Synaptic evidence for the efficacy of spaced learning
Open accessAbstract
The superiority of spaced vs. massed training is a fundamental feature of learning. Here, we describe unanticipated timing rules for the production of long-term potentiation (LTP) in adult rat hippocampal slices that can account for one temporal segment of the spaced trials phenomenon. Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used. Analyses of F-actin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were “missed” by the first stimulation bout. Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions, suggesting that intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections. We propose that a combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictate that the repetitions be widely spaced. Thus, the synaptic mechanisms described here provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.
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Written from the paper’s full text.
TL;DR
In adult rat hippocampal slices, a second theta burst stimulation delivered 60 min or more after the first produced additional LTP, whereas shorter delays did not, and this added potentiation recruited synapses missed by the first train. The findings suggest intrinsic spine threshold differences plus delayed membrane insertion events impose a spacing requirement that may explain one temporal component of distributed practice.
Key findings
- TBS2 at 10 or 30 min after TBS1 caused short-term but not additional long-term facilitation; at 60 min it doubled potentiation, and 90 min gave the same degree of LTP as 60 min. A third train at 60 min again increased potentiation, whereas a fourth and fifth had no effect.
- F-actin labeling showed TBS2 doubled the population of densely F-actin-positive spines above TBS1 alone; in GFP–phalloidin experiments, TBS1 left about 10% of spines with high F-actin versus 18% after TBS2 (P < 0.04), and the percentage of 5-μm dendritic segments with two or more labeled spines doubled after TBS2 (P < 0.005).
- Single-spine glutamate uncaging enlarged only ∼40% of targeted adult spines, compared with >80% of young spines (P < 0.005); adult spines that enlarged were refractory to successive induction even when uncaging events were separated by more than 1 h.
- Brefeldin A applied after TBS1 blocked additional LTP by TBS2 and caused LTP1 to decay; the ampakine CX614 increased LTP1 and substantially reduced LTP2.
Methods
- Acute hippocampal slices from young adult male Sprague–Dawley rats or C57BL/6 mice; Schaffer–commissural afferents in field CA1b were stimulated with TBS consisting of 10 bursts of 4 pulses at 100 Hz separated by 200 ms, with baseline/test responses at 3 pulses/min. Brefeldin A and CX614 were bath-applied at 20 μM.
- F-actin was imaged with Alexa Fluor 568–phalloidin and GFP-expressing mice using confocal microscopy; single-spine glutamate uncaging used two-photon imaging/uncaging in eGFP mice (2–3 or 8–10 wk), MNI-caged L-glutamate, and a >50% spine volume change threshold.
- Electrophysiology data are group means ± SEM with two-tailed Student t tests unless otherwise noted, significance at P < 0.05; spine volume statistics used t tests, one-way ANOVA, and repeated-measures ANOVA in SPSS and Excel.
Limitations
- Stated: the paper calls for future research on whether transcriptional mechanisms interact with the synapse-specific processes described, on longer intervals (days, weeks), and on unknown cell biological variables; the mechanism of the late priming step remains unresolved.
- Stated: brefeldin after TBS1 unexpectedly caused LTP1 to decay, and predicted AMPA receptor insertion would increase EPSPs at 30–60 min after TBS1, which was not observed, requiring alternative explanations.
- Evident: the findings are from acute hippocampal slices rather than behavioral learning or memory tests, and the uncaging experiments do not state the sex of the mice used.
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- Findingown data§ Results
Within-train facilitation of theta burst responses was not detectably different at the 10-20-min vs. 60-90-min delays.
“Within-train facilitation of theta burst responses was not detectably different at the 10–20-min vs. 60–90-min delays”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions.
“Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions”
Quote in the paperSubstantial claim - Findingown data§ Results
TBS2 doubled the level of potentiation when delayed by 60 min after TBS1.
“However, the same stimulation doubled the level of potentiation when delayed by 60 min (Fig. 1 A and B).”
Quote in the paperSubstantial claim - Findingown data§ Results
TBS2 delivered 90 min after TBS1 resulted in the same degree of LTP as obtained with a 60-min delay.
“TBS2 delivered 90 min after TBS1 resulted in the same degree of LTP as obtained with a 60-min delay (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The added LTP obtained with delayed theta trains involved recruitment of synapses that were missed by the first stimulation bout.
“Analyses of F-actin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were “missed” by the first stimulation bout.”
Quote in the paperSubstantial claim
- Findingown data§ Results
TBS1 causes a marked increase in densely F-actin-positive spines that is of comparable size at 15 and 75 min after stimulation.
“Automated counting showed that TBS1 causes a marked increase in densely F-actin-positive spines that is of comparable size at 15 and 75 min after stimulation (Fig. 2 A and B).”
Quote in the paperSubstantial claim - Findingown data§ Results
One-minute trains of 5-Hz pulses fully reversed LTP2 when delivered 60 s, but not 60 min, after TBS2.
“similarly, 1-min trains of 5-Hz pulses fully reversed LTP2 when delivered 60 s, but not 60 min, after TBS2 (Fig. 1F).”
Quote in the paperSubstantial claim - Findingown data§ Results
The induction probability was not dependent on the time that the slice was in the recording chamber.
“The induction probability was not dependent on the time that the slice was in the recording chamber (Fig. 3E, Right).”
Quote in the paperSubstantial claim - Findingown data§ Results
Spines that enlarged after glutamate uncaging were refractory to successive attempts at induction, even when the timing between uncaging events was extended beyond one hour.
“Spines that enlarged after glutamate uncaging were refractory to successive attempts at induction, even when the timing between uncaging events was extended beyond one hour (Fig. 3E, Left).”
Quote in the paperSubstantial claim - Findingown data§ Results
The percentage of 5-μm dendritic segments with two or more labeled spines after TBS2 was double that found after TBS1 (P < 0.005).
“The percentage of 5-μm dendritic segments with two or more labeled spines after TBS2 was double that found after TBS1 (P < 0.005) (Fig. 4B, Right).”
Quote in the paperSubstantial claim - Findingown data§ Results
After TBS1 about 10% of all spines had high concentrations of F-actin, whereas the value after TBS2 was 18% (P < 0.04).
“Counts showed that after TBS1 about 10% of all spines had high concentrations of F-actin, whereas the value after TBS2 was 18% (P < 0.04) (Fig. 4B, Left).”
Quote in the paperSubstantial claim - Findingown data§ Results
Most of the densely F-actin positive spines occur in clusters after TBS2.
“and (ii) most of the densely F-actin positive spines occur in clusters after TBS2 (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data§ Results
TBS1 in the presence of a positive allosteric modulator of AMPA-type glutamate receptors triggered actin polymerization in a much larger than normal population of spines.
“TBS1 in the presence of the drug triggered actin polymerization in a much larger than normal population of spines (Fig. 2D)”
Quote in the paperSubstantial claim - Findingown data§ Results
Post-TBS1 infusions of brefeldin A completely blocked the production of additional LTP by TBS2.
“In striking contrast, post-TBS1 infusions completely blocked the production of additional LTP by TBS2 (Fig. 4D, Right).”
Quote in the paperSubstantial claim - Findingown data§ Results
The second stimulation train doubled the population of densely F-actin positive spines above that caused by TBS1 alone.
“The second stimulation train doubled the population of densely F-actin positive spines above that caused by TBS1 alone”
Quote in the paperSubstantial claim - Findingreasoning§ Results
TBS1 in the presence of the drug substantially increased the size of LTP1 at the expense of LTP2.
“and, as expected from this, substantially increased the size of LTP1 at the expense of LTP2 (Fig. 2E).”
Quote in the paperSubstantial claim - Findingown data§ Results
Uncaging glutamate near small spines in young and adult slices caused an increase in head volume that remained elevated above baseline levels for at least 45 min.
“Uncaging glutamate near small spines in young and adult slices caused an increase in head volume that remained elevated above baseline levels for at least 45 min (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data§ Results
The percentage of resistant cases (∼60%) is close to that for the densely F-actin positive spines added by TBS2.
“Note that the percentage of resistant cases (∼60%) is close to that for the densely F-actin positive spines added by TBS2 (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Only ∼40% of targeted spines enlarged after SSGU in adult slices.
“However, only ∼40% of targeted spines enlarged after SSGU in adult slices (Fig. 3C)”
Quote in the paperSubstantial claim - Findingown data§ Results
TBS1 misses spines on the majority of dendritic segments.
“Frequency distribution plots of the clustering data confirmed that (i) TBS1 “misses” spines on the majority of dendritic segments”
Quote in the paperSubstantial claim - Findingown data§ Results
Spine volume changes were similar between young and adult slices.
“Spine volume changes were similar between young and adult slices (Fig. 3B).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
Appropriately spaced, repeated stimulations of the same neural circuits markedly improve encoding over the time course of a classroom session.
