Download ashavsky 2006

Progress in Neurobiology 80 (2006) 99–113
www.elsevier.com/locate/pneurobio
‘‘The seven sins’’ of the Hebbian synapse: Can the hypothesis of synaptic
plasticity explain long-term memory consolidation?
Yuri I. Arshavsky *
Institute for Nonlinear Science, University of California San Diego, La Jolla, CA 92093-0402, USA
Received 28 July 2006; received in revised form 25 September 2006; accepted 26 September 2006
Abstract
Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the
commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of
synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current
knowledge on learning and initial stages of memory consolidation (‘‘synaptic consolidation’’) is based on this hypothesis. However, the hypothesis
of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of
declarative memory (‘‘system consolidation’’). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable
declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire
lifespan should be ‘‘etched in stone.’’ The only ‘‘stone-like’’ molecules within living cells are DNA molecules. Therefore, I advocate an alternative,
genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of
DNA, and that these modifications serve as the carriers of elementary memory traces.
# 2006 Elsevier Ltd. All rights reserved.
Keywords: Declarative memory; Synaptic plasticity; Long-term potentiation; Hebbian hypothesis; Genomic hypothesis; Memory stability; Memory localization;
Reconsolidation; Adult neurogenesis; Alzheimer’s disease
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Limitations of the synaptic plasticity hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. The synaptic plasticity hypothesis cannot explain the long-life persistence of memory . . . . . . . . . . . . . . . . . . . . . .
2.2. The synaptic plasticity hypothesis’ suggestion that the same mechanism is used for memory storage and
reproduction is seriously flawed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Memory acquisition and storage have different localizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. ‘‘Synaptic’’ and ‘‘system’’ memory consolidations have different temporal characteristics. . . . . . . . . . . . . . . . . . . .
2.5. Reconsolidation of memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Neurogenesis in the adult brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. The synaptic plasticity hypothesis does not explain the specific memory impairments present in Alzheimer’s disease
Alternative (genomic) hypothesis of memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: aCaMKII, a-calcium-calmodulin kinase II; AD, Alzheimer’s disease; CPEB, cytoplasmic polyadenelation element binding protein; CRE,
cAMP-response element; CREB, cAMP response element-binding protein; EST, electroshock therapy; LTP, long-term potentiation; MTL, medial temporal lobe;
SPH, the synaptic plasticity hypothesis
* Tel.: +1 858 822 2010; fax: +1 858 534 7664.
E-mail address: [email protected].
0301-0082/$ – see front matter # 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2006.09.004
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Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
. . .the past, the memories and realities that are the bedrock
of one’s present life, brought back suddenly by a scent, the
shape of a hill, an old song – some triviality that makes one
suddenly say ‘I remember. . .’
Agatha Christie. An Autobiography.
1. Introduction
In this paper, I look at some of the issues related to
explaining the neural mechanisms of declarative (explicit)
memory, that is, conscious memory for facts, events, language,
faces, music, etc. This memory is formed through life
experience and, together with the genome, determines the
human personality. Declarative memory includes three closely
coupled processes:
1. Acquisition of input information (learning);
2. Consolidation of acquired information from initially labile to
stable memories and their long-lasting (sometimes life-long)
storage in the brain;
3. The recall and use of stored information (memory retrieval).
The retrieval of declarative memory in humans is, by
definition, the conscious recall of stored information. This is the
principal impediment in discussing the memory retrieval
mechanism, because understanding neural mechanisms of
consciousness is beyond the scope of modern science.
Therefore, I mainly concentrate on memory consolidation
and storage. However, a total avoidance of memory retrieval
is hardly possible because the memory storage can only be
tested by its retrieval. In humans, the storage of declarative
memory is usually tested through verbal accounts, whereas
homologues of human’s declarative memory in animals (see
Manns and Eichenbaum, 2006) are tested in behavioral
experiments.
