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

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.”

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

In the paper

“in rat fear conditioning spaced extinction trials are more effective than massed trials at establishing new memories22.”

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

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.”

What the sources say

• Not checked yetcites REF. 1

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.”

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

In the paper

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

In the paper

“LTF at these sensorimotor synapses is associated with a simple form of learning, long-term sensitization (LTS) of withdrawal reflexes.”

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

“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.”

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

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.”

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

In the paper

“Theta-burst stimuli applied at intervals of 10 or 40 minutes did not cumulatively increase LTP.”

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

In the paper

“Spaced training may be more effective, in part, because it may allow sufficient time for transcription factors such as CREB to be activated, bind to promoters and induce a round of transcription for the consolidation of LTP53 or for long-term facilitation (LTF) of synapses54.”

What the sources say

• Not checked yetcites [53] Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998). source
• Not checked yetcites [54] Liu, R. Y., Fioravante, D., Shah, S. & Byrne, J. H. cAMP response element-binding protein 1 feedback loop is necessary for consolidation of long-term synaptic facilitation in Aplysia. J. Neurosci. 28, 1970–1976 (2008). source

In the paper

“Thus, an additional 5-HT pulse near 12 hours after treatment might optimally reinforce LTF.”

In the paper

“However, for longer intervals (60 or 90 minutes), a cumulative increase in LTP was observed over three bursts of stimulation.”

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

In the paper

“In addition, in these sensory neurons, the level of the transcription repressor CREB2 shows a late drop at ~12 hours after treatment56.”

What the sources say

• Not checked yetcites [56] 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

In the paper

“This prolonged elevation of CREB1 levels is due to a positive feedback loop in which this protein, by binding to a CRE regulatory element near creb1, increases the expression of creb1 (REFS 54,55) and other genes that are upregulated by CREB1.”

What the sources say

• Not checked yetcites [54] Liu, R. Y., Fioravante, D., Shah, S. & Byrne, J. H. cAMP response element-binding protein 1 feedback loop is necessary for consolidation of long-term synaptic facilitation in Aplysia. J. Neurosci. 28, 1970–1976 (2008). source
• Not checked yetcites [55] 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

In the paper

“Stimulated dendritic spines were remodelled over a period of more than 1 hour, leading to enlargement of the existing functional postsynaptic density45 and the presynaptic active zone44.”

What the sources say

• Not checked yetcites [45] Bourne, J. N. & Harris, K. M. Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP. Hippocampus 21, 354–373 (2011). source
• Not checked yetcites [44] Bell, M. E. et al. Dynamics of nascent and active zone ultrastructure as synapses enlarge during LTP in mature hippocampus. J. Comp. Neurol. 522, 3861–3864 (2014). This work, one of a group of related studies by the Harris laboratory, characterized in detail pre- and postsynaptic structural changes that are necessary for the consolidation of LTP. source

In the paper

“In these sensory neurons, levels of the transcription activator CREB1 are elevated for at least 24 hours after the spaced 5-HT treatments54,55.”

What the sources say

• Not checked yetcites [54] Liu, R. Y., Fioravante, D., Shah, S. & Byrne, J. H. cAMP response element-binding protein 1 feedback loop is necessary for consolidation of long-term synaptic facilitation in Aplysia. J. Neurosci. 28, 1970–1976 (2008). source
• Not checked yetcites [55] 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

In the paper

“This drop in the level of CREB2, coupled with the rise in the level of CREB1, plausibly corresponds to an increased potential for gene induction.”

In the paper

“If the second theta-burst stimulus is applied after the refractory period, some or all of the primed spines undergo consolidation.”

In the paper

“For example, fear-conditioned memories can be alternately erased and reinstated by long-term depression (LTD) and long-term potentiation (LTP), respectively, of a defined synaptic pathway42.”

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

“The resulting increase in the numbers of AMPA-type and NMDA-type glutamate receptors at the synapse correlated with the magnitude of LTP.”