“Finally, the demonstration that appropriately spaced, repeated stimulations of the same neural circuits markedly improves encoding over the time course of a classroom session has important implications for theories of why distributed practice produces better retention.”
Quote in the paperSubstantial claim - Findingnone given§ Discussion
Induction of additional LTP only occurs when the second train is delayed by about one hour.
“Notably, induction of additional LTP only occurs when the second train is delayed by about one hour.”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
Under these conditions TBS2 produced little, if any, additional potentiation.
“Under these conditions TBS2 produced little, if any, additional potentiation, as expected if the second theta episode modified contacts missed by TBS1.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
We saw no evidence that brefeldin interfered with contributions of the perisynaptic pool to the maintenance of baseline synaptic responses at control inputs.
“However, this would be expected to interfere with any contributions of the perisynaptic pool to the maintenance of baseline synaptic responses and we saw no evidence of this at control inputs.”
Quote in the paperNot a substantial claim - Premisecitation§ Abstract
Periodic exposure to the same material results in better retention than a single cramming session.
“An extensive body of experimental work indicates that periodic exposure to the same material results in better retention than a single “cramming” session.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Ebbinghaus H. Über das Gedächtnis. Untersuchungen zur experimentellen Psychologie. Leipzig: Duncker & Humblot; 1885. [Google Scholar]
Not checked in the free run.
- cites [2] Jost A. Die Assoziationsfestigkeit in ihrer Abhängigkeit von der Verteilung der Wiederholungen. Hamburg: Leopold Voss; 1897. [Google Scholar]
Not checked in the free run.
- cites [3] Thorndike EL. Education, a first book. New York: Macmillan; 1912. [Google Scholar]
Not checked in the free run.
- cites [4] Wickelgren WA. Single-trace fragility theory of memory dynamics. Mem Cognit. 1974;2:775–780. doi: 10.3758/BF03198154. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Results
The renewed capacity for inducing potentiation at 60-90 min does not reflect slowly developing changes to release or receptor characteristics.
“indicating that the renewed capacity for inducing potentiation found at the latter time point does not reflect slowly developing changes to release or receptor characteristics (Fig. 1C).”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
A combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictates that the repetitions be widely spaced.
“We propose that a combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictate that the repetitions be widely spaced.”
Quote in the paperSubstantial claim - Premisecitation§ Results
Actin polymerization is an essential step of LTP-stabilizing processes.
“Actin polymerization is an essential step of this kind (9, 15–17)”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [9] Bramham CR. Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol. 2008;18:524–531. doi: 10.1016/j.conb.2008.09.013. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [15] Kim CH, Lisman JE. A role of actin filament in synaptic transmission and long-term potentiation. J Neurosci. 1999;19:4314–4324. doi: 10.1523/JNEUROSCI.19-11-04314.1999. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [16] Kramár EA, Lin B, Rex CS, Gall CM, Lynch G. Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci USA. 2006;103:5579–5584. doi: 10.1073/pnas.0601354103. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [17] Krucker T, Siggins GR, Halpain S. Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. Proc Natl Acad Sci USA. 2000;97:6856–6861. doi: 10.1073/pnas.100139797. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Results
Three trains each separated by 1 h fully saturate LTP within a given population of synapses.
“Three trains each separated by 1 h, thus, fully saturate LTP within a given population of synapses.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections.
“suggesting that intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
The synaptic mechanisms described provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.
“Thus, the synaptic mechanisms described here provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
The elaborate processes yielding fully developed LTP reach completion within 10-15 min.
“several types of studies point to the conclusion that the elaborate processes yielding fully developed LTP reach completion within 10–15 min (5, 7, 8);”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Lynch G, Rex CS, Chen LY, Gall CM. Synaptic mechanisms for encoding memory. In: Koob G, Thompson RF, Le Moal M, editors. Encyclopedia of Behavioral Neuroscience. London: Academic; 2009. pp. 356–366. section ed Shors T. [Google Scholar]
Not checked in the free run.
- cites [7] Lynch G, Rex CS, Gall CM. LTP consolidation: Substrates, explanatory power, and functional significance. Neuropharmacology. 2007;52:12–23. doi: 10.1016/j.neuropharm.2006.07.027. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [8] Huang CC, Liang YC, Hsu KS. A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J Neurosci. 1999;19:9728–9738. doi: 10.1523/JNEUROSCI.19-22-09728.1999. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Results
TBS1 induces LTP in low threshold spines.
“Collectively, the above findings suggest that TBS1 has two distinct effects: (i) induction of LTP in low threshold spines”
Quote in the paperSubstantial claim - Interpretationreasoning§ Results
TBS1 lowers the threshold at synapses where it does not initially induce stable potentiation.
“and (ii) TBS1 lowers the threshold at synapses where it does not initially induce stable potentiation.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Results
Promiscuous spreading of spine signaling events could contribute to the conversion of TBS1-resistant synapses into a state capable of responding to TBS2.
“From this, it follows that promiscuous spreading of spine signaling events could contribute to the conversion of TBS1-resistant synapses into a state capable of responding to TBS2.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
The differential effect of brefeldin agrees with the prediction that slowly developing membrane insertion events initiated by TBS1 prepare high threshold spines for the arrival of TBS2.
“The differential effect of brefeldin agrees with the prediction that slowly developing membrane insertion events initiated by TBS1 prepare high threshold spines for the arrival of TBS2.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
Once a synapse reaches threshold for stable plasticity, it does not contribute to further potentiation induced by subsequent stimulations.
“and that once a synapse reaches threshold for stable plasticity, it does not contribute to further potentiation induced by subsequent stimulations.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
Only a minority of adult dendritic spines can respond to plasticity-inducing stimuli.
“These data support a model where only a minority of adult dendritic spines can respond to plasticity-inducing stimuli”
Quote in the paperSubstantial claim - Interpretationown data§ Results
Subpopulations of synapses have different thresholds for LTP.
“In all, these results suggest that (i) subpopulations of synapses have different thresholds for LTP”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
The work reported here describes LTP phenomenology, arising from previously undetected synaptic properties, that is logically related to those aspects of the effect occurring over the course of hours.
“The work reported here describes LTP phenomenology, arising from previously undetected synaptic properties, that is logically related to those aspects of the effect occurring over the course of hours.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Results
The actin polymerization induced by TBS2 is largely restricted to dendritic branches that already have potentiated synapses.
“These points indicate that the actin polymerization induced by TBS2 is largely restricted to dendritic branches that already have potentiated synapses.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
A new population of synapses was potentiated by TBS2.
“supporting the idea that a new population of synapses was potentiated by TBS2 (Fig. 2B).”
Quote in the paperSubstantial claim - Interpretationown data§ Results
Individual spines of the same general type do not respond to stereotyped postsynaptic stimulations in the same way.
“indicating that individual spines of the same general type do not respond to stereotyped postsynaptic stimulations in the same way.”
Quote in the paperSubstantial claim - Premisecitation§ Results
Uncaging glutamate near the tip of a single dendritic spine results in a coordinated increase in spine volume and enhanced synaptic function lasting for more than an hour.
“Uncaging glutamate near the tip of a single dendritic spine [single spine glutamate uncaging (SSGU)] results in a coordinated increase in spine volume and enhanced synaptic function lasting for more than an hour (20, 21).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Results
Induction of plasticity at a single spine transiently lowers the plasticity threshold at adjacent spines.
“Recent studies have shown that induction of plasticity at a single spine transiently lowers the plasticity threshold at adjacent spines (20).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Discussion
Uncaging experiments indicated that intrinsic factors operating within individual spines of the same general morphological type are responsible for the distinction between low and high threshold spines.
“Uncaging experiments indicated that intrinsic factors operating within individual spines of the same general morphological type are responsible for this distinction.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
The number of AMPA receptors scales positively with the size of synapses.
“The number of AMPA receptors scales positively with the size of synapses (37)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Sassoé-Pognetto M, et al. Organization of postsynaptic density proteins and glutamate receptors in axodendritic and dendrodendritic synapses of the rat olfactory bulb. J Comp Neurol. 2003;463:237–248. doi: 10.1002/cne.10745. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Discussion
Uncaged glutamate is known from past work to produce robust, NMDAR-dependent excitatory responses at nearly all spines under the conditions used in our experiments.
“Notably, uncaged glutamate is known from past work to produce robust, NMDAR-dependent excitatory responses at nearly all spines (20, 21) under the conditions used in our experiments.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Discussion
Our results describe an interaction between spines in which induction of LTP in low threshold cases primes their initially unresponsive neighbors so that later stimulation of the same afferents initiates actin polymerization and stable potentiation.