Memorizing new facts and events means that entering
information produces specific physical changes within the brain
(the memory engram). According to the most commonly
accepted viewpoint (the synaptic plasticity hypothesis, SPH)
traces of memory are stored within the brain through structural
modifications of synaptic connections, which result in changes
of synaptic efficiency and, therefore, in formations of new
patterns of neural activity. This hypothesis, suggested by Hebb
in 1949, remains the only hypothesis on the cellular basis of
memory that guides experimental efforts in the field (see
Chklovskii et al., 2004; Kandel, 2000, 2001; Milner et al., 1998;
Squire and Kandel, 1999; Sweatt, 2003 for recent reviews). As
claimed by Bailey (1999), ‘‘it has seemed almost axiomatic that
learning and memory must be expressed as a change in synaptic
function and form.’’ The current situation in the field was
vividly described by Mel (2002):
‘‘Pull the average neuroscientist off the street and ask them
how learning occurs in the brain, and you’re likely to get a
reflex response that includes such pat phrases as ‘activitydependent changes in synaptic strength,’ ‘LTP/LTD,’ or
‘Hebbian learning’.’’
Until recently, the central Hebbian postulate which states
that ‘‘neurons that fire together wire together’’ has not been
questioned by scientists. All current discussions are mainly
concentrated around the details of the molecular mechanisms
that determine the formation and modification synaptic
connections, and maintain the stability of newly formed and
modified synapses. The following quotation from a recent
review paper demonstrates this widely held perspective:
‘‘Activity-dependent synaptic plasticity is induced at
appropriate synapses during memory formation, and is both
necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in
which that plasticity is observed.’’ (Martin et al., 2000)
I think that the major reason why the SPH has become
indisputable is rooted in the general paradigm of modern
neuroscience. According to this paradigm, neural networks
consisting of simple elements (whose own role is negligible)
perform not only the ‘‘automatic’’ functions of the nervous
system (involuntary reflexes, control of respiratory, locomotor
and other rhythmic movements, maintenance of homeostasis,
etc.), but also higher cognitive functions of the brain (the
critical consideration of this paradigm was presented elsewhere, see Arshavsky, 2001, 2003a,c, 2006b). The paradigm
goes on to say that the high complexity of cognitive functions is
solely determined by the complexity of networks (see, for
example, Koch and Laurent, 1999; Quartz and Sejnowski,
1997), while the function of single neurons is limited to the
generation of electrical potentials and the transmission of
signals to other neurons. This viewpoint was distinctly spelled
out by LeDoux (2003) as follows: ‘‘In many ways, the self is
synaptic.’’ It is evident that within this conceptual framework,
no other mechanism for memory storage – except for
modifications in synaptic connections – is possible.
Another reason for the high popularity of the SPH is the
discovery of the well-known synaptic phenomenon – long-term
potentiation (LTP). A crucial role in forming new memories
belongs to the medial temporal lobe (MTL), including the
hippocampus (see Section 2.3). It was found that a brief highfrequency train of stimuli applied to intrahippocampal pathways evoked long-lasting (up to several hours) enhancement of
synaptic transmission to target neurons (Bliss and Lømo, 1973).
Further studies showed that several trains of stimuli evoked LTP
lasted for more than 24 h, and that the same stimulation in intact
animals could evoke LTP lasting for days, and even weeks (see
Kandel, 2000). LTP was also found in other brain structures
related to the memory formation – the neocortex, cerebellum,
amygdala (Blair et al., 2001; D’Angelo et al., 2005; Linch,
2004; Teskey and Valentine, 1998). Numerous studies have
shown that LTP and memory formation share similar cellular,
biochemical, and molecular mechanisms (Dudai, 2004; Kandel,
2000; Lamprecht and LeDoux, 2004; Linch, 2004; Malenka
and Bear, 2004; Sweatt, 2003; Wang et al., 2006). In
experiments on hippocampal slices, it has been found that
LTP is accompanied by structural modifications in synaptic
connections (Engert and Bonhoeffer, 1999; Maletic-Savatic
et al., 1999; Nagerl et al., 2004; Toni et al., 1999). Thus,
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
although LTP is evoked by artificial electrical stimulation of
input pathways with frequencies of up to 100 Hz, which do not
occur in the nervous system, this phenomenon is usually
regarded as compelling evidence for the SPH. As stated by
Abraham and Williams (2003), ‘‘For three decades, long-term
potentiation (LTP) has been the gold standard synaptic model
for mammalian memory mechanisms.’’
2. Limitations of the synaptic plasticity hypothesis
In this chapter I will illustrate that the SPH, which has played a
critical role in understanding the cellular mechanisms of learning
and initial stages of memory consolidation, faces at least seven
conceptual and experimental difficulties when it seeks to explain
a mechanism for long-term (potentially permanent) storage of
declarative memory. These difficulties are as follows.
2.1. The synaptic plasticity hypothesis cannot explain the
long-life persistence of memory
The key feature of declarative memory is its permanence.
