The DOI matches its Crossref record; 111 of the 111 references it cites were found in a registry or an index; 4 of the 171 sources its claims cite were checked for support.
The right time to learn: mechanisms and optimization of spaced learning
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
104 Not checked yet · 51 Own interpretation · 1 Supported · 1 Partly supported · accuracy not yet measured
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In the paper
“Positive feedback loops that maintain key kinases and other molecules in persistently active states at strengthened synapses may also contribute to such long-term memory storage75–79.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Supportedcites [75] Miller, P., Zhabotinsky, A. M., Lisman, J. E. & Wang, X. J. The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover. PLoS Biol. 3, e107 (2005). source
The Introduction describes CaMKII as persistently active during long-term potentiation and says its autocatalytic properties could make it a synaptic memory switch. The Discussion concludes that small groups of CaMKII molecules could remain stable enough to support long-term information storage. This paper supports the claim through CaMKII as an example, rather than by establishing the same mechanism for other molecules. (LLM, conf=0.89)
- Not checked yetcites [76] Pettigrew, D. B., Smolen, P., Baxter, D. A. & Byrne, J. H. Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in Aplysia. J. Comput. Neurosci. 18, 163–181 (2005). source
- Not checked yetcites [77] Shema, R., Sacktor, T. C. & Dudai, Y. Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ. Science 317, 951–953 (2007). source
- Partly supportedcites [78] Volk, L. J., Bachman, J. L., Johnson, R., Yu, Y. & Huganir, R. L. PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature 493, 420–423 (2013). sourceExperimental — accuracy not yet measured
The paper's Abstract (page not provided) discusses sustained PKM-ζ activity as a proposed mechanism for maintaining long-term potentiation and memory, and allows that PKM-ζ may regulate plasticity and memory under some conditions. It does not describe positive feedback loops or establish persistently active molecules at strengthened synapses; its knockout results also challenge an essential role for PKM-ζ. (LLM, conf=0.82)
- Supportedcites [79] Fioriti, L. et al. The persistence of hippocampal-based memory requires protein synthesis mediated by the prion-like protein CPEB3. Neuron 86, 1433–1448 (2015). source
The Discussion proposes that CPEB3 could sustain a positive feedback loop that maintains its functional aggregate state. It also links CPEB3-containing synapses to lasting strengthening and memory persistence. This supports the cited paper’s contribution to the claim about ‘other molecules’; it does not present CPEB3 as a kinase. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In this study, a specific brain region associated with rehearsal of verbal memory, the left frontal operculum, was activated more during spaced learning of paired-word associations than during massed learning.”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
What the sources say
- Supportedcites [83] Callan, D. E. & Schweighofer, N. Neural correlates of the spacing effect in explicit verbal semantic encoding support the deficient-processing theory. Hum. Brain Mapp. 31, 645–659 (2010). source
The Materials and Methods describe an fMRI task in which participants learned associations between English words and novel phonological sequences under spaced and massed conditions. The Results section, “Differential Activity Between Spaced and Massed Encoding,” reports significantly greater activity in the left frontal operculum during spaced learning; the Discussion identifies this region as associated with verbal maintenance rehearsal. The paired associates were specifically words and novel phonological sequences, rather than two familiar words. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“in rat fear conditioning spaced extinction trials are more effective than massed trials at establishing new memories22.”
§ The right time to learn: mechanisms and optimization of spaced learning > Abstract
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Abstract
What the sources say
- Not checked yetcites REF. 1
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“subsequent spaced trains of theta-burst stimuli, with intervals of 60 minutes or more between the trains, were needed for optimal reinforcement of LTP46.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In massed training, the trials would come too close together to initiate separate rounds of transcription.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“LTF at these sensorimotor synapses is associated with a simple form of learning, long-term sensitization (LTS) of withdrawal reflexes.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The second theta-burst stimulus yielded polymerization in spines that were not apparently affected by the first stimulus, if the second followed the first by 60 or 90 minutes.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [47] Kramár, E. A. et al. Synaptic evidence for the efficacy of spaced learning. Proc. Natl Acad. Sci. USA 109, 5121–5126 (2012). This study, together with reference 48, substantiates the key hypothesis that spaced stimuli first prime and then strengthen upon repetition successive groups of dendritic spines, creating a morphological correlate of the memory trace that spaced, but not massed, protocols effectively consolidate. source
- Not checked yetcites [48] Lynch, G., Kramár, E. A., Babayan, A. H., Rumbaugh, G. & Gall, C. M. Differences between synaptic plasticity thresholds result in new timing rules for maximizing long-term potentiation. Neuropharmacology 64, 27–38 (2013). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Reliable correlates of LTP are the remodelling and enlargement of postsynaptic dendritic spines, which are small protrusions that are associated with most excitatory synapses43.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [43] Bosch, M. & Hayashi, Y. Structural plasticity of dendritic spines. Curr. Opin. Neurobiol. 22, 383–388 (2012). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 27
- Probably not a substantial claim. 23