“Our results also describe an interaction between spines in which induction of LTP in low threshold cases primes their initially unresponsive neighbors so that later stimulation of the same afferents initiates actin polymerization and stable potentiation.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
TBS causes the breakdown of actin crosslinking proteins in the subsynaptic cytoskeleton.
“TBS, in addition to its actions on kinases, causes the breakdown of actin crosslinking proteins in the subsynaptic cytoskeleton; the relevant proteases also cleave transmembrane adhesion receptors that play a critical role in LTP-related actin polymerization (40–42).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [40] Vanderklish PW, et al. Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc Natl Acad Sci USA. 2000;97:2253–2258. doi: 10.1073/pnas.040565597. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [41] Tomimatsu Y, Idemoto S, Moriguchi S, Watanabe S, Nakanishi H. Proteases involved in long-term potentiation. Life Sci. 2002;72:355–361. doi: 10.1016/s0024-3205(02)02285-3. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [42] Huttenlocher A, et al. Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem. 1997;272:32719–32722. doi: 10.1074/jbc.272.52.32719. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Discussion
The current findings provide evidence that adult spines have different thresholds for plasticity induction.
“The current findings provide evidence that adult spines have different thresholds for plasticity induction.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
This idea accords with deficient processing and cue-variability theories of the distributed practice phenomenon.
“This idea accords with deficient processing and cue-variability theories of the distributed practice phenomenon (4, 43, 44).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Wickelgren WA. Single-trace fragility theory of memory dynamics. Mem Cognit. 1974;2:775–780. doi: 10.3758/BF03198154. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [43] Glenberg AM. Component-levels theory of the effects of spacing of repetitions on recall and recognition. Mem Cognit. 1979;7:95–112. doi: 10.3758/bf03197590. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [44] Hintzman DL. In: Repetition and memory. The Psychology of Learning and Motivation. Bower GH, editor. Vol 10. New York: Academic; 1976. pp. 47–91. [Google Scholar]
Not checked in the free run.
- Interpretationreasoning§ Discussion
The low vs. high threshold distinction reflects the area of the postsynaptic component of the apposition zone.
“and so the above hypothesis can be reduced to an anatomical argument: the low vs. high threshold distinction reflects the area of the postsynaptic component of the apposition zone.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
The high threshold cases have too small a population of AMPA receptors to produce the depolarization during a theta burst needed to generate an NMDAR response sufficient to trigger reorganization of the subsynaptic cytoskeleton.
“A plausible interpretation of the findings is that the high threshold cases have too small a population of AMPA receptors to produce the depolarization (during a theta burst) needed to generate an NMDAR response sufficient to trigger reorganization of the subsynaptic cytoskeleton.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
The relevant proteases cleave transmembrane adhesion receptors that play a critical role in LTP-related actin polymerization.
“TBS, in addition to its actions on kinases, causes the breakdown of actin crosslinking proteins in the subsynaptic cytoskeleton; the relevant proteases also cleave transmembrane adhesion receptors that play a critical role in LTP-related actin polymerization (40–42).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [40] Vanderklish PW, et al. Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc Natl Acad Sci USA. 2000;97:2253–2258. doi: 10.1073/pnas.040565597. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [41] Tomimatsu Y, Idemoto S, Moriguchi S, Watanabe S, Nakanishi H. Proteases involved in long-term potentiation. Life Sci. 2002;72:355–361. doi: 10.1016/s0024-3205(02)02285-3. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [42] Huttenlocher A, et al. Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem. 1997;272:32719–32722. doi: 10.1074/jbc.272.52.32719. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationreasoning§ Discussion
Events occurring within minutes after TBS1 combine with a much later membrane insertion step to produce this unique form of spine crosstalk.
“We propose that events occurring within minutes after TBS1 combine with a much later membrane insertion step to produce this unique form of spine crosstalk.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The priming effect of TBS1 on nonresponsive spines occurs at a stage located between the transmitter receptors and the multiple steps leading to the assembly and stabilization of actin filaments.
- May combine two claims. 21
- Classified as probably not a substantial claim. 14
May combine two claims.
Findingown data§ ResultsA third train delayed by 60 min after TBS2 increased potentiation, whereas a fourth and fifth had no effect.
“A third train delayed by 60 min after TBS2 again increased potentiation, whereas a fourth and fifth had no effect (Fig. 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsTBS2 caused short-term, but not additional long-term, response facilitation when delivered at 10 or 30 min after TBS1.
“TBS2 caused short-term, but not additional long-term, response facilitation when delivered at 10 or 30 min after TBS1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractSuccessive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used.
“Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsForty-minute treatments with brefeldin A that immediately preceded TBS1, or that ended 10 min before the theta bursts, had no effect on baseline physiology or the induction of LTP1.
“Forty-minute treatments that immediately preceded TBS1, or that ended 10 min before the theta bursts, had no effect on baseline physiology or the induction of LTP1 (Fig. 4D, Left).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsBrefeldin A administered after TBS1 caused LTP1 to gradually decay back to baseline, without affecting responses to a control input.
“However, as shown in Fig. 4D, brefeldin administered after TBS1 also produced a dramatic and unexpected result: it caused LTP1 to gradually decay back to baseline, again without affecting responses to a control input.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsHead volume changes did not occur in neighboring spines, confirming that the stimulation protocol produces plasticity at a single synapse.
“Head volume changes did not occur in neighboring spines, confirming that the stimulation protocol produces plasticity at a single synapse.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsThe enlargement probability was significantly greater in young than in adult slices (P < 0.005) even though the targeted spines were of similar volume and the same induction protocol was used.
“Indeed, the enlargement probability was significantly greater in young than in adult slices (P < 0.005) even though the targeted spines were of similar volume and the same induction protocol was used (Fig. 3D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingreasoning§ DiscussionSuch an event would necessarily increase EPSPs at 30-60 min after TBS1 and this is not observed.
“Such an event would necessarily increase excitatory postsynaptic potentials (EPSPs) at 30–60 min after TBS1 and this is not observed.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DiscussionBrief treatments with a drug that selectively enhances AMPA receptor-gated synaptic currents markedly increases both the number of spines in which TBS1 triggers actin polymerization and the magnitude of LTP1.
“Regarding the cellular bases for the distinction between low and high threshold spines, we found that brief treatments with a drug that selectively enhances AMPA receptor-gated synaptic currents markedly increases both the number of spines in which TBS1 triggers actin polymerization and the magnitude of LTP1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DiscussionThe glutamate-uncaging experiments were designed to produce maximal stimulation of NMDARs and yet detected two classes of spines in the proportions expected from the LTP studies.
“Second, the glutamate-uncaging experiments were designed to produce maximal stimulation of NMDARs and yet detected two classes of spines in the proportions expected from the LTP studies.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation§ AbstractActivity-dependent synaptic plasticity, and in particular long-term potentiation of glutamatergic transmission, is thought to underlie rapid storage of new information.
“Activity-dependent synaptic plasticity, and, in particular, long-term potentiation (LTP) of glutamatergic transmission, is thought to underlie rapid storage of new information (5, 6).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Lynch G, Rex CS, Chen LY, Gall CM. Synaptic mechanisms for encoding memory. In: Koob G, Thompson RF, Le Moal M, editors. Encyclopedia of Behavioral Neuroscience. London: Academic; 2009. pp. 356–366. section ed Shors T. [Google Scholar]
Not checked in the free run.
- cites [6] Morris RG. Long-term potentiation and memory. Philos Trans R Soc Lond B Biol Sci. 2003;358:643–647. doi: 10.1098/rstb.2002.1230. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ ResultsAdditional potentiation can be induced four hours after induction of LTP1.
“Other studies using variable stimulation intensities suggest that additional potentiation can be induced four hours after induction of LTP1 (10, 12).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [10] Frey U, Morris RG. Synaptic tagging: Implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 1998;21:181–188. doi: 10.1016/s0166-2236(97)01189-2. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [12] Frey U, Schollmeier K, Reymann KG, Seidenbecher T. Asymptotic hippocampal long-term potentiation in rats does not preclude additional potentiation at later phases. Neuroscience. 1995;67:799–807. doi: 10.1016/0306-4522(95)00117-2. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Premisecitation§ ResultsLow-frequency (5-Hz) stimulation erases LTP1 if applied shortly after TBS but then becomes progressively less effective over the following 30 min.
“Low-frequency (5-Hz) stimulation erases LTP1 if applied shortly after TBS but then becomes progressively less effective over the following 30 min (8, 14);”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Huang CC, Liang YC, Hsu KS. A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J Neurosci. 1999;19:9728–9738. doi: 10.1523/JNEUROSCI.19-22-09728.1999. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [14] Barrionuevo G, Schottler F, Lynch G. The effects of repetitive low frequency stimulation on control and “potentiated” synaptic responses in the hippocampus. Life Sci. 1980;27:2385–2391. doi: 10.1016/0024-3205(80)90509-3. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationown data§ ResultsLTP has a previously undetected refractory period, lasting for 30-60 min, which creates an analog of the behavioral spaced trials effect.