Psycho-physiological studies provide evidence that human
individuals possess the ability to store and retrieve large amounts
of information throughout the entire lifetime, or at least during
several decades, even if the information is seldom or never used.
In a study on elderly individuals who had taken a Spanish course
in high school, but had never used Spanish later in their lives, it
was found that about 50% of the originally acquired knowledge
remained accessible for over 50 years (Bahrick, 1984). A similar
result was obtained in a study on memory of names and faces.
The participants were able to recognize about 90% of portraits of
their high school classmates 35 years after graduation (Bahrick
et al., 1975).1 Our inability to recall certain facts and events does
not necessarily mean that those traces of information have been
deleted from the brain. Facts and events that appear to have been
completely forgotten may be revived in the hypnotic state
(Cheek and LeCron, 1968; Luria, 1976; Fligstein et al., 1998;
Green, 1999) or in the response to electrical stimulation of the
lateral temporal lobe during brain surgery (Penfield, 1958, see
Box 1). Therefore, the inability to recall some facts and events
may signify that these memories, which continue to be stored in
the brain, are inaccessible to conscious recollection.
Particularly, pertinent evidence for the remarkable brain’s
ability to store memory has been shown in studies on mnemonists
– individuals who demonstrate an outstanding ability to
memorize and retrieve information. A mnemonist named
Shereshevskii was able to reproduce useless information, such
as long series of words, 15 years after this information was
acquired (Luria, 1968). Another mnemonist, Peek, 55 years old,
remembers by heart about 9000 books, the first of which he
acquired at the age of 18 months, as they were read to him
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Box 1. Permanency of memory (case report)
Very important observations, showing that the inability
to remember some facts and events does not signify that
the traces of information were lost, were described by the
famous Canadian neurosurgeon, Wilder Penfield.
Patients had been operated upon for the relief of focal
epileptic seizures at the Montreal Neurological Institute.
These operations were carried out under local anesthesia
and brain stimulations were applied during the operation
in an attempt to localize the origin of the patient’s seizure.
It was found that stimulation of the temporal lobe of the
cortex could cause previous experiences to be recalled
by the conscious patients. Electrically evoked recollections of previously experienced perceptions were largely
auditory, or visual, or both. This recollection was much
more vivid than normal memories, and was often about
things that remained unrecalled under ordinary circumstances. The following is an example of one of the cases
described by Penfield (1958).
A 26-year-old woman, D. F., began to have seizures at
age 6. In response to stimulation of the temporal lobe
during the operation she said: ‘‘I hear the music. It is like
the radio’’. She was asked to describe the music. When
the electrode was applied again, she began to hum a
tune. She was obviously humming along with orchestra
at about the tempo that would be expected. After the
patient had returned home, she wrote a letter that was,
in part, as follows:
‘‘Now to answer your questions: I heard the song right
from the beginning, and you know I could remember
much more of it right in the operating room . . . There
were instruments . . . It was as though it were being
played by an orchestra. Definitely it was not as though I
were imagining the tune to myself. I actually heard it. It
is not one of my favorite songs, so I don’t know why I
heard that song.’’
(Treffert and Christensen, 2005). One more case of outstanding
autobiographical memory called hyperthymestic syndrome
(from the Greek word thymesis meaning remembering) was
recently described by Parker et al. (2006). Awoman, AJ, 41 years
old, can describe with considerable accuracy what she was doing
any day of her life starting from her childhood. As was
highlighted by Treffert and Christensen (2005), we cannot say
that we understand the mechanism of memory until we can
explain these extraordinary abilities of some individuals for
memory storage and retrieval.
The question inevitably arises as to whether the SPH can
explain the potentially permanent maintenance of declarative
memory. In short, the SPH which has been described in many
reviews (Kandel, 2001; Lamprecht and LeDoux, 2004; Silva,
2003; Squire and Kandel, 1999; Sweatt, 2003; Thomas and
Huganir, 2004) suggests the following mechanism for synaptic
modifications in the hippocampus.2 Input signals carrying new
1
Recently, I had a chance to test these observations. I found a photo of my
high school class, taken in 1947. Beside me, there are 16 persons in this photo,
none of whom I have seen since then. I found that I could remember 15 of them
by first and last names. Therefore, this unused information has been stored in
my brain for almost 60 years.
