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

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.”

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

In the paper

“There is now agreement that learning is implemented, at least in part, by changes in synaptic strength (synaptic plasticity).”

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

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.”

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.”

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

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.”

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

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).”

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.”

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

In the paper

“Computational simulations have supported the plausibility of this mechanism65, but it has not been validated empirically.”

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

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.”

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

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.”

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

In the paper

“Two isoforms of D. melanogaster CREB — dCREB2-a and dCREB2-r — can activate and repress transcription, respectively.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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.”

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

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.”

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

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.”

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.”

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.”

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.”

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

In the paper

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

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).”

In the paper

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

In the paper

“Indeed, different theories may be more or less applicable to different memory systems.”

In the paper

“These variants have also been argued not to readily accommodate certain verbal learning observations2.”

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

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.”

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.”

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

In the paper

“For example, subsequent trials that are delivered at times that coincide with kinase activity peaks might optimally reinforce learning.”

In the paper

“This standard protocol yielded an intermediate peak value of inducer and was predicted to have an intermediate effectiveness (FIG. 4c).”

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

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.”

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

In the paper

“In response to each 5-HT pulse, PKA activity increases rapidly and decays rapidly (FIG. 4c).”

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

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.”

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

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.”

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.”

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

In the paper

“Cbp+/− mice show impaired LTP and long-term memory95.”

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

In the paper

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

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

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.”

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”

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

In the paper

“LTP impairment seen in a mouse model of RTS95 was first simulated.”

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

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.”

In the paper

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

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

In the paper

“Indeed, enhancing normal learning by judicious pharmacotherapy has recently received attention111”

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

In the paper

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

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

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.”

In the paper

“However, this explanation may not suffice when comparing training intervals of ~1 day versus many days.”

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.”

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