“In all, the present results show that LTP has a previously undetected refractory period, lasting for 30–60 min, which creates an analog of the behavioral spaced trials effect (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Anderson MJ, Jablonski SA, Klimas DB. Spaced initial stimulus familiarization enhances novelty preference in Long-Evans rats. Behav Processes. 2008;78:481–486. doi: 10.1016/j.beproc.2008.02.005. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Premisecitation§ ResultsThe mechanism underlying this phenomenon involves local spreading of signaling cascades from the activated spine to its neighbors, and some of these spreading signals are potent drivers of F-actin dynamics.
“The mechanism underlying this phenomenon involves local spreading of signaling cascades from the activated spine to its neighbors, and some of these spreading signals are potent drivers of F-actin dynamics (24–26).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [25] Harvey CD, Yasuda R, Zhong H, Svoboda K. The spread of Ras activity triggered by activation of a single dendritic spine. Science. 2008;321:136–140. doi: 10.1126/science.1159675. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [26] Rex CS, et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol. 2009;186:85–97. doi: 10.1083/jcb.200901084. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionThe spaced-trial effect operates across multiple time frames, ranging from a few seconds to weeks.
“The spaced-trial effect operates across multiple time frames, ranging from a few seconds to weeks (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Cepeda NJ, Pashler H, Vul E, Wixted JT, Rohrer D. Distributed practice in verbal recall tasks: A review and quantitative synthesis. Psychol Bull. 2006;132:354–380. doi: 10.1037/0033-2909.132.3.354. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionPrevious efforts to find neurobiological explanations for the advantages of distributed practice obtained evidence that spaced trials can offset memory defects in mice lacking two variants of the transcription factor CREB.
“Previous efforts to find neurobiological explanations for the advantages of distributed practice obtained evidence that spaced trials can offset memory defects in mice lacking two variants of the transcription factor CREB (31, 32).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [31] Kogan JH, et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol. 1997;7:1–11. doi: 10.1016/s0960-9822(06)00022-4. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [32] Yin JC, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell. 1994;79:49–58. doi: 10.1016/0092-8674(94)90399-9. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ ResultsThis form of plasticity shares many properties with Schaffer collateral LTP, including dependence on NMDARs, Rho GTPase signaling, CaMKII phosphorylation, F-actin polymerization and synaptic AMPAR insertion.
“This form of plasticity shares many properties with Schaffer collateral LTP, including dependence on N-methyl-d-aspartate receptors (NMDARs), Rho GTPase signaling, Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, F-actin polymerization and synaptic AMPAR insertion (20–24).”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [22] Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H. The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron. 2008;57:719–729. doi: 10.1016/j.neuron.2008.01.013. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [23] Makino H, Malinow R. AMPA receptor incorporation into synapses during LTP: The role of lateral movement and exocytosis. Neuron. 2009;64:381–390. doi: 10.1016/j.neuron.2009.08.035. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.
Interpretationown data§ ResultsSimilarly delayed events set in motion by TBS1 serve to anchor LTP in one set of spines and to provide ingredients needed for potentiation in a second.
“The latter finding points to a hypothesis in which similarly delayed events set in motion by TBS1 serve to anchor LTP in one set of spines and to provide ingredients needed for potentiation in a second.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ ResultsThe low success rate in adults was unlikely related to technical issues because a strong induction protocol caused structural plasticity in >80% of young spines.
“The low success rate in adults was unlikely related to technical issues because we used a strong induction protocol (20) that caused structural plasticity in >80% of young spines (Fig. 3C), a value in good agreement with previous studies (20, 21).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationown data§ ResultsTBS1 converts TBS1-resistant spines into the low threshold state, providing a refreshed pool of synapses capable of responding to TBS2.
“and (ii) conversion of TBS1-resistant spines into the low threshold state, which provides a refreshed pool of synapses capable of responding to TBS2.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone given§ Materials and MethodsPrecise alignment of the stimulation scanner to the image scanner was confirmed by ablation of a 0.5-μm tetraspec bead with a high-energy pulse of 720-nm light.
“Precise alignment of the stimulation scanner to the image scanner was confirmed by ablation of a 0.5-μm tetraspec bead (Invitrogen) with a high-energy pulse of 720-nm light.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DiscussionThe kinase PKMζ is engaged at ≥1 h after induction and then contributes to maintenance of LTP.
“several studies have shown that the kinase PKMζ is engaged at ≥1 h after induction and then contributes to maintenance of LTP (39).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Sacktor TC. PKMzeta, LTP maintenance, and the dynamic molecular biology of memory storage. Prog Brain Res. 2008;169:27–40. doi: 10.1016/S0079-6123(07)00002-7. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationown data§ DiscussionOne aspect of our data links the requirement for long delays to machinery that also serves to stabilize previously induced LTP and, thereby, supports consolidation explanations for the behavioral effects.
“One aspect of our data links the requirement for long delays to machinery that also serves to stabilize previously induced LTP and, thereby, supports consolidation explanations (43) for the behavioral effects.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Glenberg AM. Component-levels theory of the effects of spacing of repetitions on recall and recognition. Mem Cognit. 1979;7:95–112. doi: 10.3758/bf03197590. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionStrong stimulation of single synapses causes the spread of active GTPases to neighboring spines.
“Prior work suggesting that strong stimulation of single synapses causes the spread of active GTPases to neighboring spines (24, 25) is of interest in this regard because these enzymes play critical roles in the production of stable LTP.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [25] Harvey CD, Yasuda R, Zhong H, Svoboda K. The spread of Ras activity triggered by activation of a single dendritic spine. Science. 2008;321:136–140. doi: 10.1126/science.1159675. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionThese enzymes play critical roles in the production of stable LTP.
“because these enzymes play critical roles in the production of stable LTP.”
- Also stated in: § Discussion · plain
“spines (24, 25) is of interest in this regard because these enzymes play critical roles in the production of stable LTP.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [25] Harvey CD, Yasuda R, Zhong H, Svoboda K. The spread of Ras activity triggered by activation of a single dendritic spine. Science. 2008;321:136–140. doi: 10.1126/science.1159675. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Also stated in: § Discussion · plain
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ DiscussionThe delayed membrane insertion step indicated by the brefeldin experiments involves delivery of AMPA receptors to synapses.
“First, it implies that the delayed membrane insertion step indicated by the brefeldin experiments involves delivery of AMPA receptors to synapses.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitation§ Materials and MethodsThe threshold for deeming a spine enlarged (>50% volume change 2 min after uncaging) was chosen before the experiments were conducted and was based on prior studies.
“This threshold was chosen before the experiments were conducted and was based on prior studies (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone given§ Materials and MethodsVolume changes at nearby spines were analyzed to ensure that laser targeting of individual spines was specific.
“Volume changes at nearby spines were also analyzed to ensure that laser targeting of individual spines was specific.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ DiscussionPreviously undetected cellular mechanisms impose temporal spacing requirements for synaptic plasticity and, thereby, provide a neurobiological explanation for one temporal segment of a ubiquitous feature of learning.
“Thus, previously undetected cellular mechanisms impose temporal spacing requirements for synaptic plasticity and, thereby, provide a neurobiological explanation for one temporal segment of a ubiquitous feature of learning.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionInduction of LTP is accompanied by prolonged activation of CaMKII, a kinase localized to synapses.
“Reports that induction of LTP is accompanied by prolonged activation of CaMKII (38), a kinase localized to synapses, suggest a candidate for this role.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002;3:175–190. doi: 10.1038/nrn753. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationown data§ DiscussionThe spine threshold component of the present results implies that spaced trials capture a greater percentage of the information carried by activated afferent systems, something that would allow for easier cue recognition during retention tests.
“The spine threshold component of the present results implies that spaced trials capture a greater percentage of the information carried by activated afferent systems, something that would allow for easier cue recognition during retention tests.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
The priming effect of TBS1 on nonresponsive spines occurs at a stage located between the transmitter receptors and the multiple steps leading to the assembly and stabilization of actin filaments.
“We, therefore, assume that the priming effect of TBS1 on nonresponsive spines occurs at a stage located between the transmitter receptors and the multiple steps leading to the assembly and stabilization of actin filaments.”
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?
For longer intervals of 60 or 90 minutes, a cumulative increase in LTP was observed over three bursts of stimulation in rat hippocampal slices.
