 0.04).

    “Pair-wise comparisons (SNK tests) indicated that both the Standard protocol (q2 = 3.12, n = 12, p < 0.04) and Enhanced protocol (q3 = 4.13, n = 14, p < 0.02) induced LTS that lasted 1 d.”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared to the Standard protocol, the Enhanced protocol induced significantly higher levels of CREB1 phosphorylation immediately after treatment (q2 = 6.94, n = 4, p < 0.001).

    “Pair-wise comparisons (SNK tests) indicated that compared to the Standard protocol, the Enhanced protocol induced significantly higher levels of CREB1 phosphorylation immediately (q2 = 6.94, n = 4, p < 0.001), and 18 h after treatment (q2 = 3.69, n = 7, p < 0.02).”
    Quote in the paperSubstantial claim
  • Findingown data

    Two-way ANOVA indicated significant overall differences in EPSP amplitude among the three treatment groups (F2,73 = 22.06, p < 0.001).

    “Statistical analyses (two-way ANOVA) indicated significant overall differences in the amplitude of EPSPs among the three treatment groups (F2,73 = 22.06, p < 0.001) and among the three time points (F2,73 = 7.28, p < 0.002).”
    Quote in the paperSubstantial claim
  • May combine two claims. 7
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data

    Simulations of the massed protocol produced a peak level of inducer of only 0.00016 μM, which was at the low end of the distribution.

    “Simulations of this massed protocol produced a peak level of inducer of only 0.00016 µM, which was at the low end of the distribution illustrated in Supplementary Fig. 1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The model was able to predict submaximal performance, which helped to increase confidence in its predictive power.

    “Thus, the model was able to predict submaximal performance, which helped to increase confidence in its predictive power.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The peak level of inducer, corresponding to the peak synergistic interaction between PKA and ERK, predicts the efficacy of stimulus protocols.

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

    Premisecitation

    The Standard protocol, consisting of five 5-min pulses of 5-HT with uniform 20-min interstimulus intervals, has been widely used in experimental studies since 1986.

    “This 'Standard' protocol has been widely used in experimental studies since its introduction in 198623.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] 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.

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

    Interpretationcitation

    Several factors may contribute to the discrepancy between LTF and LTS time course and magnitude, including a nonlinear transformation of LTF into motor neuron activity and plasticity at other loci in the neural circuit.

    “Several factors may contribute to this discrepancy, including a nonlinear transformation of LTF into motor neuron activity and plasticity at other loci in the neural circuit that contribute to the behavioral enhancement36,37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Cleary, L.J. & Byrne, J.H. Identification and characterization of a multifunction neuron contributing to defensive arousal in Aplysia. J. Neurophysiol. 70, 1767–1776 (1993). source

      Not checked in the free run.

    • cites [37] White, J.A., Ziv, I., Cleary, L.J., Baxter, D.A. & Byrne, J.H. The role of interneurons in controlling the tail-withdrawal reflex in Aplysia: a network model. J. Neurophysiol. 70, 1777–1786 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Modeling the dynamics of biochemical cascades could play an essential role in understanding why specific training protocols are more effective than others, and thereby help guide the development of better learning paradigms.

    “The present results suggested that modeling the dynamics of biochemical cascades could play an essential role in understanding why specific training protocols are more effective than others, and thereby, help guide the development of better learning paradigms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ERK is activated more slowly, with maximal activation about 45 min after a single trial.

    “In contrast, ERK is activated more slowly with maximal activation occurring about 45 min after a single trial7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] 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.

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

    Premisecitation

    Postsynaptic protein kinase C, upregulation of local protein synthesis in the vicinity of the synapse, and synthesis of the peptide sensorin in response to retrograde signals are involved in LTF.

    “In addition, the model did not include descriptions of postsynaptic protein kinase C33, upregulation of local protein synthesis in the vicinity of the synapse34 or synthesis of the peptide sensorin in response to retrograde signals35, which are involved in LTF.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Hu, J.Y., Chen, Y. & Schacher, S. Protein kinase C regulates local synthesis and secretion of a neuropeptide required for activity-dependent long-term synaptic plasticity. J. Neurosci. 27, 8927–8939 (2007). source

      Not checked in the free run.

    • cites [34] Wang, D.O. et al. Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324, 1536–1540 (2009). source

      Not checked in the free run.

    • cites [35] Cai, D., Chen, S. & Glanzman, D.L. Postsynaptic regulation of long-term facilitation in Aplysia. Curr. Biol. 18, 920–925 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanistic underpinnings of expanding-ISI training are not well understood and provide little guidance for designing protocols that maximize retention.

