Abstract
We review recent work on three major lines of memory research: a) the possible role of the protein kinase M-zeta (PKMzeta) in memory persistence; b) the processes of “synaptic tagging and capture” in memory formation; c) the modulation of extinction learning, widely used in the psychotherapy of fear memories under the name of “exposure therapy”. PKMzeta is a form of protein kinase C (PKC) that apparently remains stimulated for months after the consolidation of a given memory. Synaptic tagging is a mechanism whereby the weak activation of one synapse can tag it with a protein so other synapses in the same cell can reactivate it by producing other proteins that bind to the tag. Extinction, once mistakenly labeled as a form of forgetting, is by itself a form of learning; through it animals can learn to inhibit a response. We now know it can be modulated by neurotransmitters or by synaptic tagging, which should enable better control of its clinical use.
Memory; persistence; consolidation; synaptic tagging; extinction
Introduction
There have been many advances in the study of the mechanisms of memory in the past few years.
Perhaps the most salient are: a) the discovery of a role of an atypical isoform of protein kinase C
(PKC), protein kinase M-zeta (PKMzeta), in memory consolidation and persistence;11. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage
of spatial information by the maintenance mechanism of LTP. Science.
2006;313:1141-4.,22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol
Brain. 2012;5:31. b) the wide acceptance and
extension of the mechanism known as “synaptic tagging” or “synaptic tagging and
capture”33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6.,44. Frey S, Frey JU. ‘Synaptic tagging’ and
‘cross-tagging’ and related associative reinforcement processes of functional
plasticity as the cellular basis for memory formation. Prog Brain Res.
2008;169:117-43. to a
variety of memory forms55. Ballarini F, Moncada D, Martinez MC, Alen N, Viola H. Behavioral tagging is a
general mechanism of long-term memory formation. Proc Natl Acad Sci U S A.
2009;106:14599-604.,66. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6.
including extinction77. Myskiw JC, Benetti F, Izquierdo I. Behavioral tagging of extinction learning.
Proc Natl Acad Sci U S A. 2013;110:1071-6.; and c) the demonstration that
extinction, now generally recognized not as forgetting but just as another form of learning,88. Rescorla RA. Spontaneous recovery. Learn Mem. 2004;11:501-9.
9. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience:
ten years of progress. Annu Rev Psychol. 2012;63:129-51.-8-1010. Fiorenza NG, Rosa J, Izquierdo I, Myskiw JC. Modulation of the extinction of two
different fear-motivated tasks in three distinct brain areas. Behav Brain Res.
2012;232:210-6. can be modulated by several systems and procedures.1010. Fiorenza NG, Rosa J, Izquierdo I, Myskiw JC. Modulation of the extinction of two
different fear-motivated tasks in three distinct brain areas. Behav Brain Res.
2012;232:210-6. This should make it amenable to both psychotherapeutic and pharmacologic
interventions.
These three discoveries open new vistas for the understanding and treatment of memory disorders.
The three derive from hypotheses or findings published more than 10 years ago, which illustrates how
research in this area relies on continuity in spite of major technological changes that take place
all the time.11. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage
of spatial information by the maintenance mechanism of LTP. Science.
2006;313:1141-4.,33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6.1010. Fiorenza NG, Rosa J, Izquierdo I, Myskiw JC. Modulation of the extinction of two
different fear-motivated tasks in three distinct brain areas. Behav Brain Res.
2012;232:210-6. None of these discoveries would have been possible without the perhaps final
agreement that long-term potentiation (LTP) is indeed the basis of memory consolidation at the
cellular level in the hippocampus.1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in
the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem.
1997;68:285-316.
12. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M.
Different molecular cascades in different sites of the brain control consolidation. Trends Neurosci.
2006;29:496-505.
13. Gruart A, Muãoz MD, Delgado-García JM. Involvement of the CA3-CA1 synapse in the
acquisition of associative learning in behaving mice. J Neurosci. 2006;26:1077-87.
14. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term
potentiation in the hippocampus. Science. 2006;313:1093-7.-1515. Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delgado-García JM. Plastic
modifications induced by object recognition memory processing. Proc Natl Acad Sci U S A.
2010;107:2652-7. This had been repeatedly proposed by many to be the case in the 30 years that followed
its original discovery in 1973 by Bliss et al. (see references1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in
the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem.
1997;68:285-316.,1616. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in
the hippocampus. Nature. 1993;361:31-9.
17. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res
Brain Res Rev. 1993;18:115-22.-1818. Kandel ER, Squire LR. Neuroscience: breaking down scientific barriers to the
study of brain and mind. Science. 2000;290:1113-20.) and work on “in vitro” LTP models was widely hailed as representing
work on the actual mechanisms of memory formation in vertebrates,1717. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res
Brain Res Rev. 1993;18:115-22.,1818. Kandel ER, Squire LR. Neuroscience: breaking down scientific barriers to the
study of brain and mind. Science. 2000;290:1113-20. which eventually proved true. But the final agreement
required the demonstration that the nature and sequence of the biochemical steps of hippocampal LTP
were the same as those of memory consolidation in awake, behaving animals in tasks effectively
mediated by this structure,1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in
the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem.
1997;68:285-316.,1212. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M.
Different molecular cascades in different sites of the brain control consolidation. Trends Neurosci.
2006;29:496-505. that the consolidation of those tasks is indeed accompanied by hippocampal LTP,1313. Gruart A, Muãoz MD, Delgado-García JM. Involvement of the CA3-CA1 synapse in the
acquisition of associative learning in behaving mice. J Neurosci. 2006;26:1077-87.
14. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term
potentiation in the hippocampus. Science. 2006;313:1093-7.-1515. Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delgado-García JM. Plastic
modifications induced by object recognition memory processing. Proc Natl Acad Sci U S A.
2010;107:2652-7. and that consolidation can be occluded by previous saturation of hippocampal LTP
mechanisms.1313. Gruart A, Muãoz MD, Delgado-García JM. Involvement of the CA3-CA1 synapse in the
acquisition of associative learning in behaving mice. J Neurosci. 2006;26:1077-87.,1515. Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delgado-García JM. Plastic
modifications induced by object recognition memory processing. Proc Natl Acad Sci U S A.
2010;107:2652-7.
A role for PKMzeta in memory
Clearly, then, hippocampal LTP is at the center of the initial, post-acquisition process of
memory consolidation.1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in
the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem.
1997;68:285-316.
12. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M.
Different molecular cascades in different sites of the brain control consolidation. Trends Neurosci.
2006;29:496-505.
13. Gruart A, Muãoz MD, Delgado-García JM. Involvement of the CA3-CA1 synapse in the
acquisition of associative learning in behaving mice. J Neurosci. 2006;26:1077-87.
14. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term
potentiation in the hippocampus. Science. 2006;313:1093-7.
15. Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delgado-García JM. Plastic
modifications induced by object recognition memory processing. Proc Natl Acad Sci U S A.
2010;107:2652-7.
16. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in
the hippocampus. Nature. 1993;361:31-9.
17. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res
Brain Res Rev. 1993;18:115-22.
18. Kandel ER, Squire LR. Neuroscience: breaking down scientific barriers to the
study of brain and mind. Science. 2000;290:1113-20.-1919. Morris RG, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and
blockade of long-term potentiation by an N-methyl-D-aspartate antagonist. Nature.
1986;319:774-6. It has recently been shown to be one of the very few
attributes of memory that is partly modulated by cholinergic transmission,2020. Martyn AC, De Jaeger X, Magalhães AC, Kesarwani R, Gonçalves DF, Raulic S, et
al. Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and
deficits in spatial memory and long-term potentiation. Proc Natl Acad Sci U S A.
2012;109:17651-6. which explains the effect of pro-cholinergic drugs on memory impairments.
Memory consolidation is the process of formation of a memory archive in the brain. This takes place initially in the hippocampus, often with the concomitant participation of the entorhinal and posterior parietal cortex and the basolateral nuclear complex of the amygdala. The process takes 1-6 hours and involves the serial and parallel activation of several hippocampal protein kinase systems,1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem. 1997;68:285-316.,1212. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M. Different molecular cascades in different sites of the brain control consolidation. Trends Neurosci. 2006;29:496-505.,1717. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res Brain Res Rev. 1993;18:115-22. and the resulting stimulation of diverse cellular proteins including nuclear transcription factors which trigger DNA transcription, which is followed by protein synthesis in ribosomes2121. Igaz LM, Vianna MR, Medina JH, Izquierdo I. Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning. J Neurosci. 2002;22:6781-9. and coexists with the independent extra-ribosomal dendritic system mediated by mTOR (mammalian target of rapamycin), which uses pre-existent mRNAs.2222. Myskiw JC, Rossato JI, Bevilaqua LR, Medina JH, Izquierdo I, Cammarota M. On the participation of mTOR in recognition memory. Neurobiol Learn Mem. 2008;89:338-51.,2323. Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One. 2009;4:e6007. The mTOR system is also triggered by protein kinases and by brain-derived neurotrophic factor (BDNF) (see below) and produces the GLUR1 subunit of the glutamate AMPA receptor, which is necessary for consolidation.2323. Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One. 2009;4:e6007. Due to its localization near synapses, the mTOR system is believed to play a key role in the processing of proteins related to the processing of recent information by specific synapses, as is believed to happen in memory consolidation, which is accompanied and underlain by morphological synaptic changes.1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem. 1997;68:285-316.,1212. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M. Different molecular cascades in different sites of the brain control consolidation. Trends Neurosci. 2006;29:496-505. The processes summarized above (protein kinase activation, protein synthesis, synaptic change) integrate what is now called “cellular consolidation” and cannot be delayed without loss; it has to occur immediately following acquisition.1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem. 1997;68:285-316.,2424. McGaugh JL. Memory--a century of consolidation. Science. 2000;287:248-51. An additional consolidation process, termed “systems consolidation”, which is initiated simultaneously, takes place in the prefrontal cortex and other cortical regions, lasts for many weeks or even years, and frequently results in changes in the content of each memory, which can in many cases become falsified.2525. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu Rev Neurosci. 2011;34:259-88.