“However, for longer intervals (60 or 90 minutes), a cumulative increase in LTP was observed over three bursts of stimulation.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
Theta-burst stimuli applied at intervals of 10 or 40 minutes did not cumulatively increase LTP in rat hippocampal slices.
“Theta-burst stimuli applied at intervals of 10 or 40 minutes did not cumulatively increase LTP.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
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 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.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
The 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 rodents.
“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.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
For the spaced LTP protocol of Gall, Lynch and colleagues, an interval of 40-60 minutes is needed for successive theta-burst stimuli to further increase LTP.
“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.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In hippocampal slices, additional potentiation can be induced up to 4 hours after induction of the first LTP increment.
“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.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
The required refractory period of about 1 hour between successive theta-burst stimuli to induce progressive increments in hippocampal LTP may be in line with the variant that short intervals are insufficient for consolidation and consequent summation of memory traces.
“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.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
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.
CREB study described as involving mice is cited as a Drosophila study
MinorThe discussion describes references 31 and 32 as studies of memory defects in mice, but reference 32 explicitly concerns Drosophila.
“Previous efforts to find neurobiological explanations for the advantages of distributed practice obtained evidence that spaced trials can offset memory defects in mice lacking two variants of the transcription factor CREB (31, 32).”
“32.Yin JC, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.”
Cites
Rescorla, R. A. (1972) · Medical Entomology and Zoology · Cited by 7,268 · see citing works
Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP
Feng, G., Mellor, R. H., Bernstein, M., Keller-Peck, C., Nguyen, Q. T., Wallace, M., Nerbonne, J. M., Lichtman, J. W., & Sanes, J. R. (2000) · Neuron · doi:10.1016/s0896-6273(00)00084-2 · Cited by 3,042 · see citing works
Structural basis of long-term potentiation in single dendritic spines
Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. R., & Kasai, H. (2004) · Nature · doi:10.1038/nature02617 · Cited by 2,500 · see citing works
Distributed practice in verbal recall tasks: A review and quantitative synthesis.
Cepeda, N. J., Pashler, H., Vul, E., Wixted, J. T., & Rohrer, D. (2006) · Psychological Bulletin · doi:10.1037/0033-2909.132.3.354 · Cited by 1,888 · cited 2× · see citing works
“Discussion The spaced-trial effect operates across multiple time frames, ranging from a few seconds to weeks (30).”
BackgroundThe molecular basis of CaMKII function in synaptic and behavioural memory
Lisman, J., Schulman, H., & Cline, H. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn753 · Cited by 1,860 · see citing works
Brefeldin A: insights into the control of membrane traffic and organelle structure.
Klausner, R. D., Donaldson, J. G., & Lippincott‐Schwartz, J. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.116.5.1071 · Cited by 1,852 · see citing works
Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila
Yin, J. C. P., Wallach, J. S., Del Vecchio, M., Wilder, E. L., Zhou, H., Quinn, W. G., & Tully, T. (1994) · Cell · doi:10.1016/0092-8674(94)90399-9 · Cited by 959 · see citing works
Locally dynamic synaptic learning rules in pyramidal neuron dendrites
Harvey, C. D., & Svoboda, K. (2007) · Nature · doi:10.1038/nature06416 · Cited by 625 · see citing works
Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation
Frey, U., & Morris, R. G. M. (1998) · Trends in Neurosciences · doi:10.1016/s0166-2236(97)01189-2 · Cited by 615 · see citing works
Local, persistent activation of Rho GTPases during plasticity of single dendritic spines
Murakoshi, H., Wang, H., & Yasuda, R. (2011) · Nature · doi:10.1038/nature09823 · Cited by 564 · see citing works
AMPA Receptor Incorporation into Synapses during LTP: The Role of Lateral Movement and Exocytosis
Makino, H., & Malinow, R. (2009) · Neuron · doi:10.1016/j.neuron.2009.08.035 · Cited by 501 · see citing works
The Subspine Organization of Actin Fibers Regulates the Structure and Plasticity of Dendritic Spines
Honkura, N., Matsuzaki, M., Noguchi, J., Ellis-Davies, G. C. R., & Kasai, H. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.013 · Cited by 490 · see citing works
Brefeldin A: Deciphering an Enigmatic Inhibitor of Secretion
Nebenführ, A., Ritzenthaler, C., & Robinson, D. G. (2002) · PLANT PHYSIOLOGY · doi:10.1104/pp.011569 · Cited by 487 · see citing works
Component-levels theory of the effects of spacing of repetitions on recall and recognition
Glenberg, A. M. (1979) · Memory & Cognition · doi:10.3758/bf03197590 · Cited by 444 · see citing works
The Spread of Ras Activity Triggered by Activation of a Single Dendritic Spine
Harvey, C. D., Yasuda, R., Zhong, H., & Svoboda, K. (2008) · Science · doi:10.1126/science.1159675 · Cited by 434 · see citing works
Regulation of Cell Migration by the Calcium-dependent Protease Calpain
Huttenlocher, A., Palecek, S. P., Lu, Q., Zhang, W., Mellgren, R. L., Lauffenburger, D. A., Ginsberg, M. H., & Horwitz, A. F. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.52.32719 · Cited by 390 · see citing works
Hintzman, D. L. (1976) · Psychology of Learning and Motivation · doi:10.1016/s0079-7421(08)60464-8 · Cited by 388 · see citing works
A Role of Actin Filament in Synaptic Transmission and Long-Term Potentiation
Kim, C.-H., & Lisman, J. E. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-11-04314.1999 · Cited by 386 · see citing works
Krucker, T., Siggins, G. R., & Halpain, S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.100139797 · Cited by 374 · see citing works
Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning
Kim, J. J., & Thompson, R. F. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)10081-3 · Cited by 357 · see citing works
Spaced training induces normal long-term memory in CREB mutant mice
Kogan, J. H., Frankland, P. W., Blendy, J. A., Coblentz, J., Marowitz, Z., Schütz, G., & Silva, A. J. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00022-4 · Cited by 350 · see citing works
Rex, C. S., Lin, C.-Y., Kramár, E. A., Chen, L. Y., Gall, C. M., & Lynch, G. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4037-06.2007 · Cited by 324 · see citing works
Self-citationBarrionuevo, G., Schottler, F., & Lynch, G. (1980) · Life Sciences · doi:10.1016/0024-3205(80)90509-3 · Cited by 321 · see citing works
Self-citationLocal protein synthesis, actin dynamics, and LTP consolidation
Bramham, C. R. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.09.013 · Cited by 301 · see citing works
Rex, C. S., Chen, L. Y., Sharma, A., Liu, J., Babayan, A. H., Gall, C. M., & Lynch, G. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200901084 · Cited by 293 · see citing works
Self-citationÜber das Gedächtnis. Untersuchungen zur experimentellen Psychologie
Ebbinghaus, H. (2018) · Cited by 286 · see citing works
Encyclopedia of Behavioral Neuroscience
(2011) · Choice Reviews Online · doi:10.5860/choice.48-5432 · Cited by 266 · see citing works
Long-term potentiation and memory
Morris, R. G. M. (2003) · Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences · doi:10.1098/rstb.2002.1230 · Cited by 232 · see citing works
Single-trace fragility theory of memory dynamics
Wickelgren, W. A. (1974) · Memory & Cognition · doi:10.3758/bf03198154 · Cited by 224 · see citing works
Integrin-driven actin polymerization consolidates long-term potentiation
Kramár, E. A., Lin, B., Rex, C. S., Gall, C. M., & Lynch, G. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601354103 · Cited by 221 · see citing works
Self-citationLTP consolidation: Substrates, explanatory power, and functional significance
Lynch, G., Rex, C. S., & Gall, C. M. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.07.027 · Cited by 214 · see citing works
Self-citationPharmacology of Ampakine Modulators: From AMPA Receptors to Synapses and Behavior
Arai, A., & Kessler, M. (2007) · Current Drug Targets · doi:10.2174/138945007780618490 · Cited by 211 · see citing works
Chapter 2 PKMζ, LTP maintenance, and the dynamic molecular biology of memory storage
Sacktor, T. C. (2008) · Progress in Brain Research · doi:10.1016/s0079-6123(07)00002-7 · Cited by 208 · see citing works
Ebbinghaus, H. (1996) · University of Toronto eBooks · Cited by 203 · see citing works
Vanderklish, P. W., Krushel, L. A., Holst, B. H., Gally, J. A., Crossin, K. L., & Edelman, G. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.040565597 · Cited by 163 · see citing works
Fanselow, M. S. (1998) · Neuron · doi:10.1016/s0896-6273(00)81002-8 · Cited by 159 · see citing works
Arai, A., Kessler, M., Rogers, G. A., & LYNCH, G. S. (2000) · Molecular Pharmacology · doi:10.1124/mol.58.4.802 · Cited by 141 · see citing works
Self-citationAMPA receptor modulators as cognitive enhancers
LYNCH, G. S. (2003) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2003.09.009 · Cited by 138 · see citing works
Self-citationHuang, C.-C., Liang, Y.-C., & Hsu, K.-S. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-22-09728.1999 · Cited by 127 · see citing works
Fanselow, M. S., & Tighe, T. J. (1988) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037/0097-7403.14.2.187 · Cited by 101 · see citing works
Frey, U., Schollmeier, K., Reymann, K. G., & Seidenbecher, T. (1995) · Neuroscience · doi:10.1016/0306-4522(95)00117-2 · Cited by 93 · see citing works
Die Assoziationsfestigkeit in ihrer Abh?ngigkeit von der Verteilung der Wiederholungen.
