Review Article | Published:

Synaptic tagging during memory allocation

Nature Reviews Neuroscience volume 15, pages 157169 (2014) | Download Citation

Abstract

There is now compelling evidence that the allocation of memory to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random and that instead specific mechanisms, such as increases in neuronal excitability and synaptic tagging and capture, determine the exact sites where memories are stored. We propose an integrated view of these processes, such that neuronal allocation, synaptic tagging and capture, spine clustering and metaplasticity reflect related aspects of memory allocation mechanisms. Importantly, the properties of these mechanisms suggest a set of rules that profoundly affect how memories are stored and recalled.

Key points

  • Memory allocation to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random; instead, specific mechanisms determine which synapses and neurons go on to store a specific memory.

  • Mechanisms that determine which neurons are recruited to store a given memory include activation of the transcription factor cyclic AMP-dependent element-binding protein (CREB) and increases in neuronal excitability, such as decreases in the afterhyperpolarization.

  • Synaptic tagging and capture, as well as synaptic clustering mechanisms determine which synapses go on to encode a given memory; therefore, they are key mechanisms of memory allocation.

  • In the Review, we introduce an integrated view of neuronal allocation, synaptic tagging and capture, spine clustering and metaplasticity. We propose that these processes reflect different memory allocation mechanisms.

  • We also discuss how deficits in memory allocation could result in cognitive pathologies, such as those associated with ageing or schizophrenia.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    A cortical–hippocampal system for declarative memory. Nature Rev. Neurosci. 1, 41–50 (2000).

  2. 2.

    et al. The labile nature of consolidation theory. Nature Rev. Neurosci. 1, 216–219 (2000).

  3. 3.

    et al. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 24, 540–546 (2001).

  4. 4.

    Context and behavioral processes in extinction. Learn. Mem. 11, 485–494 (2004).

  5. 5.

    & Neuronal signalling of fear memory. Nature Rev. Neurosci. 5, 844–852 (2004).

  6. 6.

    & The neuroscience of mammalian associative learning. Annu. Rev. Psychol. 56, 207–234 (2005).

  7. 7.

    & Consolidation and reconsolidation: two lives of memories? Neuron 71, 224–233 (2011).

  8. 8.

    et al. Molecular and cellular approaches to memory allocation in neural circuits. Science 326, 391–395 (2009). This review developed the hypothesis that a CREB-dependent increase in excitability is a mechanism by which memories are allocated and thereby linked in the brain.

  9. 9.

    Simple memory: a theory for archicortex. Phil. Trans. R. Soc. Lond. B 262, 23–81 (1971).

  10. 10.

    & Natural image statistics and neural representation. Annu. Rev. Neurosci. 24, 1193–1216 (2001).

  11. 11.

    & Sparse coding of sensory inputs. Curr. Opin. Neurobiol. 14, 481–487 (2004).

  12. 12.

    et al. Sparse but not 'grandmother-cell' coding in the medial temporal lobe. Trends Cogn. Sci. 12, 87–91 (2008).

  13. 13.

    , & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995).

  14. 14.

    Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44, 109–120 (2004).

  15. 15.

    et al. Neuronal competition and selection during memory formation. Science 316, 457–460 (2007). This paper shows that the levels of CREB in the lateral amygdala can modulate the probability that a given neuron will be involved in an auditory fear memory.

  16. 16.

    et al. CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nature Neurosci. 12, 1438–1443 (2009). A study showing that CREB regulates neuronal excitability and therefore the probability that a given lateral amygdala neuron will be involved in tone conditioning and conditioned taste aversion.

  17. 17.

    & The amygdala and fear conditioning: has the nut been cracked? Neuron 16, 237–240 (1996).

  18. 18.

    et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nature Neurosci. 4, 724–731 (2001).

  19. 19.

    et al. Neural substrates for expectation-modulated fear learning in the amygdala and periaqueductal gray. Nature Neurosci. 13, 979–986 (2010).

  20. 20.

    , & Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995).

  21. 21.

    et al. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

  22. 22.

    et al. Localization of a stable neural correlate of associative memory. Science 317, 1230–1233 (2007).