After memories are consolidated in the CA1 region, they are stored in a long-lasting form (days,
weeks, years) elsewhere, as attested by studies of humans or animals with anatomical or biochemical
lesions of the hippocampus and its surrounding areas; the most famous and best studied human case is
that of patient HM.1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in
the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem.
1997;68:285-316.,2424. McGaugh JL. Memory--a century of consolidation. Science.
2000;287:248-51.,2525. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88. Subjects with those lesions can retain declarative
memories for a few minutes or sometimes hours, but are unable to store them for longer periods; they
can, however, remember facts and events that antedate the lesion, indicating that declarative
memories do require the hippocampus early on but then must be stored somewhere else in the
brain.2424. McGaugh JL. Memory--a century of consolidation. Science.
2000;287:248-51.
25. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88.
27. Eichenbaum H. What H.M. taught us. J Cogn Neurosci.
2013;25:14-21.-2626. Sacco T, Sacchetti B. Role of secondary sensory cortices in emotional memory
storage and retrieval in rats. Science. 2010;329:649-56. Recent evidence suggests that the secondary sensory cortices2727. Eichenbaum H. What H.M. taught us. J Cogn Neurosci.
2013;25:14-21. and some prefrontal and parietal regions,2525. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88.,2626. Sacco T, Sacchetti B. Role of secondary sensory cortices in emotional memory
storage and retrieval in rats. Science. 2010;329:649-56. but not the hippocampus,2525. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88. are sites of long-term memory storage.
Notwithstanding this, several recent studies have implicated the hippocampus in the initiation of
“permanent” memory storage, in some cases through local biochemical changes.2828. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH.
Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase
in the hippocampus. Neuron. 2007;53:261-77.
29. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, et al.
BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A.
2008;105:2711-6.
30. Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, et al. Circadian
oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat
Neurosci. 2008;11:1074-82.
31. Eckel-Mahan KL, Storm DR. Circadian rhythms and memory: not so simple as cogs
and gears. EMBO Rep. 2009;10:584-91.
32. Parfitt GM, Campos RC, Barbosa AK, Koth AP, Barros DM. Participation of
hippocampal cholinergic system in memory persistence for inhibitory avoidance in rats. Neurobiol
Learn Mem. 2012;97:183-8.-3333. Parfitt GM, Barbosa ÂK, Campos RC, Koth AP, Barros DM. Moderate stress enhances
memory persistence: are adrenergic mechanisms involved? Behav Neurosci.
2012;126:729-34. These biochemical changes involve the production of local BDNF2828. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH.
Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase
in the hippocampus. Neuron. 2007;53:261-77.,2929. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, et al.
BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A.
2008;105:2711-6. and/or the local activation of a circadian
cycle of simultaneous increases of hippocampal mitogen-activated protein kinase (MAPK) activity and
cyclic adenosine monophosphate (cAMP),3030. Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, et al. Circadian
oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat
Neurosci. 2008;11:1074-82.,3131. Eckel-Mahan KL, Storm DR. Circadian rhythms and memory: not so simple as cogs
and gears. EMBO Rep. 2009;10:584-91. and/or the triggering of a dual muscarinic and nicotinic cholinergic
mechanism within the hippocampus,3232. Parfitt GM, Campos RC, Barbosa AK, Koth AP, Barros DM. Participation of
hippocampal cholinergic system in memory persistence for inhibitory avoidance in rats. Neurobiol
Learn Mem. 2012;97:183-8. or the participation of a
hippocampal β-noradrenergic mechanism activated by mild stress, presumably that of the
training experience.3333. Parfitt GM, Barbosa ÂK, Campos RC, Koth AP, Barros DM. Moderate stress enhances
memory persistence: are adrenergic mechanisms involved? Behav Neurosci.