Smith, W. G. (1897) · Psychological Review · doi:10.1037/h0065777 · Cited by 88 · see citing works
Proteases involved in long-term potentiation
Tomimatsu, Y., Idemoto, S., Moriguchi, S., Watanabe, S., & Nakanishi, H. (2002) · Life Sciences · doi:10.1016/s0024-3205(02)02285-3 · Cited by 88 · see citing works
Teo, J., Swayne, O. B. C., Cheeran, B., Greenwood, R., & Rothwell, J. C. (2010) · Cerebral Cortex · doi:10.1093/cercor/bhq231 · Cited by 88 · see citing works
Thorndike, E. L. (1974) · Medical Entomology and Zoology · Cited by 73 · see citing works
Sassoé‐Pognetto, M., Utvik, J. K., Camoletto, P., Watanabe, M., Stephenson, F. A., Bredt, D. S., & Ottersen, O. P. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10745 · Cited by 45 · see citing works
Lin, C., LYNCH, G. S., & Gall, C. M. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03203.x · Cited by 37 · see citing works
Self-citationSpaced initial stimulus familiarization enhances novelty preference in Long-Evans rats
Anderson, M. J., Jablonski, S. A., & Klimas, D. B. (2008) · Behavioural Processes · doi:10.1016/j.beproc.2008.02.005 · Cited by 30 · see citing works
Synaptic Mechanisms for Encoding Memory
LYNCH, G. S., Rex, C. S., Chen, L. Y., & Gall, C. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-08-045396-5.00149-4 · Cited by 5 · see citing works
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Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression
Cole, E. J., Stimpson, K. H., Bentzley, B. S., Gulser, M., Cherian, K., Tischler, C., Nejad, R., Pankow, H., Choi, E., Aaron, H., et al. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19070720 · Cited by 802 · see citing works
Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial
Cole, E. J., Phillips, A. L., Bentzley, B. S., Stimpson, K. H., Nejad, R., Barmak, F., Veerapal, C., Khan, N., Cherian, K., Felber, E., et al. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2021.20101429 · Cited by 795 · see citing works
Dendritic Spines: The Locus of Structural and Functional Plasticity
Sala, C., & Segal, M. (2014) · Physiological Reviews · doi:10.1152/physrev.00012.2013 · Cited by 465 · see citing works
Structural Components of Synaptic Plasticity and Memory ConsolidationPreprint
Bailey, C. H., Kandel, E. R., & Harris, K. M. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021758 · Cited by 393 · see citing works
The right time to learn: Mechanisms and optimization of spaced learning
Smolen, P., Zhang, Y., & Byrne, J. H. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.18 · Cited by 326 · see citing works
Nanoconnectomic upper bound on the variability of synaptic plasticity
Bartol, T. M., Bromer, C., Kinney, J. P., Chirillo, M. A., Bourne, J. N., Harris, K. M., & B, T. J. S. A. (2015) · eLife · doi:10.7554/elife.10778 · Cited by 319 · see citing works
Larson, J., & Munkácsy, E. (2015) · Brain Research · doi:10.1016/j.brainres.2014.10.034 · Cited by 285 · see citing works
Greif, R. T., Bhanji, F., Bigham, B. L., Bray, J., Breckwoldt, J., Cheng, A., Duff, J. P., Gilfoyle, E., Hsieh, M., Iwami, T., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000896 · Cited by 228 · see citing works
High-dose spaced Theta-burst TMS as a rapid-acting antidepressant in highly refractory depression
Williams, N. R., Sudheimer, K. D., Bentzley, B. S., Pannu, J., Stimpson, K. H., Duvio, D., Cherian, K., Hawkins, J., Scherrer, K. H., Vyssoki, B., et al. (2018) · Brain · doi:10.1093/brain/awx379 · Cited by 215 · see citing works
Synaptic clustering within dendrites: An emerging theory of memory formation
Kastellakis, G., Cai, D. J., Mednick, S. C., Silva, A. J., & Poirazi, P. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.12.002 · Cited by 190 · see citing works
Form and function of sleep spindles across the lifespan
Clawson, B. C., Durkin, J., & Aton, S. J. (2016) · Neural Plasticity · doi:10.1155/2016/6936381 · Cited by 178 · see citing works
“This represents a significant gap in the literature, as puberty and adolescence are times of significant change in both body and brain development,marking the transition from childhood to adulthood.”
BackgroundKwapis, J. L., Alaghband, Y., Kramár, E. A., López, A. J., Ciernia, A. V., White, A. O., Shu, G., Rhee, D., Michael, C. M., Montellier, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05868-0 · Cited by 162 · see citing works
Self-citationGreif (2020) · doi:10.1016/j.resuscitation.2020.09.014 · Cited by 158 · see citing works
Accelerated TMS - moving quickly into the future of depression treatment
van Rooij, S. J. H., Arulpragasam, A. R., McDonald, W. M., & Philip, N. S. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01599-z · Cited by 139 · see citing works
UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis
Sun, J., Zhu, G., Liu, Y., Standley, S., Ji, A., Tunuguntla, R., Wang, Y., Claus, C., Luo, Y., Baudry, M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.023 · Cited by 131 · see citing works
Dendritic spines: Morphological building blocks of memory
Segal, M. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.06.007 · Cited by 123 · see citing works
Zhu, G., Liu, Y., Wang, Y., Bi, X., & Baudry, M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2193-14.2015 · Cited by 120 · see citing works
Lattal, K. M., & Wood, M. A. (2013) · Nature Neuroscience · doi:10.1038/nn.3302 · Cited by 116 · see citing works
Tse, N. Y., Goldsworthy, M. R., Ridding, M. C., Coxon, J. P., Fitzgerald, P. B., Fornito, A., & Rogasch, N. C. (2018) · Scientific Reports · doi:10.1038/s41598-018-26791-w · Cited by 113 · see citing works
Cellular and Molecular Differences Between Area CA1 and the Dentate Gyrus of the Hippocampus
Alkadhi, K. A. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1541-2 · Cited by 113 · see citing works
The effect of distributed practice: Neuroscience, cognition, and education
Gerbier, É., & Toppino, T. C. (2015) · Trends in Neuroscience and Education · doi:10.1016/j.tine.2015.01.001 · Cited by 108 · see citing works
Making long-term memories in minutes: a spaced learning pattern from memory research in education
Kelley, P., & Whatson, T. S. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00589 · Cited by 106 · see citing works
Accelerated theta burst stimulation for the treatment of depression: a randomised controlled trial
Chen, L., Thomas, E. H. X., Kaewpijit, P., Miljevic, A., Hughes, R., Hahn, L., Kato, Y., Gill, S., Clarke, P., Ng, F., et al. (2021) · Brain Stimulation · doi:10.1016/j.brs.2021.07.018 · Cited by 105 · see citing works
Baudry, M., Zhu, G., Liu, Y., Wang, Y., Briz, V., & Bi, X. (2014) · Brain Research · doi:10.1016/j.brainres.2014.11.033 · Cited by 100 · see citing works
Chung, S. W., Rogasch, N. C., Hoy, K. E., & Fitzgerald, P. B. (2018) · Brain Stimulation · doi:10.1016/j.brs.2018.01.002 · Cited by 98 · see citing works
Lynch, G., Kramár, E. A., Babayan, A. H., Rumbaugh, G., & Gall, C. M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.07.006 · Cited by 97 · see citing works
Self-citationTranscranial magnetic stimulation (TMS) for geriatric depression
Cappon, D., den Boer, T., Jordan, C., Yu, W., Metzger, E., & Pascual-Leone, A. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101531 · Cited by 97 · see citing works
Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton
Kramár, E. A., Babayan, A. H., Gall, C. M., & LYNCH, G. S. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.10.038 · Cited by 97 · see citing works
Self-citationIntegrin Dynamics Produce a Delayed Stage of Long-Term Potentiation and Memory Consolidation
Babayan, A. H., Kramár, E. A., Barrett, R. M., Jafari, M., Häettig, J., Chen, L. Y., Rex, C. S., Lauterborn, J. C., Wood, M. A., Gall, C. M., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.2024-12.2012 · Cited by 93 · see citing works
Self-citationSpaced learning versus massed learning in resuscitation — A systematic review