    “The mechanistic underpinnings of this form of training are not well understood, and therefore provide little guidance for designing protocols that maximize retention1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] 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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, a number of cognitive models have been proposed to explain the superiority of spaced training or practice, but no consensus has emerged as to their usefulness or generality.

    “In humans, a number of cognitive models have been proposed to explain the superiority of spaced training or practice1,30, but no consensus has emerged as to their usefulness or generality31.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] 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). source

      Not checked in the free run.

    • cites [30] Hintzman, D.L. Repetition and memory. in The Psychology of Learning and Motivation Vol. 10 (ed. Bower, G.H.) 47–93 (Academic Press, 1976). source

      Not checked in the free run.

    • cites [31] Cepeda, N.J. et al. Optimizing distributed practice: theoretical analysis and practical implications. Exp. Psychol. 56, 236–246 (2009). source

      Not checked in the free run.

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

    Premisecitation

    A form of training with expanding interstimulus intervals appears to lead to enhanced performance in verbal recall tasks.

    “For example, a form of training with expanding ISIs appears to lead to enhanced performance in verbal recall tasks1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] 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). source

      Not checked in the free run.

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

    Premisecitation

    Slow dynamics of additional biochemical cascades contribute to LTM, such as changes in the synthesis of transcription factors CREB1 and CREB2.

    “For example, the slow dynamics of additional biochemical cascades contribute to LTM (e.g., changes in the synthesis of transcription factors such as CREB1 and CREB22,32).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Liu, R.Y., Cleary, L.J. & Byrne, J.H. The requirement for enhanced CREB1 expression in consolidation of long-term synaptic facilitation and long-term excitability in sensory neurons of Aplysia. J. Neurosci. 31, 6871–6879 (2011). source

      Not checked in the free run.

    • cites [32] Liu, R.Y., Shah, S., Cleary, L.J. & Byrne, J.H. Serotonin- and training-induced dynamic regulation of CREB2 in Aplysia. Learn. Mem. 18, 245–249 (2011). source

      Not checked in the free run.

11 of 11

  • The authors state this as an assumption.

    The peak level of inducer, corresponding to the peak synergistic interaction between PKA and ERK, predicts the efficacy of stimulus protocols.

    “The peak levels of inducer, which corresponded to the peak synergistic interaction between PKA and ERK, were hypothesized to predict the efficacy of stimulus protocols.”

  • The authors state this as an assumption.

    The model captures the salient features of the dynamics of PKA and ERK, and the synergism between PKA and ERK activity is essential for LTF.

    “To the extent that the model captured the salient features of the dynamics of PKA and ERK and the extent to which the synergism between PKA and ERK activity is essential for LTF, the Enhanced protocol was predicted to induce more LTF than the Standard protocol.”

  • The paper relies on this without support.

    Long-term synaptic plasticity and modifications in CREB1 are key processes underlying long-term memory.

    “Both long-term synaptic plasticity and modifications in CREB1 are thought to be key processes underlying long-term memory.”
3 of 3

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  • Standard-protocol animal count increases between tests

    Minor

    The paper says every animal was tested at both 1 and 5 days, but reports 12 Standard-protocol animals at day 1 and 14 at day 5. If all animals received both tests, the day-5 count cannot exceed the day-1 count.

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Authors
Zhang, Y., Liu, R.-Y., Heberton, G. A., Smolen, P., Baxter, D. A., Cleary, L. J., & Byrne, J. H.
Affiliations
The University of Texas Health Science Center at Houston (US)
Corresponding author
Byrne, John H
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2011-12-25
Volume
15
Issue
2
Pages
294-297
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2990
PMC
PMC3267874
OpenAlex
W2067549555
Semantic Scholar
23a873ad4f5bbbec60aff1f1e6a76c3227f561ff
Cited by
80
References
46
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 10 · 2015: 3 · 2014: 10 · 2013: 10 · 2012: 5
FWCI
4.06
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p01ns038310-10)
  • National Institute of Neurological Disorders and Stroke (R01NS019895, R01NS073974, P01 NS-038310)
  • U.S. National Library of Medicine (T15LM007093)
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 › Neurobiology and Insect Physiology Research
Keywords
protein kinase A, extracellular signal-regulated kinase, MAPK signaling, Aplysia, computational modeling of signaling, memory enhancement, long-term memory
MeSH terms
Analysis of Variance, Animals, Aplysia, Cells, Cultured, Computer Simulation, Electric Stimulation, Humans, Functional Laterality, Learning, Models, Biological, Motor Neurons, Sensory Receptor Cells, Serotonin, Signal Transduction, Long-Term Potentiation, Cyclic AMP-Dependent Protein Kinases, Ganglia, Invertebrate, Coculture Techniques, Extracellular Signal-Regulated MAP Kinases, CREB-Binding Protein

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