  23. 23.

    et al. Selective erasure of a fear memory. Science 323, 1492–1496 (2009). The authors of this study ablated a set of neurons constituting a CREB-biased auditory fear memory trace and demonstrated that those neurons were needed for recall.

  24. 24.

    et al. Selective and quickly reversible inactivation of mammalian neurons in vivo using the Drosophila allatostatin receptor. Neuron 51, 157–170 (2006).

  25. 25.

    et al. Blockade of stimulus convergence in amygdala neurons disrupts taste associative learning. J. Neurosci. 33, 4958–4963 (2013).

  26. 26.

    Functional organization and plasticity in the adult rat barrel cortex: moving out-of-the-box. Curr. Opin. Neurobiol. 16, 445–450 (2006).

  27. 27.

    et al. Vibrissa-signaled eyeblink conditioning induces somatosensory cortical plasticity. J. Neurosci. 26, 6062–6068 (2006).

  28. 28.

    et al. A novel method for precisely timed stimulation of mouse whiskers in a freely moving preparation: application for delivery of the conditioned stimulus in trace eyeblink conditioning. J. Neurosci. Methods 177, 434–439 (2009).

  29. 29.

    et al. Associative fear learning enhances sparse network coding in primary sensory cortex. Neuron 75, 121–132 (2012).

  30. 30.

    et al. Infragranular barrel cortex activity is enhanced with learning. J. Neurophysiol. 108, 1278–1287 (2012).

  31. 31.

    et al. Dorsal hippocampal CREB is both necessary and sufficient for spatial memory. Learn. Mem. 17, 280–283 (2010).

  32. 32.

    et al. Viral-mediated expression of a constitutively active form of CREB in hippocampal neurons increases memory. Hippocampus 19, 228–234 (2009).

  33. 33.

    et al. cAMP response element-binding protein-mediated gene expression increases the intrinsic excitability of CA1 pyramidal neurons. J. Neurosci. 27, 13909–13918 (2007).

  34. 34.

    et al. Intracellular determinants of hippocampal CA1 place and silent cell activity in a novel environment. Neuron 70, 109–120 (2011).

  35. 35.

    et al. Hippocampal place fields emerge upon single-cell manipulation of excitability during behavior. Science 337, 849–853 (2012).

  36. 36.

    et al. CREB modulates excitability of nucleus accumbens neurons. Nature Neurosci. 9, 475–477 (2006).

  37. 37.

    & Preplay of future place cell sequences by hippocampal cellular assemblies. Nature 469, 397–401 (2011).

  38. 38.

    et al. Driving opposing behaviors with ensembles of piriform neurons. Cell 146, 1004–1015 (2011).

  39. 39.

    & Aberrant dendritic excitability: a common pathophysiology in CNS disorders affecting memory? Mol. Neurobiol. 45, 478–487 (2012).

  40. 40.

    et al. Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation. Neuroscience 8, 33–55 (1983).

  41. 41.

    et al. Neural activity in the primate prefrontal cortex during associative learning. Neuron 21, 1399–1407 (1998).

  42. 42.

    et al. Cross-modal and cross-temporal association in neurons of frontal cortex. Nature 405, 347–351 (2000).

  43. 43.

    et al. Generation of a synthetic memory trace. Science 335, 1513–1516 (2012). In this study, the authors created a synthetic memory trace derived from the conjunction of a context and an artificially activated ensemble of neurons.

  44. 44.

    et al. Creating a false memory in the hippocampus. Science 341, 387–391 (2013).

  45. 45.

    & A distributed representation of temporal context. J. Math. Psychol. 46, 269–299 (2002).

  46. 46.

    et al. Linking neuronal ensembles by associative synaptic plasticity. PLoS ONE 6, e20486 (2011).

  47. 47.

    et al. Dendritic coding of multiple sensory inputs in single cortical neurons in vivo. Proc. Natl Acad. Sci. USA 108, 15420–15425 (2011).

  48. 48.

    & Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (1996).

  49. 49.