Yeung, J., Djärv, T., Hsieh, M., Sawyer, T., Lockey, A. S., Finn, J., Greif, R. T., Lightfoot, D., Singletary, E. M., Morley, P. T., et al. (2020) · Resuscitation · doi:10.1016/j.resuscitation.2020.08.132 · Cited by 92 · see citing works
Synaptic Clustering and Memory Formation
Kastellakis, G., & Poirazi, P. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00300 · Cited by 89 · see citing works
Wang, W., Trieu, B. H., Palmer, L. C., Jia, Y., Pham, D. T., Jung, K., Karsten, C. A., Merrill, C. B., Mackie, K., Gall, C. M., et al. (2016) · eNeuro · doi:10.1523/eneuro.0160-16.2016 · Cited by 87 · see citing works
Self-citationA molecular brake controls the magnitude of long-term potentiation
Wang, Y., Zhu, G., Briz, V., Hsu, Y., Bi, X., & Baudry, M. (2014) · Nature Communications · doi:10.1038/ncomms4051 · Cited by 82 · see citing works
Accelerated Theta Burst Stimulation: Safety, Efficacy, and Future Advancements
Cole, E., O’Sullivan, S. J., Tik, M., & Williams, N. R. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.12.004 · Cited by 79 · see citing works
Bell, M. E., Bourne, J. N., Chirillo, M. A., Mendenhall, J. M., Kuwajima, M., & Harris, K. M. (2014) · Journal of Comparative Neurology · doi:10.1002/cne.23646 · Cited by 72 · see citing works
The After-Effect of Accelerated Intermittent Theta Burst Stimulation at Different Session Intervals
Yu, F., Tang, X., Hu, R., Liang, S., Wang, W., Tian, S., Wu, Y., Yuan, T.-F., & Zhu, Y. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00576 · Cited by 70 · see citing works
Architecture and Dynamics of the Neuronal Secretory Network
Kennedy, M. J., & Hanus, C. (2019) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100818-125418 · Cited by 63 · see citing works
Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats
Lauterborn, J. C., Palmer, L. C., Jia, Y., Pham, D. T., Hou, B., Wang, W., Trieu, B. H., Cox, C. D., Kantorovich, S., Gall, C. M., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3157-15.2016 · Cited by 61 · see citing works
Self-citationAziz, W., Wang, W., Kesaf, S., Mohamed, A. A., Fukazawa, Y., & Shigemoto, R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303317110 · Cited by 60 · see citing works
Sex differences in synaptic plasticity underlying learning
Gall, C. M., Le, A. A., & LYNCH, G. S. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24844 · Cited by 59 · see citing works
Self-citationAccelerated intermittent theta burst stimulation in major depressive disorder: A systematic review.
Neuteboom, D., Zantvoord, J., Goya-Maldonado, R., Wilkening, J., Dols, A., van Exel, E. V., Lok, A., de Haan, L., & Scheepstra, K. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115429 · Cited by 54 · see citing works
Long-term potentiation expands information content of hippocampal dentate gyrus synapses
Bromer, C., Bartol, T. M., Bowden, J. B., Hubbard, D. D., Hanka, D. C., Gonzalez, P. V., Kuwajima, M., Mendenhall, J. M., Parker, P. H., Abraham, W. C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1716189115 · Cited by 59 · see citing works
Chen, L., Klooster, D., Tik, M., Thomas, E. H. X., Downar, J. H., Fitzgerald, P. B., Williams, N., & Baeken, C. (2023) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000364 · Cited by 58 · see citing works
Thomson, A. C., & Sack, A. T. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.599918 · Cited by 55 · see citing works
Wimmer, G. E., Li, J. K., Gorgolewski, K. J., & Poldrack, R. A. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0075-18.2018 · Cited by 53 · see citing works
Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice
Seese, R. R., Wang, K., Yao, Y. Q., Lynch, G., & Gall, C. M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413335111 · Cited by 52 · see citing works
Self-citationCurrent Updates on Newer Forms of Transcranial Magnetic Stimulation in Major Depression
Cheng, C., Li, C., & Tsai, S. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-33-6044-0_18 · Cited by 50 · see citing works
Prefrontal synaptic regulation of homeostatic sleep pressure revealed through synaptic chemogenetics
Sawada, T., Iino, Y., Yoshida, K., Okazaki, H., Nomura, S., Shimizu, C., Arima, T., Juichi, M., Zhou, S., Kurabayashi, N., et al. (2024) · Science · doi:10.1126/science.adl3043 · Cited by 50 · see citing works
Influence of inter-train interval on the plastic effects of rTMS
Cash, R. F. H., Dar, A., Hui, J., Ruiter, L. D., Baarbé, J. K., Fettes, P., Peters, S., Fitzgerald, P. B., Downar, J. H., & Chen, R. E. (2017) · Brain stimulation · doi:10.1016/j.brs.2017.02.012 · Cited by 50 · see citing works
Pharmacological enhancement of memory or cognition in normal subjects
Lynch, G. (2014) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2014.00090 · Cited by 46 · see citing works
Self-citationIigaya, K. (2016) · eLife · doi:10.7554/elife.18073 · Cited by 43 · see citing works
Cao, G., & Harris, K. M. (2014) · Journal of Neurophysiology · doi:10.1152/jn.00297.2014 · Cited by 41 · see citing works
Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace
Ramos, S. O., Feld, M., & Fustiñana, M. S. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.988790 · Cited by 41 · see citing works
Iwashita, H., Matsumoto, Y., Maruyama, Y., Watanabe, K., Chiba, A., & Hattori, A. (2020) · Journal of Pineal Research · doi:10.1111/jpi.12703 · Cited by 41 · see citing works
Boone, C. E., Davoudi, H., Harrold, J. B., & Foster, D. J. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.05.012 · Cited by 40 · see citing works
Unifying practice schedules in the timescales of motor learning and performance
Verhoeven, F. M., & Newell, K. M. (2018) · Human Movement Science · doi:10.1016/j.humov.2018.04.004 · Cited by 39 · see citing works
Shi, R., Wang, Z., Yang, D., Hu, Y., Zhang, Z., Lan, D., Su, Y., & Wang, Y. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-05545-1 · Cited by 35 · see citing works
Trieu, B. H., Kramár, E. A., Cox, C. D., Jia, Y., Wang, W., Gall, C. M., & LYNCH, G. S. (2015) · The Journal of Physiology · doi:10.1113/jp270398 · Cited by 34 · see citing works
Self-citationPattern and predictability in memory formation: From molecular mechanisms to clinical relevance
Philips, G. T., Kopec, A. M., & Carew, T. J. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.05.003 · Cited by 33 · see citing works
Lefaucheur, J., Colzi, C., Hollander, E., Pampaloni, I., van Ameringen, M. V., Baeken, C., Fusar-Poli, P., Arango, C., Fontenelle, L. F., Batail, J., et al. (2025) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106140 · Cited by 31 · see citing works
Nonaka, M., Fitzpatrick, R., Lapira, J., Wheeler, D. G., Spooner, P. A., Parada, M. C., Muñoz, M., Tully, T., Peters, M., & Morris, R. (2017) · European Journal of Neuroscience · doi:10.1111/ejn.13637 · Cited by 33 · see citing works
Protein synthesis and consolidation of memory-related synaptic changes
LYNCH, G. S., Kramár, E. A., & Gall, C. M. (2014) · Brain Research · doi:10.1016/j.brainres.2014.11.060 · Cited by 31 · see citing works
Self-citationActivity-dependent expression of Channelrhodopsin at neuronal synapses
Gobbo, F., Marchetti, L., Jacob, A., Pinto, B., Binini, N., Bisogni, F. P., Alia, C., Luin, S., Caleo, M., Fellin, T., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01699-7 · Cited by 31 · see citing works
Cole, E., Gulser, M., Stimpson, K., Bentzley, B., Hawkins, J., Xiao, X., Schatzberg, A., Sudheimer, K., & Williams, N. (2019) · Brain Stimulation · doi:10.1016/j.brs.2018.12.299 · Cited by 31 · see citing works
Mechanism based approaches for rescuing and enhancing cognition
LYNCH, G. S. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00143 · Cited by 30 · see citing works
Self-citationSpaced training enhances memory and prefrontal ensemble stability in mice
Glas, A., Hübener, M., Bonhoeffer, T., & Goltstein, P. M. (2021) · Current Biology · doi:10.1016/j.cub.2021.06.085 · Cited by 30 · see citing works
No additive meta plasticity effects of accelerated iTBS with short inter-session intervals
Thomson, A. C., de Graaf, T. A., Kenis, G., Rutten, B. P. F., Schuhmann, T., & Sack, A. T. (2019) · Brain stimulation · doi:10.1016/j.brs.2019.05.012 · Cited by 29 · see citing works