2012;126:729-34. The BDNF mechanism appears to be
triggered by dopaminergic fibers from the ventral tegmental area acting on hippocampal D1
receptors.3030. Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, et al. Circadian
oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat
Neurosci. 2008;11:1074-82.,3131. Eckel-Mahan KL, Storm DR. Circadian rhythms and memory: not so simple as cogs
and gears. EMBO Rep. 2009;10:584-91.
Interestingly, all these mechanisms have been proposed to enter into play several hours after
training, when the ensuing cellular consolidation process are already over,2828. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH.
Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase
in the hippocampus. Neuron. 2007;53:261-77.
29. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, et al.
BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A.
2008;105:2711-6.
30. Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, et al. Circadian
oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat
Neurosci. 2008;11:1074-82.
31. Eckel-Mahan KL, Storm DR. Circadian rhythms and memory: not so simple as cogs
and gears. EMBO Rep. 2009;10:584-91.
32. Parfitt GM, Campos RC, Barbosa AK, Koth AP, Barros DM. Participation of
hippocampal cholinergic system in memory persistence for inhibitory avoidance in rats. Neurobiol
Learn Mem. 2012;97:183-8.
33. Parfitt GM, Barbosa ÂK, Campos RC, Koth AP, Barros DM. Moderate stress enhances
memory persistence: are adrenergic mechanisms involved? Behav Neurosci.
2012;126:729-34.
34. Izquierdo I, Bevilaqua LR, Rossato JI, Lima RH, Medina JH, Cammarota M.
Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining
methylphenidate administration. Proc Natl Acad Sci U S A. 2008;105:19504-7.-3535. Rossato JI, Bevilaqua LR, Izquierdo I, Medina JH, Cammarota M. Dopamine controls
persistence of long-term memory storage. Science. 2009;325:1017-20. and they are not mutually incompatible,
which means they might occur simultaneously and eventually interact with each other in the fostering
of memory persistence.
Perhaps in a different class, but not necessarily, is the suggestion by Sacktor et al.11. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006;313:1141-4.,22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31.,3636. Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory association in the cortex by an inhibitor of PKM zeta. Science. 2007;317:951-3. of a role of the autonomously active, atypical PKC isoform PKMzeta in both memory consolidation and persistence. Regular PKC had been proposed as a key step in LTP generation - and, consequently, in memory formation - nearly three decades ago.1717. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res Brain Res Rev. 1993;18:115-22.,3737. Meberg PJ, Barnes CA, McNaughton BL, Routtenberg A. Protein kinase C and F1/GAP-43 gene expression in hippocampus inversely related to synaptic enhancement lasting 3 days. Proc Natl Acad Sci U S A. 1993;90:12050-4. PKCs, including PKMzeta, are involved in the phosphorylation of a wide number of proteins, including membrane proteins, other kinases, receptors and nuclear transcription factors.3737. Meberg PJ, Barnes CA, McNaughton BL, Routtenberg A. Protein kinase C and F1/GAP-43 gene expression in hippocampus inversely related to synaptic enhancement lasting 3 days. Proc Natl Acad Sci U S A. 1993;90:12050-4. Inhibitors of PKMzeta infused into the hippocampus block both consolidation and persistence; the latter, even many days or weeks after the memories had been acquired.22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31.,3636. Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory association in the cortex by an inhibitor of PKM zeta. Science. 2007;317:951-3. The effect was originally described for the lengthening of the duration of hippocampal LTP and subsequently for hippocampus-based spatial memories.11. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006;313:1141-4.,22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31.,3636. Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory association in the cortex by an inhibitor of PKM zeta. Science. 2007;317:951-3. Recent findings, however, indicate a completely different and in fact opposite role of PKMzeta in memory formation: its decrease correlates with an enhancement of the learning of familiarization to a new environment.3838. Moncada D, Viola H. PKMzeta inactivation induces spatial familiarity. Learn Mem. 2008;15:810-4. The overwhelming majority of papers mentioning a role of PKMzeta in memory, however, support a key role for this enzyme in memory persistence, at least for several weeks.22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31.,3636. Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory association in the cortex by an inhibitor of PKM zeta. Science. 2007;317:951-3. Inhibition of the enzyme rapidly erases memories acquired 1 day11. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006;313:1141-4.,22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31. or several weeks before.22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31.,3636. Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory association in the cortex by an inhibitor of PKM zeta. Science. 2007;317:951-3. The finding also applies to forms of neuronal plasticity other than LTP3939. Cai D, Pearce K, Chen S, Glanzman DL. Protein kinase M maintains long-term sensitization and long-term facilitation in aplysia. J Neurosci. 2011;31:6421-31. and to many other forms of memory in invertebrates.22. Sacktor TC. Memory maintenance by PKMζ--an evolutionary perspective. Mol Brain. 2012;5:31.,3939. Cai D, Pearce K, Chen S, Glanzman DL. Protein kinase M maintains long-term sensitization and long-term facilitation in aplysia. J Neurosci. 2011;31:6421-31.