    & Metaplasticity: new insights through electrophysiological investigations. J. Integr. Neurosci. 7, 315–336 (2008).

  50. 50.

    & Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181–188 (1998).

  51. 51.

    & Making memories last: the synaptic tagging and capture hypothesis. Nature Rev. Neurosci. 12, 17–30 (2011).

  52. 52.

    et al. Specific long-lasting potentiation of synaptic transmission in hippocampal slices. Nature 266, 736–737 (1977).

  53. 53.

    et al. Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature 266, 737–739 (1977).

  54. 54.

    & Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997). This paper shows that a strong synaptic input creates a protein synthesis-independent synaptic tag at potentiated synapses that sequesters proteins needed for a late phase of a synaptic potentiation.

  55. 55.

    & Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP. Neuropharmacology 37, 545–552 (1998).

  56. 56.

    & Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD. Neurobiol. Learn. Mem. 82, 12–25 (2004).

  57. 57.

    et al. Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927–938 (1997).

  58. 58.

    et al. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99, 221–237 (1999).

  59. 59.

    & Interfering with the actin network and its effect on long-term potentiation and synaptic tagging in hippocampal CA1 neurons in slices in vitro. J. Neurosci. 29, 12167–12173 (2009).

  60. 60.

    et al. Synaptic tagging and capture: differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation. J. Neurosci. 30, 4981–4989 (2010).

  61. 61.

    & A novel cholinergic induction of long-term potentiation in rat hippocampus. J. Neurophysiol. 72, 2034–2040 (1994).

  62. 62.

    et al. Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. J. Neurosci. 22, 7453–7461 (2002).

  63. 63.

    et al. Synergistic requirements for the induction of dopaminergic D1/D5-receptor-mediated LTP in hippocampal slices of rat CA1 in vitro. Neuropharmacology 52, 1547–1554 (2007).

  64. 64.

    et al. The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140 (2008). This study shows that LTP triggers biochemical changes that are shared by nearby synapses in the same dendrite and that this affects thresholds of LTP in these synapses.

  65. 65.

    , & AMPA receptors are exocytosed in stimulated spines and adjacent dendrites in a Ras–ERK-dependent manner during long-term potentiation. Proc. Natl Acad. Sci. USA 107, 15951–15956 (2010).

  66. 66.

    , & Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472, 100–104 (2011).

  67. 67.

    et al. The dendritic branch is the preferred integrative unit for protein synthesis-dependent LTP. Neuron 69, 132–146 (2011).

  68. 68.

    , & A clustered plasticity model of long-term memory engrams. Nature Rev. Neurosci. 7, 575–583 (2006).

  69. 69.

    & Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24, 299–325 (2001).

  70. 70.

    & Synaptic tagging — who's it? Nature Rev. Neurosci. 3, 813–820 (2002).

  71. 71.

    & Plasticity of dendritic excitability. J. Neurobiol. 64, 100–115 (2005).

  72. 72.

    & Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging. J. Neurosci. 27, 7476–7481 (2007). This study uncovers interactions between memories that exhibit the defining features of the synaptic tagging and capture hypothesis.

  73. 73.

    et al. Behavioral tagging is a general mechanism of long-term memory formation. Proc. Natl Acad. Sci. USA 106, 14599–14604 (2009).

  74. 74.

    et al. Recognition memory for single tones with and without context. J. Exp. Psychol. Hum. Learn. Mem. 3, 60–67 (1977).

  75. 75.

    et al. Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. Proc. Natl Acad. Sci. USA 107, 19537–19542 (2010).

  76. 76.

    et al. Novelty causes time-dependent retrograde amnesia for one-trial avoidance in rats through NMDA receptor- and CaMKII-dependent mechanisms in the hippocampus. Eur. J. Neurosci. 11, 3323–3328 (1999).

  77. 77.

    & Impact of active dendrites and structural plasticity on the memory capacity of neural tissue. Neuron 29, 779–796 (2001).

  78. 78.

    & Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Neuron 50, 291–307 (2006).

  79. 79.

    et al. Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature 483, 92–95 (2012). This paper shows that there is synaptic clustering of functionally related inputs in the motor cortex during a forelimb motor-learning task.