What the sources say

• Not checked yetcites [44] Bell, M. E. et al. Dynamics of nascent and active zone ultrastructure as synapses enlarge during LTP in mature hippocampus. J. Comp. Neurol. 522, 3861–3864 (2014). This work, one of a group of related studies by the Harris laboratory, characterized in detail pre- and postsynaptic structural changes that are necessary for the consolidation of LTP. source
• Not checked yetcites [45] Bourne, J. N. & Harris, K. M. Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP. Hippocampus 21, 354–373 (2011). source

In the paper

“Studies using rat hippocampal slices found that LTP induced by multiple trains of theta-burst stimuli was accompanied by extensive remodelling of synaptic ultrastructures44,45”

What the sources say

• Not checked yetcites [44] Bell, M. E. et al. Dynamics of nascent and active zone ultrastructure as synapses enlarge during LTP in mature hippocampus. J. Comp. Neurol. 522, 3861–3864 (2014). This work, one of a group of related studies by the Harris laboratory, characterized in detail pre- and postsynaptic structural changes that are necessary for the consolidation of LTP. source
• Not checked yetcites [45] Bourne, J. N. & Harris, K. M. Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP. Hippocampus 21, 354–373 (2011). source

In the paper

“These data suggest that, in this system, the dynamics of transcription activation and gene expression have slow components that can summate over multiple days, yielding long-lasting memory.”

In the paper

“However, it appears to be likely that a similar type of mechanism that is based on competition between an activator of long-term memory formation and a repressor, with the repressor only activated at short intervals, might be needed to explain any similar data in which massed training is less effective than spaced training even given equal total training times.”

In the paper

“These BDNF dynamics result from a positive feedback loop in which C/ebp induction leads to Bdnf upregulation, with the resulting increase in BDNF levels further activating the C/EBP signalling pathway60.”

What the sources say

• Not checked yetcites [60] Bambah-Mukku, D., Travaglia, A., Chen, D. Y., Pollonini, G. & Alberini, C. M. A positive autoregulatory BDNF feedback loop via C/EBPβ mediates hippocampal memory consolidation. J. Neurosci. 34, 12547–12559 (2014). This study characterizes the dynamics of a molecular positive feedback loop demonstrated to be important for the consolidation of long-term (24 hours or more) memory, as well as the late repression of Bdnf that terminates the feedback. source

In the paper

“A study involving A. californica sensory neuron–motor neuron co-cultures62 found that protein kinase C (PKC) is activated to a greater extent during a massed stimulus (continuous 5-HT application) than during a spaced stimulus (15-minute intervals between applications).”

What the sources say

• Not checked yetcites [62] Farah, C. A., Weatherill, D., Dunn, T. W. & Sossin, W. S. PKC differentially translocates during spaced and massed training in Aplysia. J. Neurosci. 29, 10281–10286 (2009). source

In the paper

“It is known that this delayed MAPK activation requires protein synthesis12”

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

In the paper

“Spaced (15-minute) intervals were more effective than massed (1-minute) intervals in inducing olfactory learning, even given the same total training time (and thus more massed presentations)63.”

What the sources say

• Not checked yetcites [63] Tully, T., Preat, T., Boynton, S. & Del Vecchio, M. Genetic dissection of consolidated memory in Drosophila melanogaster. Cell 79, 35–47 (1994). source

In the paper

“The 45-minute optimum was associated with activation of MAPK.”

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

“Recent data also illustrate that, in the hippocampus, CREB and CCAAT enhancer-binding protein (C/EBP), another transcription factor that is important for LTP, can remain active for many hours after learning.”

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
• Not checked yetcites [60] Bambah-Mukku, D., Travaglia, A., Chen, D. Y., Pollonini, G. & Alberini, C. M. A positive autoregulatory BDNF feedback loop via C/EBPβ mediates hippocampal memory consolidation. J. Neurosci. 34, 12547–12559 (2014). This study characterizes the dynamics of a molecular positive feedback loop demonstrated to be important for the consolidation of long-term (24 hours or more) memory, as well as the late repression of Bdnf that terminates the feedback. source

In the paper

“Stimuli at intervals much shorter than this would not be able to generate summation of the rate-limiting process and would therefore not cause additional LTP.”

In the paper

“However, it is evident that even for systems such as honeybee olfactory learning that involve short, spaced intervals, effective long-term memory formation relies on the activation of transcription and translation, downstream of the intracellular signalling pathways that are activated by these intervals17,70.”

What the sources say

• 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
• Not checked yetcites [70] Chen, C. et al. Visualizing long-term memory formation in two neurons of the Drosophila brain. Science 335, 678–685 (2012). source

In the paper

“An implication of the work outlined above is that multiple temporal domains of spaced training may be engaged in spaced training (FIG. 3).”