It has been known for over a decade that the persistence of episodic declarative memories depends substantially on the degree of emotional alertness associated with its initial consolidation.2424. McGaugh JL. Memory--a century of consolidation. Science. 2000;287:248-51.,4040. Cahill L, McGaugh JL. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci. 1998;21:294-9.,4141. McGaugh JL, Cahill L. Interaction of neuromodulatory systems in modulating memory storage. Behav Brain Res. 1997;83:31-8. Thus, Americans are prone to remember details of where they were and whom they were with at the time President Kennedy was assassinated, whereas Brazilians tend to remember similar details of the time at which ace driver Ayrton Senna was killed, but neither can remember equally well incidents that occurred the day before or the day after such events. Perhaps the role of PKMzeta in the triggering of persistence is therefore related to its role (or to that of other PKCs) in memory consolidation, which has long been described.1111. Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection with activity in other brain structures. Neurobiol Learn Mem. 1997;68:285-316.,1717. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res Brain Res Rev. 1993;18:115-22. Indeed, a role of regular PKC in the persistence of LTP over 3 days was described nearly 20 years ago.3737. Meberg PJ, Barnes CA, McNaughton BL, Routtenberg A. Protein kinase C and F1/GAP-43 gene expression in hippocampus inversely related to synaptic enhancement lasting 3 days. Proc Natl Acad Sci U S A. 1993;90:12050-4.
However, a role of PKMzeta or PKC in consolidation would mingle with its role in promoting persistence, and if this were so, the other persistence mechanisms that have been postulated (BDNF-mediated, MAPK/CaMKII-dependent, noradrenergic, cholinergic (see above) may just be accessory or alternative.
More research into this area is desirable. In particular, the exact role of PKMzeta in consolidation and persistence should be more clearly laid out. A prolongation of the former into the time in which the latter operates could be as self-defeating in terms of memory persistence, as remembering where we parked our car yesterday when looking for it when we leave our office today, or remembering how we reacted to a cake we ate at 3 p.m. today instead of how we should react to the tiger that attacked us 1 hour after the cake and is attacking us again now.
It bears stressing that the wholesale, uncritical acceptance of a role for PKMzeta in memory
persistence collides head-on with all we have learned from years of research on patient HM and
others with hippocampal lesions that came after him,2424. McGaugh JL. Memory--a century of consolidation. Science.
2000;287:248-51.
25. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88.
27. Eichenbaum H. What H.M. taught us. J Cogn Neurosci.
2013;25:14-21.-2626. Sacco T, Sacchetti B. Role of secondary sensory cortices in emotional memory
storage and retrieval in rats. Science. 2010;329:649-56. mainly, that the hippocampus
ceases to play a role in memory maintenance or persistence shortly after cellular consolidation is
over. Patients with hippocampal lesions can remember declarative memories from weeks before the
lesions but are unable to form new memories of that kind.2525. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88.,2626. Sacco T, Sacchetti B. Role of secondary sensory cortices in emotional memory
storage and retrieval in rats. Science. 2010;329:649-56. Just how long the PKMzeta mechanism remains operational for
each memory remains to be established with much more precision than that emanating from the data
published on that enzyme so far. If it stays on for weeks, this would not be incompatible with what
we learned from HM.2626. Sacco T, Sacchetti B. Role of secondary sensory cortices in emotional memory
storage and retrieval in rats. Science. 2010;329:649-56. If it has to stay on for months or
years, its role would be hardly credible, inasmuch as memories are made constantly and animals would
find it impossible to tell one from the other. Perhaps the most parsimonious assumption would be
that the PKMzeta molecules that are altered remain in this state for a few weeks at the most, and
are located at the synapses specifically used by each one of those memories. The two human
hippocampi together have at least 400 million pyramidal cells, each receiving about 10,000 synapses,
which makes it an apparatus with potentially formidable, though not infinite, synaptic processing
properties. If specific connections between the hippocampal synapses that are involved in
consolidation1828. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH.
Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase
in the hippocampus. Neuron. 2007;53:261-77.
29. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, et al.
BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A.
2008;105:2711-6.
30. Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, et al. Circadian
oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nat
Neurosci. 2008;11:1074-82.