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“There is now agreement that learning is implemented, at least in part, by changes in synaptic strength (synaptic plasticity).”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [42] Nabavi, S. et al. Engineering a memory with LTD and LTP. Nature 511, 348–352 (2014). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [52] Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1249–1254 (2001). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Each theta-burst stimulus led to actin filament polymerization in spines, which is known to be important for the stabilization of LTP49.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Spines that undergo priming but not consolidation exhibit a refractory period of ~60 minutes, suggesting that priming takes time to complete (FIG. 2a).”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Computational simulations have supported the plausibility of this mechanism65, but it has not been validated empirically.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Protein phosphatase 1 (PP1) appeared to be necessary for this spacing effect, because PP1 inhibition allowed the shorter interval to activate CREB.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [61] Genoux, D. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–974 (2002). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Two isoforms of D. melanogaster CREB — dCREB2-a and dCREB2-r — can activate and repress transcription, respectively.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [61] Genoux, D. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–974 (2002). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
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In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
What the sources say
- Not checked yetcites [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
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
What the sources say
- Not checked yetcites [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
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Priming allows these spines to potentiate after the second stimulus, and thus constitutes a biochemical stimulus trace (FIGS 1d,2a).”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For intervals longer than the maximum, the individual biochemical traces would decay and not overlap.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, different theories may be more or less applicable to different memory systems.”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
In the paper
“These variants have also been argued not to readily accommodate certain verbal learning observations2.”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Recent data and learning theories
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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 yetcites [84] Karpicke, J. D. & Roediger, H. L. Is expanding retrieval a superior method for learning text materials? Mem. Cognit. 38, 116–124 (2010). source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, subsequent trials that are delivered at times that coincide with kinase activity peaks might optimally reinforce learning.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This standard protocol yielded an intermediate peak value of inducer and was predicted to have an intermediate effectiveness (FIG. 4c).”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“In response to each 5-HT pulse, PKA activity increases rapidly and decays rapidly (FIG. 4c).”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“Cbp+/− mice show impaired LTP and long-term memory95.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“MAPK activity rises and decays more slowly, not peaking until ~45 minutes after a pulse.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This last pulse activates PKA, so that a PKA peak is approximately coincident with peak MAPK activation, maximizing inducer and the predicted LTF.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [94] Park, E. et al. Epigenetic mechanisms of Rubinstein–Taybi syndrome. Neuromolecular Med. 16, 16–24 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“LTP impairment seen in a mouse model of RTS95 was first simulated.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Future directions
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“Similar blocking effects were obtained by the indiscriminate activation of neurons that overexpressed CREB.”
§ The right time to learn: mechanisms and optimization of spaced learning > Future directions
What the sources say
- Not checked yetcites [110] Hsiang, H. L. et al. Manipulating a “cocaine engram” in mice. J. Neurosci. 34, 14115–14127 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Indeed, enhancing normal learning by judicious pharmacotherapy has recently received attention111”
§ The right time to learn: mechanisms and optimization of spaced learning > Future directions
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The second pair corresponded to a PDE inhibitor paired with a deacetylase inhibitor.”
§ The right time to learn: mechanisms and optimization of spaced learning > Irregular spacing can enhance learning
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Future directions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, this explanation may not suffice when comparing training intervals of ~1 day versus many days.”
§ The right time to learn: mechanisms and optimization of spaced learning > Future directions
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The right time to learn: mechanisms and optimization of spaced learning > Future directions
What the sources say
- Not checked yetcites [86] Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999). source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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).”
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?
The cited source says what the claim attributes to it.
In the citing paper
“Although the spacing effect is recognized as a solid psychological law, in this review, neurodidactics is used as an integrative conceptual framework.”
From Systematic Review of the Effectiveness of Neurodidactic Spaced Learning Strategies in Long-Term Memory (2026) · cites this paper as Smolen et al., 2016
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
“Theta-burst stimuli applied at intervals of 10 or 40 minutes did not cumulatively increase LTP. However, for longer intervals (60 or 90 minutes), a cumulative increase in LTP was observed over three bursts of stimulation.”
§ The right time to learn: mechanisms and optimization of spaced learning > Molecular traces of time
“For the spaced LTP protocol of Gall, Lynch and colleagues47,48, an interval of 40–60 minutes is needed for successive theta-burst stimuli to further increase LTP. 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.”
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Metadata
- Authors
- Smolen, P., Zhang, Y., & Byrne, J. H.
- Corresponding author
- Byrne, John H.
- Venue
- Nature Reviews Neuroscience
- Published
- 2016-01-25
- Volume
- 17
- Issue
- 2
- Pages
- 77-88
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
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