In the paper

“About twice as many dendrites with active ERK1/2 were found following spaced bursts, suggesting that spaced trials may recruit additional synapses on different dendrites for LTP.”

What the sources say

• Not checked yetcites [69] Ajay, S. M. & Bhalla, U. S. A propagating ERKII switch forms zones of elevated dendritic activation correlated with plasticity. HFSP J. 1, 49–66 (2007). source

In the paper

“Thus, in A. californica, D. melanogaster and mammals, MAPK activation appears to be a component of the molecular mechanism that underlies the spacing effect.”

In the paper

“Spaced learning with these long intervals would reactivate critical components at these synapses, and in particular reactivate NMDA receptors at these synapses.”

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.”

What the sources say

• Not checked yetcites [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
• 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
• Not checked yetcites [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). source
• Not checked yetcites [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

In the paper

“Reactivation of memory traces may constitute an additional temporal substrate that underlies the longest reported effective intervals, on the order of a week71.”

What the sources say

• Not checked yetcites [71] Cepeda, N. J. et al. Optimizing distributed practice: theoretical analysis and practical implications. Exp. Psychol. 56, 236–246 (2009). source

In the paper

“About twice as many dendrites with active ERK1/2 were found following spaced bursts, suggesting that spaced trials may recruit additional synapses on different dendrites for LTP.”

In the paper

“It is plausible that the minimum inter-stimulus interval for effective learning, for a given protocol and system, corresponds to the interval that is necessary to allow each stimulus to contribute separately to a rate-limiting biochemical process.”

In the paper

“For LTF and LTS in A. californica, transcription, as discussed above, may constitute a rate-limiting process that helps to determine the efficacy of spaced training.”

In the paper

“For intervals of 1 minute or more, each stimulus would be able to contribute a discrete increment to the rate-limiting process, allowing effective learning.”

In the paper

“For example, in honeybee olfactory learning, efficient spaced training can occur with intervals as short as 1 minute17.”

What the sources say

• 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

In the paper

“This 60-minute interval was predicted to be optimal for learning because stimuli separated by 60 minutes had previously been found to enhance LTP in wild-type rodents47.”

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

In the paper

“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.”

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

In the paper

“Thus, a range of molecular and cellular mechanisms appears to contribute to the efficacy of spaced training, in parallel or in series.”

In the paper

“Indeed, an effective protocol for LTS training in A. californica is the use of four trials with an inter-trial interval of 30 minutes, repeated four times with a 1-day inter-trial interval13.”

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

In the paper

“Nevertheless, the key finding from these studies is that delayed activation of MAPK is intimately associated with the effectiveness of spaced stimuli to induce long-term memory.”

In the paper

“In A. californica, D. melanogaster and mammals, the data discussed above indicate that commonly reported intervals, ranging from ~5 minutes to 1 hour, may allow for the reinforcement of the activities of key kinases essential for LTP or LTF, and consolidate structural changes in dendritic spines.”

In the paper

“Thus, at least in some cases, there appears to be a hierarchy of temporal domains of training protocols, with briefer protocols embedded within longer ones.”

In the paper

“Studies using inducible and reversible NMDA receptor knockouts have demonstrated that such NMDA receptor reactivation, which may also in part result from spontaneous neuronal activity, is required to sustain remote memory storage73,74.”

What the sources say

• Not checked yetcites [73] Cui, Z. et al. Inducible and reversible NR1 knockout reveals a crucial role of the NMDA receptor in preserving remote memories in the brain. Neuron 41, 781–793 (2004). This study demonstrates the key point that ongoing neural activity and NMDA receptor activation are essential for long-lasting preservation of stored memory. source
• Not checked yetcites [74] Tetzlaff, C., Kolodziejski, C., Timme, M., Tsodyks, M. & Worgotter, F. Synaptic scaling enables dynamically distinct short- and long-term memory formation. PLoS Comput. Biol. 9, e1003307 (2013). source

In the paper

“Such intervals are likely to reactivate and reinforce consolidated patterns of strengthened synapses that correspond to memory traces that are maintained by neuronal network activity72.”