31. Eckel-Mahan KL, Storm DR. Circadian rhythms and memory: not so simple as cogs
and gears. EMBO Rep. 2009;10:584-91.
32. Parfitt GM, Campos RC, Barbosa AK, Koth AP, Barros DM. Participation of
hippocampal cholinergic system in memory persistence for inhibitory avoidance in rats. Neurobiol
Learn Mem. 2012;97:183-8.-3333. Parfitt GM, Barbosa ÂK, Campos RC, Koth AP, Barros DM. Moderate stress enhances
memory persistence: are adrenergic mechanisms involved? Behav Neurosci.
2012;126:729-34. and those that house their more permanent storage forms2525. Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu
Rev Neurosci. 2011;34:259-88.,2727. Eichenbaum H. What H.M. taught us. J Cogn Neurosci.
2013;25:14-21. exist, they must be modest in size and
number.
Synaptic tagging as a physiological process in memory formation
In 1997, Frey and Morris proposed a mechanism whereby weak LTPs that last only 30 min or so could
be turned into full-fledged processes lasting several hours by other LTPs developed in other
synapses of the same neuron.33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6. The mechanism involves tagging
of the synapses participating in the weak LTP by local proteins and the capture by these tags of
other proteins, called plasticity-related proteins (PRPs), generated at the synapses involved in the
other LTP process. This mechanism has been called the “tagging and capture”
hypothesis33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6.,44. Frey S, Frey JU. ‘Synaptic tagging’ and
‘cross-tagging’ and related associative reinforcement processes of functional
plasticity as the cellular basis for memory formation. Prog Brain Res.
2008;169:117-43.,66. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6. and has been found appropriate to explain both the switch from an early,
brief form of LTP to a long-lasting (days, weeks) form33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6.,44. Frey S, Frey JU. ‘Synaptic tagging’ and
‘cross-tagging’ and related associative reinforcement processes of functional
plasticity as the cellular basis for memory formation. Prog Brain Res.
2008;169:117-43. and the facilitation of “weak” memories by simple
exposure to a novel experience.44. Frey S, Frey JU. ‘Synaptic tagging’ and
‘cross-tagging’ and related associative reinforcement processes of functional
plasticity as the cellular basis for memory formation. Prog Brain Res.
2008;169:117-43.
5. Ballarini F, Moncada D, Martinez MC, Alen N, Viola H. Behavioral tagging is a
general mechanism of long-term memory formation. Proc Natl Acad Sci U S A.
2009;106:14599-604.-66. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6.,4242. Moncada D, Viola H. Induction of long-term memory by exposure to novelty
requires protein synthesis: evidence for a behavioral tagging. J Neurosci.
2007;27:7476-81.4444. Almaguer-Melian W, Bergado-Rosado J, Pavón-Fuentes N, Alberti-Amador E,
Mercerón-Martínez D, Frey JU. Novelty exposure overcomes foot shock-induced spatial-memory
impairment by processes of synaptic-tagging in rats. Proc Natl Acad Sci U S A.
2012;109:953-8. In the latter case, it is often called
“behavioral tagging.”55. Ballarini F, Moncada D, Martinez MC, Alen N, Viola H. Behavioral tagging is a
general mechanism of long-term memory formation. Proc Natl Acad Sci U S A.
2009;106:14599-604.,66. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6. The original learning would produce a protein that tags a set of hippocampal synapses so
that the tag would then capture the PRPs generated by novelty (or some other learning, or a second
LTP) in other synapses of the same cells. This would explain the well-known associative property of
learning, particularly of recently made memories. Clearly, synaptic tagging may explain not only the
associative property of memory, but also the interactions between memories of different content but
close in time.33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6.,66. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6.,4242. Moncada D, Viola H. Induction of long-term memory by exposure to novelty
requires protein synthesis: evidence for a behavioral tagging. J Neurosci.
2007;27:7476-81.
43. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6.-4444. Almaguer-Melian W, Bergado-Rosado J, Pavón-Fuentes N, Alberti-Amador E,
Mercerón-Martínez D, Frey JU. Novelty exposure overcomes foot shock-induced spatial-memory
impairment by processes of synaptic-tagging in rats. Proc Natl Acad Sci U S A.
2012;109:953-8.
One recent paper has proposed that PKMzeta may be one of, if not the key PRP to be captured by
the tags left by “weak” learning.4545. Smolen P, Baxter DA, Byrne JH. Molecular constraints on synaptic tagging and
maintenance of long-term potentiation: a predictive model. PLoS Comput Biol.