2
In addition to studies on the hippocampus, an important role in understanding the molecular mechanisms of synaptic plasticity was played by studies
of post-stimulatory sensitization of the withdrawal reflex in the marine mollusk,
Aplysia (Kandel, 2000; Squire and Kandel, 1999).
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information act on the glutamatergic receptors of the target
hippocampal neurons resulting in Ca2+ influx. Ca2+ initiates an
intracellular signal transduction cascade: the activation of the
Ca2+-calmodulin-dependent adenyl cyclase, the increased
synthesis of cAMP, and the activation of several protein
kinases. Activated kinases are translocated to the cell nucleus,
where they phosphorylate the cAMP response element-binding
protein (CREB). CREB binds to the cAMP-response elements
(CRE) in regulatory regions of target genes and stimulates their
transcription. The products of these genes may be transcription
factors themselves that regulate the transcription of the
downstream genes. The final step of this cascade is the
transient activation of the genes involved in the synthesis of the
proteins essential both for the modification of preexisting
synapses and for the formation of new ones.
Thousands of works using different experimental
approaches have found that the mechanism described above
is involved in learning and memory formation. Particularly, it
has been shown that inhibitors of protein (Davis and Squire,
1984; McGaugh, 2000) and mRNA (Bailey et al., 1999; Igaz
et al., 2002) synthesis administered before or shortly after
learning precluded the consolidation of long-term memory (see
Section 2.4). The latter fact is regarded as compelling evidence
that memory formation depends on protein synthesis-dependent modifications of synaptic connections. However, the
question remains, whether modifications of synaptic connections are used only at the initial stages of memory formation, or
whether they are also used as the mechanism for the persistent
memory storage. This is a fundamental question about memory,
which must be discussed in detail.
While developing the idea that ‘‘the self is synaptic,’’
LeDoux (2003) claimed that ‘‘Genes and experience . . . are . . .
not different things, but different ways of doing the same thing
– wiring the synapses of our brain.’’ This statement is
disputable. Here, I will clarify why I do not think that genes and
experience (as it is interpreted by the SPH) are the same things.
The basic organization of the brain is determined by genetic
mechanisms. Although the way from the genotype to the
organization of the brain consisting of 1011 neurons connected
through 1013 to 1015 synapses is very complex and enigmatic, it
is evident that genetic programs determine not only gross
connections between different brain structures, but also the
organization of synaptic connections within circuitries (Benson
et al., 2001). Otherwise, the existence of cytoarchitectonic
atlases of cerebral neurons and their connections, as well as the
reproducibility of electrophysiological results obtained in
studies of synaptic connections within microcircuits, would
be impossible. The stability of synaptic connections in the
neocortex was recently confirmed in in vivo studies, using twophoton microscopy and transgenic mice expressing green
fluorescent protein (Grutzendler et al., 2002; Zuo et al., 2005;
De Paola et al., 2006). Although dendrite spines and axonal
branches were continuously changing due to their elongation
and retraction, the overall density of synaptic contacts did not
change for a fairly long period (up to several months in mice).
One can suggest that this stability of synaptic connections is
maintained by the same genetic mechanisms which are
responsible for the organization of intra- and internetwork
connections during brain development.
In contrast, the SPH suggests that experience-dependent
modifications in synaptic connections are realized at the
transcriptional/translational level and do not involve genomic
changes. Therefore, it is assumed that structural synaptic
modifications result from a transient activation of the protein
synthesis (see above). Since proteins have a very short lifetime
as compared with memory lifetime, additional hypotheses are
required to explain how stable synaptic modifications could
result from a transient activation of the protein synthesis. This
difficulty of the SPH was recently highlighted by several
authors in the following ways:
‘‘Maintaining an increased synaptic connection over many
protein half-lives, in the face of complete breakdown and
resynthesis of all the protein components that make up that
synapse, requires a self-reinforcing signal’’ (Sweatt, 2003)
and
‘‘The structural change once initiated is not sufficient as a
maintenance mechanism for long-term memory. The
structural change itself must be actively maintained’’
(Bailey et al., 2004).
Several hypothetical mechanisms for the stabilization of
learning-related synaptic modifications have been suggested.
These hypotheses assume that the stabilization of experiencerelated synaptic modifications is maintained by local selfperpetuating translational and posttranslational mechanisms
(Bailey et al., 2004; Routtenberg and Rekart, 2005; Yi and
Ehlers, 2005). The most elaborate hypothesis was advanced by
Kandel and coworkers (Bailey et al., 2004; Si et al., 2003a,b).