What the sources say

• Not checked yetcites [72] Wei, Y. & Koulakov, A. A. Long-term memory stabilized by noise-induced rehearsal. J. Neurosci. 34, 15804–15815 (2014). source

In the paper

“ERK1 and ERK2 (ERK1/2) activation is needed for some forms of LTP68”

What the sources say

• Not checked yetcites [68] Rosenblum, K. et al. The role of extracellular regulated kinases I/II in late-phase long-term potentiation. J. Neurosci. 22, 5432–5441 (2002). source

In the paper

“In rat hippocampal slices, theta-burst stimuli lead to proteolytic inactivation of integrin receptors at stimulated dendritic spines82.”

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

“Although finer-grain analyses are necessary, a study using functional MRI during verbal learning supports this assumption83.”

What the sources say

• Not checked yetcites [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

In the paper

“The refractory period appears to be necessary to complete the priming of dendritic spines that were stimulated, but not potentiated, by the first theta-burst stimulus.”

In the paper

“The required refractory period of ~1 hour between successive theta-burst stimuli to induce progressive increments in hippocampal LTP46,47 may be in line with the first of these variants, which is that short intervals are insufficient for consolidation and consequent summation of memory traces.”

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
• 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

In the paper

“Consequently, most, if not all, training protocols used in animal and human studies are probably not optimal.”

In the paper

“Substantial behavioural evidence suggests that this latter voluntary, short-term rehearsal is not essential for spaced learning31,34.”

What the sources say

• Not checked yetcites [31] Hintzman, D. L. in Theories in Cognitive Psychology: The Loyola Symposium (ed. Solso, R. L.) 77–90 (Erlbaum, 1974).
• Not checked yetcites [34] Hintzman, D. L. in The Psychology of Learning and Motivation Vol. 10 (ed. Bower, G. H.) 47–91 (Academic Press, 1976). source

In the paper

“and in some systems training may only be effective if inter-trial intervals are long enough so that each trial can induce a separate round of transcription and translation.”

In the paper

“These receptors are then replaced by vesicular transport of new receptors over a period of ~40–60 minutes”

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

“Similarly, short (massed) inter-trial intervals may not lead to sufficient levels, or a sufficient duration, of activated MAPK or other kinases to support the consolidation of long-term memory.”

In the paper

“The stimulus trace associated with priming may therefore take at least 4 hours to decay.”

In the paper

“Kramár et al.47 noted that in hippocampal slices, additional potentiation can be induced up to 4 hours after induction of the first LTP increment81.”

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 [81] Frey, U. & Morris, R. G. Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181–188 (1998). source

In the paper

“However, a meta-analysis2 and a text learning study84 found no substantial evidence for the superiority of this approach in terms of promoting long-term memory formation.”

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

“Transcription factor activation also constitutes a biochemical trace”

In the paper

“Such a long trace lifetime might allow a broad temporal window for optimal training trials.”

In the paper

“At this point, much of the extant cellular data seem to be compatible with the deficient-processing theory, particularly two of its variants: the consolidation theory and the lack of cognitive rehearsals theory.”

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.”

What the sources say

• Not checked yetcites [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

In the paper

“We note that these posited memory reactivations, on timescales of ~1 hour or longer, are distinct from voluntary rehearsals of a memory on a short timescale (seconds or ~1 minute).”

In the paper

“The remaining variants of the deficient-processing theory, which focus on habituation or on a lack of voluntary attention during massed presentations, do not appear to relate as readily to the current single-neuron data.”

In the paper

“This receptor replacement may constitute, at least in part, the priming of dendritic spines discussed above.”

In the paper

“A memory reactivation would be analogous to a theta-burst stimulus in that both events would initiate priming and potentiation.”

In the paper

“The variant of deficient-processing theory positing that only spaced trials can generate sufficient cognitive rehearsals or reactivations of a memory to support long-term memory consolidation may also correspond to the empirical finding that repeated theta-burst stimuli, spaced by ~1 hour, can recruit additional dendritic spines by potentiating spines that were primed by preceding stimuli.”

In the paper

“The simulations determined that, of these protocols, a massed protocol (FIG. 4b) produced the lowest peak value of inducer, consistent with data that massed 5-HT application fails to produce LTF14.”

What the sources say

• 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

In the paper

“Simulations have reproduced the dynamics of MAPK during LTP induction80,86,88.”

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
• 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

In the paper

“These predictions were empirically validated.”

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 recent years, models have described the dynamics of the biochemical reactions that transduce stimuli into LTP86–88.”