2012;8:e1002620. Another
paper, without going as far as advancing this proposal, has nevertheless suggested a key role for
PKMzeta in the persistence of the tagging and capture process.4646. Li Q, Rothkegel M, Xiao ZC, Abraham WC, Korte M, Sajikumar S. Making synapses
strong: metaplasticity prolongs associativity of long-term memory by switching synaptic tag
mechanisms. Cereb Cortex. 2012 Oct 9. [Epub ahead of print] Many other papers have suggested a variety of other PRPs.44. Frey S, Frey JU. ‘Synaptic tagging’ and
‘cross-tagging’ and related associative reinforcement processes of functional
plasticity as the cellular basis for memory formation. Prog Brain Res.
2008;169:117-43.,66. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6. There is usually a time constraint of about 1 h between
tagging and capture.33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature.
1997;385:533-6.,4646. Li Q, Rothkegel M, Xiao ZC, Abraham WC, Korte M, Sajikumar S. Making synapses
strong: metaplasticity prolongs associativity of long-term memory by switching synaptic tag
mechanisms. Cereb Cortex. 2012 Oct 9. [Epub ahead of print]
This time constraint is particularly evident in behavioral tagging (i.e., that between a
“weak” memory trace and a novelty).55. Ballarini F, Moncada D, Martinez MC, Alen N, Viola H. Behavioral tagging is a
general mechanism of long-term memory formation. Proc Natl Acad Sci U S A.
2009;106:14599-604.,4242. Moncada D, Viola H. Induction of long-term memory by exposure to novelty
requires protein synthesis: evidence for a behavioral tagging. J Neurosci.
2007;27:7476-81.
43. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H. Identification of
transmitter systems and learning tag molecules involved in behavioral tagging during memory
formation. Proc Natl Acad Sci U S A. 2011;108:12931-6.-4444. Almaguer-Melian W, Bergado-Rosado J, Pavón-Fuentes N, Alberti-Amador E,
Mercerón-Martínez D, Frey JU. Novelty exposure overcomes foot shock-induced spatial-memory
impairment by processes of synaptic-tagging in rats. Proc Natl Acad Sci U S A.
2012;109:953-8.,4747. Pavlov IP. Conditioned reflexes. London: Oxford University Press;
1927. A metaplasticity process has been suggested to activate
PKMzeta and lengthen this tag-to-capture interval considerably.4646. Li Q, Rothkegel M, Xiao ZC, Abraham WC, Korte M, Sajikumar S. Making synapses
strong: metaplasticity prolongs associativity of long-term memory by switching synaptic tag
mechanisms. Cereb Cortex. 2012 Oct 9. [Epub ahead of print] It remains to be determined, however, whether such lengthening can occur physiologically
and, if it does, whether it would be useful for the associative property of memory formation, which
is usually known to be quite brief.4747. Pavlov IP. Conditioned reflexes. London: Oxford University Press;
1927.
A possibility that cannot be dismissed without experimental data is that the activity of PKMzeta is not the cause of persistent memories but a consequence thereof, much as fever is not a cause but rather a consequence of infectious disease. Unless proven otherwise, this remains a hindrance to accepting that PKMzeta is at the source of memory persistence.
The modulation of extinction
Extinction was originally described in the early 20th century by Pavlov4747. Pavlov IP. Conditioned reflexes. London: Oxford University Press; 1927. as the process by which the repetition of a conditioned stimulus in the absence of any further reinforcement leads to the inhibition of the conditioned response. For example, if a tone which had been paired with food is then repeated alone several times, the salivation that had developed to the tone as a conditioned response gradually disappears. Extinction was introduced into psychiatry by Freud in the 1920s, who applied it to the successful treatment of phobias under the name of “habituation”,4848. Izquierdo I. Freud and memory neurobiology. Rev Psiquiatr Rio Gd Sul. 2006;28:243-4. a name which was not accepted by most because it designates a different process: the gradual inhibition of an unconditioned response.4747. Pavlov IP. Conditioned reflexes. London: Oxford University Press; 1927.,4949. Vianna MR, Alonso M, Viola H, Quevedo J, de Paris F, Furman M, et al. Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. Learn Mem. 2000;7:333-40. In recent years, often under the name of “exposure therapy”, extinction has been also successfully applied to the treatment of posttraumatic stress disorder (PTSD).99. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol. 2012;63:129-51.,5050. Beckett WS. Post-traumatic stress disorder. N Engl J Med. 2002;346:1495-8; author reply 1495-8.,5151. Sher L, Vilens A. Neurobiology of post-traumatic stress disorder. Hauppauge: Nova; 2010. Extinction can reverse either spontaneously88. Rescorla RA. Spontaneous recovery. Learn Mem. 2004;11:501-9. or by reintroduction of the reinforcement: just one tone-food pairing can fully reinstate the original Pavlovian conditioned salivation reflex.4747. Pavlov IP. Conditioned reflexes. London: Oxford University Press; 1927.