They suggested that a critical role in stabilizing local synaptic
changes belongs to the neuron-specific isoform of cytoplasmic
polyadenelation element binding protein (CPEB). A synaptic
input increases the amount of the CPEB protein in a restricted
postsynaptic area and switches CPEB into a self-perpetuating
prion-like form that has a great capacity to facilitate mRNA
translation. Thus, conformation of CPEB into the selfperpetuating prion-like state determines both prolonged and
local translation of mRNAs in the activated synapses.
Essentially, all these hypotheses deal with phenomena (such
as LTP in the hippocampus, or long-term sensitization of the
gill-withdrawal reflex in Aplysia) that last days or weeks.
Therefore, more evidence is needed to establish whether the
hypothesized mechanisms (i.e., the mechanisms based on the
suggestion that experience-dependent changes in the brain are
realized at the transcriptional/translational level and do not
involve genomic changes) can be used to form persistent
declarative memories lasting years and even whole lifespan.
2.2. The synaptic plasticity hypothesis’ suggestion that the
same mechanism is used for memory storage and
reproduction is seriously flawed
It is commonly accepted that changes in the strength of
synaptic connections lead to the formation of new patterns of
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
neural activity, while a reactivation of these patterns results in
memory retrieval. In a recent book on neural mechanisms of
memory, Maroun et al. (2001) claimed:
‘‘According to this view [the SPH], coactive and potentially
interconnected neurons would, after repeated reactivity,
become more strongly connected. These changes in
connection strength implemented learning, its persistence
comprised memory, and the reactivation of assemblies of
such neurons was memory retrieval.’’
Thus, the SPH assumes that the same synaptic mechanisms
are used for both memory storage and retrieval. Although this
idea may initially seem appealing, it is the ‘‘Achilles heel’’ of
the SPH. If we look at any artificial memory device (ranging
from notebooks to video tapes and hard drives), we can see
that each system requires separate mechanisms (or separate
communicational channels) to save and to reproduce
information. For example, recording a phone number in a
notebook requires the use of our motor system and a pen, while
reading the number requires the use of the visual system.
Imagine what would happen if we needed to use the motor
system and a pen not only to save the phone number, but to
‘‘read’’ it as well. If one had to trace the written number with a
pen each time it was ‘‘read’’, the written number would soon
become muddled, as our motor system has a lot of sources of
noise and we cannot trace the original lines perfectly. The more
it was accessed, the faster the written information would erode.
Another example is the VCR. To record a movie, a VCR
produces physical changes in a magnetic tape; to show a
movie, it reads the tape and sends signals in ‘‘the opposite
direction,’’ without affecting the stored information. Thus, the
storage of information in all artificial systems is organized in
such a way that information cannot be lost by being
reproduced, and this allows us to use it as many times as
we like. Information can solely be lost because of a physical
destruction of its carrier.
Unlike a VCR, in neural networks signals cannot be sent in
the opposite direction through the same synaptic connections
because of unilateral transmission in synapses. Consequently,
the SPH assumes that the same communicational channels are
used both for the memory storage and reproduction. I cannot
exclude that a mechanism of this kind could be used in an ideal
system lacking any noise. However, as was mentioned, the real
nervous system has many sources of noise. Therefore, patterns
of synaptic excitation during repeated memory retrieval will
always have slight variations. If plasticity is an inherent
property of synapses, each memory reactivation must lead to
further modification in synaptic connections and, eventually, to
memory erosion, in direct correlation to how frequently it is
accessed (see the aforementioned example with the notebook).
Since this is not the case, and repetitive retrievals lead to
memory strengthening rather than erosion, we must conclude
that memory is resistant to the synaptic activity that
accompanies memory retrieval.
This is not the only example that shows the resistance of
memory to synaptic activity. Another example is the resistance
of memory to spontaneous neuronal activity. According to the
103
SPH, we must expect that ongoing spontaneous activity will
lead to incessant, uncontrolled modifications in synaptic
connections and, eventually, to erosions in older memories.
This glitch in the SPH was distinctly formulated by Eccles
(1972) as follows:
‘‘The simple concept that disuse leads to regression of spine
synapses and excess usage to hypertrophy can be criticized
because . . . almost all cells . . . are discharging continuously.
One can imagine therefore that there would be overall
hypertrophy of all synapses under such conditions . . .
Evidently frequent synaptic excitation could hardly provide
a satisfactory explanation of synaptic changes involved in
learning.’’