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 [87] Kim, M., Huang, T., Abel, T. & Blackwell, K. T. Temporal sensitivity of protein kinase A activation in late-phase long term potentiation. PLoS Comput. Biol. 6, e1000691 (2010). 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

In the paper

“It seems to be evident that at least part of the improvement in learning that is found with spaced training protocols can be explained by the dynamic relationships between the training trials and the underlying cellular and molecular mechanisms that are associated with memory formation (FIG. 3).”

In the paper

“The magnitude of LTF and LTS produced by the enhanced protocol exceeded that produced by the standard protocol85 (FIG. 4d).”

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

“Models have also simulated the activity time courses of PKA, calcium/calmodulin-dependent protein kinase II (CaMKII), other key enzymes and downstream transcription factors during LTP induction88–90.”

What the sources say

• 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
• Not checked yetcites [89] Aslam, N. & Shouval, H. Z. Regulation of cytoplasmic polyadenylation can generate a bistable switch. BMC Syst. Biol. 6, 12–20 (2012). source
• Not checked yetcites [90] Liu, R. Y. et al. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J. Neurosci. 33, 6944–6949 (2013). source

In the paper

“One study from our laboratory developed a model describing the 5-HT-induced PKA and ERK signalling pathways that are essential for LTF in A. californica85.”

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

“The ‘best’ protocol, yielding the highest peak value for inducer, termed the ‘enhanced’ protocol (FIG. 4b), had irregular intervals.”

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

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

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

“Similarly, relief of transcriptional repression owing to ATF4, a mammalian analogue of CREB2, seems to be important for the maintenance of hippocampal LTP102,103.”

What the sources say

• Not checked yetcites [102] Dong, C., Upadhya, S. C., Ding, L., Smith, T. K. & Hegde, A. N. Proteosome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation. Learn. Mem. 15, 335–347 (2008). source
• Not checked yetcites [103] Pasini, S., Corona, C., Liu, J., Greene, L. A. & Shelanski, M. L. Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory. Cell Rep. 11, 183–191 (2015). source

In the paper

“The four initial pulses initiate a surge of MAPK activity, which peaks near the time of the last pulse.”

In the paper

“This rescue protocol was empirically validated to restore normal LTF in A. californica.”

What the sources say

• Not checked yetcites [90] Liu, R. Y. et al. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J. Neurosci. 33, 6944–6949 (2013). source

In the paper

“In this study, the model previously used85 to predict optimal, irregularly spaced protocols that would enhance LTF (FIG. 4a) was extended to represent induction of c/ebp, a transcription factor known to be essential for LTF96.”

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
• Not checked yetcites [96] Alberini, C. M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009). source

In the paper

“CBP is also required for the consolidation of long-term memory93.”

What the sources say

• Not checked yetcites [93] Korzus, E., Rosenfeld, M. G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004). source

In the paper

“LTF relies on deactivation of CREB2, a transcriptional repressor101.”

What the sources say

• Not checked yetcites [101] Bartsch, D. et al. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83, 979–992 (1995). source

In the paper

“The recent study90 used small-interfering RNA (siRNA) knockdown of CBP in A. californica sensory neurons to impair LTF.”

What the sources say

• Not checked yetcites [90] Liu, R. Y. et al. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J. Neurosci. 33, 6944–6949 (2013). source

In the paper

“A ‘rescue’ protocol with irregularly spaced intervals was predicted to restore peak pC/EBP levels and, correspondingly, LTF.”

What the sources say

• Not checked yetcites [90] Liu, R. Y. et al. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J. Neurosci. 33, 6944–6949 (2013). source

In the paper

“However, no single-drug effect completely rescued LTP.”

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

“Simulations showed a substantial decrease in pC/EBP levels when the level of CBP was reduced by a decrement that corresponded to the siRNA effect.”

What the sources say

• Not checked yetcites [90] Liu, R. Y. et al. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J. Neurosci. 33, 6944–6949 (2013). source

In the paper

“and both rely on cooperative gene induction by pCREB and CBP53,96,99,100.”