Fonseca‐Gomes, J., Costa-Coelho, T., Ferreira-Manso, M., Inteiro-Oliveira, S., Vaz, S. H., Alemãn-Serrano, N., Atalaia-Barbacena, H., Ribeiro‐Rodrigues, L., Ramalho, R. M., Pinto, R. R., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.08.022 · Cited by 27 · see citing works
Al-Rawi, W., Easterling, L., & Edwards, P. C. (2015) · Journal of Dental Education · doi:10.1002/j.0022-0337.2015.79.4.tb05902.x · Cited by 27 · see citing works
Bello-Medina, P. C., Carrasco, L., González-Ornelas, N. R., Jeffery, K. J., & Ramı́rez-Amaya, V. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.04.047 · Cited by 27 · see citing works
Cui, H., Ding, H., Hu, L., Zhao, Y., Shu, Y., & Voon, V. (2024) · Psychological Medicine · doi:10.1017/s0033291724002289 · Cited by 25 · see citing works
Health-Related Decision-Making in HIV Disease
Doyle, K. L., Woods, S. P., Morgan, E. E., Iudicello, J. E., Cameron, M. V., Gilbert, P. E., & Beltran, J. (2016) · Journal of Clinical Psychology in Medical Settings · doi:10.1007/s10880-016-9455-x · Cited by 24 · see citing works
Weak DCS causes a relatively strong cumulative boost of synaptic plasticity with spaced learning
Sharma, M., Farahani, F., Bikson, M., & Parra, L. C. (2021) · Brain stimulation · doi:10.1016/j.brs.2021.10.552 · Cited by 24 · see citing works
Wrightson, J. G., Cole, J., Sohn, M. N., & McGirr, A. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01575-7 · Cited by 23 · see citing works
Learning and memory: An emergent property of cell motility
Baudry, M., & Bi, X. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.04.012 · Cited by 23 · see citing works
Chang, P. K. ‐., Prenosil, G. A., Verbich, D., Gill, R., & McKinney, R. A. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12638 · Cited by 23 · see citing works
Synapse-specific structural plasticity that protects and refines local circuits during LTP and LTD
Harris, K. M., Kuwajima, M., Flores, J. C., & Zito, K. (2024) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2023.0224 · Cited by 22 · see citing works
Tan, B., Chen, J., Liu, Y., Lin, Q.-Y., Wang, Y., Shi, S., Yang, Y., & Che, X. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00451 · Cited by 22 · see citing works
Mobile app technology is associated with improved otolaryngology resident in‐service performance
Kuperstock, J. E., Horný, M., & Platt, M. P. (2018) · The Laryngoscope · doi:10.1002/lary.27299 · Cited by 21 · see citing works
Félix-Oliveira, A., Dias, R. B., Colino-Oliveira, M., Rombo, D. M., & Sebastião, A. M. (2014) · Journal of Neurophysiology · doi:10.1152/jn.00058.2014 · Cited by 20 · see citing works
Martín, A. S., Rela, L., Gelb, B. D., & Pagani, M. R. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2607-16.2017 · Cited by 19 · see citing works
zapERtrap: A light-regulated ER release system reveals unexpected neuronal trafficking pathways
Bourke, A. M., Schwartz, S. L., Bowen, A. B., Kleinjan, M. S., Winborn, C. S., Kareemo, D. J., Gutnick, A., Schwarz, T. L., & Kennedy, M. J. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202103186 · Cited by 19 · see citing works
A Neuroscience Perspective on Learning
Sloan, D., & Norrgran, C. (2016) · Chemical Engineering Education · Cited by 18 · see citing works
CaMKII binding to GluN2B is important for massed spatial learning in the Morris water maze
Stein, I. S., Donaldson, M. S., & Hell, J. W. (2014) · F1000Research · doi:10.12688/f1000research.4660.1 · Cited by 18 · see citing works
Overcoming Pavlovian bias in semantic space
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Rudy, J. W. (2014) · Brain Research · doi:10.1016/j.brainres.2014.12.009 · Cited by 17 · see citing works
Successive and discrete spaced conditioning in active avoidance learning in young and aged zebrafish
Yang, P., Kajiwara, R., Tonoki, A., & Itoh, M. (2017) · Neuroscience Research · doi:10.1016/j.neures.2017.10.005 · Cited by 17 · see citing works
Ito, W., Fusco, B., & Morozov, A. (2020) · Neurophotonics · doi:10.1117/1.nph.7.1.015007 · Cited by 16 · see citing works
Macheda, T., Roberts, K. N., Morganti, J. M., Braun, D. J., & Bachstetter, A. D. (2020) · PLoS ONE · doi:10.1371/journal.pone.0232862 · Cited by 16 · see citing works
Histone deacetylase inhibition facilitates massed pattern-induced synaptic plasticity and memoryPreprint
Pandey, K. R., Sharma, K. P., & Sharma, S. K. (2015) · Learning & Memory · doi:10.1101/lm.039289.115 · Cited by 16 · see citing works
Yu, T., Chen, W., Huo, L., Luo, X., Wang, J., & Zhang, B. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115260 · Cited by 15 · see citing works
Sundelin, A., Fagerlund, M. J., Flam, B., & Djärv, T. (2023) · Resuscitation Plus · doi:10.1016/j.resplu.2023.100413 · Cited by 15 · see citing works
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Lauterborn, J. C., Schultz, M. N., Le, A. A., Amani, M., Friedman, A. E., Leach, P. T., Gall, C. M., LYNCH, G. S., & Crawley, J. N. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0495-5 · Cited by 15 · see citing works
Self-citationZheng, Y., Ma, X., Dong, L., Ma, W., & Cheng, J. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146487 · Cited by 15 · see citing works
Developmental onset of enduring long‐term potentiation in mouse hippocampus
Ostrovskaya, O. I., Cao, G., Eroğlu, Ç., & Harris, K. M. (2020) · Hippocampus · doi:10.1002/hipo.23257 · Cited by 15 · see citing works
A Map of LTP-Related Synaptic Changes in Dorsal Hippocampus Following Unsupervised Learning
Cox, C. D., Rex, C. S., Palmer, L. C., Babayan, A. H., Pham, D. T., Corwin, S. D., Trieu, B. H., Gall, C. M., & LYNCH, G. S. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4159-13.2014 · Cited by 15 · see citing works
Self-citationNeuroscience and education: Mind the gap
Morris, J., & Sah, P. (2016) · Australian Journal of Education · doi:10.1177/0004944116652913 · Cited by 15 · see citing works
Protein Phosphatase-Dependent Circadian Regulation of Intermediate-Term Associative Memory
Michel, M., Gardner, J. S., Green, C. L., Organ, C. L., & Lyons, L. C. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4534-12.2013 · Cited by 14 · see citing works
Thomae, A. V., Verweij, L., Witt, C. M., Blum, D. L., Feusi, E., Fringer, A., Huber, M., Roos, M., Lal, J. A., & Naef, R. (2023) · Medical Education Online · doi:10.1080/10872981.2023.2198177 · Cited by 13 · see citing works
Nonlinear slow-timescale mechanisms in synaptic plasticity
O’Donnell, C. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102778 · Cited by 13 · see citing works
- Authors
- Kramár, E. A., Babayan, A. H., Gavin, C. F., Cox, C. D., Jafari, M., Gall, C. M., Rumbaugh, G., & Lynch, G.
- Affiliations
- Departments of aAnatomy and Neurobiology and
- Scripps Research Institute (US)
- University of California, Irvine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-03-12
- Volume
- 109
- Issue
- 13
- Pages
- 5121-5126
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3323981
- OpenAlex
- W1998698062
- Cited by
- 192
- References
- 49
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 24 · 2023: 17 · 2022: 8 · 2021: 13 · 2020: 15 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 10 · 2012: 4
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH083346)
- National Institute of Neurological Disorders and Stroke (P01NS045260, NS045260, R01NS064079, NS064079)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- spaced learning, massed training, long-term potentiation, theta burst stimulation, hippocampal CA1, synaptic plasticity, glutamate uncaging, synaptic variability, membrane insertion
- MeSH terms
- Actins, Animals, Learning, Male, Mice, Inbred C57BL, Synaptic Transmission, Synapses, Theta Rhythm, Time Factors, Rats, Sprague-Dawley, Long-Term Potentiation, Dendritic Spines, Mice, Rats, Polymerization, In Vitro Techniques
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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