If a behavioral procedure is to be used in therapy, it should be amenable to modulation, and
therefore manageable by the therapist. If it were so rigid that once set into action it cannot be
stopped, accelerated or decelerated, it would be psychologically dangerous to use it; a
misapplication or an unwilling error could lead to serious long-lasting consequences. We have
recently found that extinction in two different aversive paradigms in rats can indeed by modulated
by eight different treatments infused shortly after the first of two sessions of extinction in three
different areas of the brain: the ventromedial prefrontal cortex, the basolateral amygdala and the
CA1 region of the hippocampus.1010. Fiorenza NG, Rosa J, Izquierdo I, Myskiw JC. Modulation of the extinction of two
different fear-motivated tasks in three distinct brain areas. Behav Brain Res.
2012;232:210-6. These three areas have been
previously shown to be effectively involved in the generation of extinction learning in the two
tasks, both by the occurrence of protein synthesis in them when extinction learning is consolidated
and by other parameters.5252. Santini E, Ge H, Ren K, Peãa de Ortiz S, Quirk GJ. Consolidation of fear
extinction requires protein synthesis in the medial prefrontal cortex. J Neurosci.
2004;24:5704-10.
53. Vianna MR, Szapiro G, McGaugh JL, Medina JH, Izquierdo I. Retrieval of memory
for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus.
Proc Natl Acad Sci U S A. 2001;98:12251-4.-5454. Vianna MR, Coitinho AS, Izquierdo I. Role of the hippocampus and amygdala in the
extinction of fear-motivated learning. Curr Neurovasc Res. 2004;1:55-60. The treatments found to modulate extinction are known to act
upon dopaminergic, noradrenergic, histaminergic or glutamatergic synapses,1010. Fiorenza NG, Rosa J, Izquierdo I, Myskiw JC. Modulation of the extinction of two
different fear-motivated tasks in three distinct brain areas. Behav Brain Res.
2012;232:210-6. i.e., four typical modulatory sets of synapses, and some of them have been tried
therapeutically to good effect in many situations that do not involve extinction learning, so side
effects would presumably be few.
In addition, we also found that a brief exposure to novelty (see above) may enhance extinction if presented 2 h before or 1 h after the first of two sessions of extinction; i.e., at the time when recent extinction learning is being consolidated.77. Myskiw JC, Benetti F, Izquierdo I. Behavioral tagging of extinction learning. Proc Natl Acad Sci U S A. 2013;110:1071-6.
These findings obviously open an entirely new vista over the use of “exposure” (extinction) therapy of PTSD. Once initiated, treatment can be accelerated or decelerated according to the reaction of the patient. To some, this form of therapy may appear intolerable, especially in the first few sessions; to others, who want to get rid of their syndrome quickly, it might be too slow. It would certainly be practical to modulate the speed of treatment by drug administration or by the interposition of other psychological stimuli, such as the perception of a novelty.
A reflection
It is often said that memory research, or research in neuroscience as a whole, has progressed more in the last five than in the preceding five or 50 years. This is because there are many more trained scientists dedicated to these overlapping areas now than ever before, and the techniques at our disposal are better and much more accurate now than they were a few years ago. However, in the account given above of the three areas of memory research that perhaps stand out today at their frontiers, it is clear that all derive from findings and ideas originated several decades ago.
Modern memory research probably began with the careful analysis of the results of the brain damage suffered during bilateral temporal lobe surgery by the famous patient HM in 1953, and of the overwhelming irruption of molecular biology in life sciences research starting with the discovery of the double helix in 1954. Those were times of great innovation in biology; advances in neuroscience since then have been enormous, and the field of memory was changed forever. Later, brain imaging and sophisticated molecular pharmacology added to the methods of analysis and paved the road for the findings and concepts of today. It is good to reflect on this chain of events and realize that, although the findings summarized herein are new, they are based on ideas and other findings dating back several years. A role of PKC in memory was first described in the 1970s,1717. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res Brain Res Rev. 1993;18:115-22. the idea of synaptic tagging was introduced in 1997,33. Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature. 1997;385:533-6. and extinction was discovered over one century ago.4747. Pavlov IP. Conditioned reflexes. London: Oxford University Press; 1927.
This paper was prepared with the financial help of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), both directly and through its program for National Institutes, as part of the work of the National Science and Technology Institute for Translational Medicine (INCT-TM).
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Publication Dates
-
Publication in this collection
April-June 2013
History
-
Received
08 Nov 2012 -
Accepted
26 Nov 2012