What the sources say

• Not checked yetcites [53] Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998). source
• Not checked yetcites [96] Alberini, C. M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009). source
• Not checked yetcites [99] Bartsch, D., Casadio, A., Karl, K. A., Serodio, P. & Kandel, E. R. CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. Cell 95, 211–223 (1998). source
• Not checked yetcites [100] Kida, S. A functional role for CREB as a positive regulator of memory formation and LTP. Exp. Neurobiol. 21, 136–140 (2012). source

In the paper

“Although these empirical studies were conducted in A. californica, it should be noted that key molecular mechanisms of memory are substantially conserved from simple model organisms such as A. californica to mammals52,96.”

What the sources say

• 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
• Not checked yetcites [96] Alberini, C. M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009). source

In the paper

“For example, LTF and LTP both rely on PKA and ERK activation12,92,98”

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 [92] Müller, U. & Carew, T. J. Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21, 1423–1434 (1998). source
• Not checked yetcites [98] Abel, T. & Nguyen, P. V. Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog. Brain Res. 169, 97–115 (2008). source

In the paper

“A similar predicted rescue protocol of irregularly spaced intervals rescued a deficit in LTF that was produced by siRNA knockdown of CREB1 (REF. 97).”

What the sources say

• Not checked yetcites [97] Zhou, L. et al. Rescue of impaired long-term facilitation at sensorimotor synapses of Aplysia following siRNA knockdown of CREB1. J. Neurosci. 35, 1617–1626 (2015). source

In the paper

“Thus, the results with A. californica suggest that it may be possible, in complex organisms including mammals, to computationally predict the efficacies of numerous learning or training protocols, a process that is impractical using empirical studies alone.”

In the paper

“For both pairs, additive drug synergism, defined as a combined-drug effect that exceeds the summed effects of the individual drugs, was also evident, as quantified by a simple additive measure (FIG. 5).”

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

“In the first case, an increased rate constant for histone acetylation, corresponding to application of an acetyltransferase activator, was paired with an increased duration of stimulus-induced increase in cAMP levels, corresponding to application of a cAMP phosphodiesterase (PDE) 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

“A subsequent empirical study by another group did find that pairing a PDE inhibitor with a deacetylase inhibitor was effective in rescuing a deficit of LTP in a mouse model of Alzheimer disease105.”

What the sources say

• Not checked yetcites [105] Cuadrado-Tejedor, M. et al. Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease. Clin. Epigenetics 7, 108 (2015). source

In the paper

“With relatively short retention intervals (~1 minute−2 hours), training intervals in the broad range of ~1 minute to 3 hours yield greater verbal learning than do training intervals of 2 days or more2.”

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

“as does repeated replay or rehearsal of assemblies that encode recent experiences108,109.”

What the sources say

• Not checked yetcites [108] Karlsson, M. P. & Frank, L. M. Awake replay of remote experiences in the hippocampus. Nat. Neurosci. 12, 913–919 (2009). source
• Not checked yetcites [109] Wu, X. & Foster, D. J. Hippocampal replay captures the unique topological structure of a novel environment. J. Neurosci. 34, 6459–6469 (2014). source

In the paper

“Repeated spontaneous activation of neuron assemblies does occur106,107”

What the sources say

• Not checked yetcites [106] Ikegaya, Y. et al. Synfire chains and cortical songs: temporal modules of cortical activity. Science 304, 559–564 (2004). source
• Not checked yetcites [107] Miller, J. E., Ayzenshtat, I., Carrillo-Reid, L. & Yuste, R. Visual stimuli recruit intrinsically generated cortical ensembles. Proc. Natl Acad. Sci. USA 111, E4053–E4061 (2014). source

In the paper

“For example, in human verbal learning, an interesting positive correlation exists between the length of inter-trial intervals for effective spaced learning and the retention interval (that is, the interval between the final training trial and the test of memory retention).”

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

In the paper

“For verbal learning with a retention interval of 6 months, a training interval of 7 days was superior to an interval of 3 days71.”

What the sources say

• Not checked yetcites [71] Cepeda, N. J. et al. Optimizing distributed practice: theoretical analysis and practical implications. Exp. Psychol. 56, 236–246 (2009). source

In the paper

“With a longer retention interval of 1 day, a 1-day training interval yielded greater learning than did a very short (<30-second) interval.”

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

“One study supporting the necessity of such replay found that the post-training suppression of activity of neurons that were engineered to overexpress CREB in the amygdala blocked the consolidation of a memory of association between cocaine and a location110.”

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

“Thus, pairs of parameter changes were considered, corresponding to plausible paired-drug effects. Two pairs were identified that restored LTP.”

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