The third example of declarative memory’s resistance to
synaptic activity is memory survival of epileptic fits and
electroshock therapy (EST). Epileptic fits are accompanied by
bursts of synchronous high-frequency discharges of cerebral
neurons. In experiments on animals, it was found that the intraburst spike frequencies (80–200 Hz, Grenier et al., 2003) are
comparable with the frequency of electrical stimulation used
for receiving LTP (see above) and undoubtedly overcome the
frequency of sensory signals leading to the formation of
declarative memory. Nonetheless, although this non-controlled
synaptic activity comprises widespread areas of the cerebral
cortex, and is strong enough to produce substantial remodifications of all synaptic connections, it does not affect
long-term memory. In most cases, seizure victims only suffer
memory loss for the period during and immediately prior to
the seizure (Thompson, 1991; see also Footnote 3). The
same can be said of EST. Repetitive electroconvulsive
treatments, which evoke synchronous excitation of most
cerebral neurons and intracerebral pathways, do not affect
remote declarative memory (Greenberg and Kellner, 2005;
Squire et al., 1976).
Together, these data, interpreted within the SPH, lead to an
apparent logical paradox: declarative memory that is assumed
to be based on activity-dependent modifications in synaptic
connections is resistant to synaptic activity which uses the same
exact synapses. The direct conclusion from this paradox is that,
contrary to the SPH, the same mechanism is not used to save
and retrieve memory. To save information, physical changes are
produced in the neurons serving as memory carriers, and these
changes must not to be affected by memory reactivations or
other types of synaptic activity.
2.3. Memory acquisition and storage have different
localizations
Memory of new facts and events is progressively
consolidated from an unstable state, vulnerable to different
interventions (such as an electroshock, epileptic episode, brain
trauma, hypothermia, etc.), to a stable state, resistant to these
interventions (Dudai, 2004; McGaugh, 2000; Squire, 1992;
Squire et al., 2001). The process of consolidation includes
different aspects. One of these aspects is the role of different
cerebral structures in memory consolidation.
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The MTL (which includes the hippocampus, as well as
adjacent entorhinal, perirhinal, and parahippocampal cortices)
plays a critical role in acquiring new information about facts
and events. About 50 years ago, the patient H.M. underwent a
bilateral resection of most of his MTL, which resulted in
persisted anterograde amnesia (Scoville and Milner, 1957; see
also Milner et al., 1998; Squire and Kandel, 1999). Although
his perceptual and cognitive abilities were not destroyed, and
H.M. was able to hold immediate perceptions in his mind, all
these perceptions were lost as soon as his attention was turned
to some other object. For example, he could not remember what
he had eaten for breakfast, recognize members of the hospital
staff, or acquire the meaning of unknown words. The inability
of patients with bilateral lesions of the MTL to acquire new
semantic knowledge was confirmed in further clinical
observations (Bayley and Squire, 2005; Rosenbaum et al.,
2005).
Although the MTL plays an enabling role in learning and
memory consolidation, it has a time-limited significance in
memory storage (Bayley et al., 2005; Milner et al., 1998;
Squire, 1992; Squire and Kandel, 1999; Squire et al., 2001). In
patients with damage to the MTL, recent memory suffers,
whereas remote memory is spared. For example, H.M. cannot
acquire the meaning of new words, but remembers his native
language, and has no evident problems in language comprehension, production, and reading. Although he did not
recognize members of the hospital staff, he could recognize
Dr. Scoville (see Scoville and Milner, 1957) whom he had met
before his operation.3 In a recent study with an improved
quantitative method for memory scoring, it has been shown that
patients with large MTL lesions can still recall autobiographical memories from early in their lives, at the same rate as
control individuals (Bayley et al., 2005).
In addition to clinical observations, numerous experimental
studies have shown the critical role of the MTL in acquisition of
new information and its transient role in memory storage (see
Frankland and Bontempi, 2005; Wiltgen et al., 2004; Wang
et al., 2006 for recent reviews). I will describe four examples for
illustration:
(i) Inhibitors of protein synthesis administered before or
shortly after training on rats prevented memory formation
both when they were infused systemically and when they
were locally applied to the hippocampus (Taubenfeld et al.,
2001).