  80. 80.

    et al. Elimination of dendritic spines with long-term memory is specific to active circuits. J. Neurosci. 32, 12570–12578 (2012).

  81. 81.

    et al. Opposite effects of fear conditioning and extinction on dendritic spine remodelling. Nature 483, 87–91 (2012).

  82. 82.

    & Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008).

  83. 83.

    et al. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999).

  84. 84.

    , & Presynaptic remodeling contributes to activity-dependent synaptogenesis. J. Neurosci. 23, 8498–8505 (2003).

  85. 85.

    , & Control of synapse development and plasticity by Rho GTPase regulatory proteins. Prog. Neurobiol. 94, 133–148 (2011).

  86. 86.

    & Synaptic clustering by dendritic signalling mechanisms. Curr. Opin. Neurobiol. 18, 321–331 (2008).

  87. 87.

    , & Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452, 436–441 (2008).

  88. 88.

    The Child's Conception of the World (Routledge, 1929).

  89. 89.

    Remembering: A Study in Experimental and Social Psychology (Cambridge Univ. Press, 1932).

  90. 90.

    et al. Schema-dependent gene activation and memory encoding in neocortex. Science 333, 891–895 (2011). This study suggests that schema in the neocortex can account for the rapid acquisition and consolidation of related information.

  91. 91.

    et al. Schemas and memory consolidation. Science 316, 76–82 (2007).

  92. 92.

    et al. Learning causes reorganization of neuronal firing patterns to represent related experiences within a hippocampal schema. J. Neurosci. 33, 10243–10256 (2013).

  93. 93.

    et al. Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation. Proc. Natl Acad. Sci. USA 108, 12931–12936 (2011).

  94. 94.

    , & Hippocampal and ventral medial prefrontal activation during retrieval-mediated learning supports novel inference. Neuron 75, 168–179 (2012).

  95. 95.

    et al. Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res. 824, 300–303 (1999).

  96. 96.

    , & Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus. Dis. Markers 27, 239–252 (2009).

  97. 97.

    et al. CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 107, 22687–22692 (2010).

  98. 98.

    , & Increasing CREB function in the CA1 region of dorsal hippocampus rescues the spatial memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 36, 2169–2186 (2011).

  99. 99.

    , & Network excitability dysfunction in Alzheimer's disease: insights from in vitro and in vivo models. Rev. Neurosci. 21, 153–171 (2010).

  100. 100.

    & Alterations in intrinsic neuronal excitability during normal aging. Aging Cell 6, 327–336 (2007).

  101. 101.

    & Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies. Curr. Pharm. Biotechnol. 13, 1557–1562 (2012).

  102. 102.

    & A single standard for memory: the case for reconsolidation. Nature Rev. Neurosci. 10, 224–234 (2009).

  103. 103.

    & The organization of recent and remote memories. Nature Rev. Neurosci. 6, 119–130 (2005).

Download references

Acknowledgements

We thank members of the Silva laboratory and P. Golshani's laboratory (see Further information box for the link to the homepage) for discussions that shaped the material and ideas in this Review. The work was supported by grants P50 MH077972, R37 AG013622, and from the Dr. Miriam & Sheldon G. Adelson Medical Research Foundation to A.J.S., 1T32NS058280, 1F31MH092057-01, 2012–13 DYF to T.R., Human Frontiers to M.L.A. and 5 F32 MH097413-02 to D.C.

Author information

Affiliations

  1. Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, California 90095–1761, USA.

    • Thomas Rogerson
    • , Denise J. Cai
    • , Adam Frank
    • , Yoshitake Sano
    • , Justin Shobe
    • , Manuel F. Lopez-Aranda
    •  & Alcino J. Silva

Authors

  1. Search for Thomas Rogerson in:

  2. Search for Denise J. Cai in:

  3. Search for Adam Frank in:

  4. Search for Yoshitake Sano in:

  5. Search for Justin Shobe in:

  6. Search for Manuel F. Lopez-Aranda in:

  7. Search for Alcino J. Silva in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alcino J. Silva.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrn3667