3
There is one more reason why the H.M. case is essential to understanding
the mechanism of memory consolidation. H.M. was surgically treated to help
his epilepsy, which originated within the MTL. He had at least one major
seizure nearly each week. According to the SPH, which assumes that plasticity
is an inherent property of synapses, each seizure had to radically rewire the
existing patterns of synaptic connections and, therefore, to destroy memories
consolidated before the beginning of each epileptic attack. Evidently, this is not
the case, as H.M. remembers fact and events acquired before the surgery. This is
one of the examples (see Section 2.2) that disprove the idea that the memory
storage is based on activity-dependent structural modifications of synaptic
connections.
(ii) Lesions in the hippocampus abolished contextual fear
memory in rats trained for 1 day before the lesion, but not
in those trained for 28 days before the lesion (Anagnostaras
et al., 1999). In contrast, lidocaine-induced inactivation of
the prefrontal cortex disrupted the retrieval of remote (18
or 36 days after training), but not recent (1 or 3 days)
contextual fear memories (Frankland et al., 2004).
Similarly, lidocaine-induced inactivation of the hippocampus or the anterior cingulate cortex blocked recent or
remote spatial memory, respectively (Teixeira et al., 2006;
but see Broadbent et al., 2006 who found that lidocaineinduced inactivation of the hippocampus disrupted both
recent and remote spatial memory).
(iii) Monkeys with hippocampal lesions were severely
impaired in discriminating recently learned objects.
However, they remembered objects they had learned long
ago as well as normal monkeys did (Zola-Morgan and
Squire, 1990; compare with results of clinical observations
by Bayley et al., 2005).
(iv) Results of imaging studies on rodents showed that memory
retrieval 1–5 days after learning was associated with
increased activity in the hippocampus and related
structures, and low activity in the neocortex. In contrast,
the same tests taken 3 weeks later were associated with low
hippocampal and increased neocortical activity (Bontempi
et al., 1999; Ross and Eichenbaum, 2006).
Thus, although declarative memory is primarily dependent
on the MTL, it is eventually consolidated in the neocortex and
probably in some other structures of the brain, which are the
ultimate repositories for persistent MTL-independent memories. The role of the MTL in cortical memory consolidation is
still poorly understood. However, regardless of the MTL’s role
in cortical memory consolidation, the fact that different
cerebral structures are used for temporary and permanent
storage of information goes against the SPH, which states that
‘‘changes in the connection strength implement learning,’’
while memory retrieval is ‘‘the reactivation of assemblies of
such neurons’’ (Maroun et al., 2001, see above). It is evident
that the mode of memory representation in the neocortex cannot
be a direct replica of the mode in which the information is
originally acquired in the MTL because of different cytoarchitecture of the MTL and neocortex. This means that the nature
of memory representation is different in these two structures
and that the mechanisms used by the neocortex for the
persistent storage of declarative memory is not equivalent to the
mechanisms used by the MTL for learning and temporary
maintenance of memory traces. In any case, memory retrieval
cannot occur through the reactivation of the same neural
assemblies that are involved in initial learning, because these
two processes have different localizations.
2.4. ‘‘Synaptic’’ and ‘‘system’’ memory consolidations
have different temporal characteristics
The process of memory consolidation from the unstable to
stable state takes a long time and occurs in several stages
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
(Eichenbaum, 1997; McGaugh, 2000; Squire, 1992; Squire and
Kandel, 1999). Recently, the terms ‘‘synaptic’’ and ‘‘system’’
consolidation have been suggested to emphasize certain
functional aspects of memory consolidation (Dudai, 2004;
Frankland and Bontempi, 2005; Wang et al., 2006). Synaptic
consolidation includes the signaling cascade outlined above
(see Section 2.1), which is initiated by hippocampal inputs and
lead to protein synthesis-dependent modifications of synaptic
connections. The duration of synaptic consolidation is
measured by the period of time when memory is sensitive to
the inhibition of protein synthesis (Dudai, 2004). Synaptic
consolidation is completed several hours after learning, and
there is no evidence for the involvement of protein synthesis in
further memory consolidation.
System consolidation leading to the formation of persistent
memory occurs in the neocortex (see Section 2.3). This process
of memory conservation takes weeks, months, and even years
(in humans) to be completed. The duration of synaptic
consolidation is measured by the time it takes for memory
to become independent on the MTL (Dudai, 2004). Between
synaptic and system consolidation, there is a prolonged
transient period when the memory storage still depends on
the MTL.
Little is known about the physiological mechanisms
underlying system consolidation and mode of the information
storage within the neocortex. The terms ‘‘synaptic’’ and
‘‘system’’ consolidation seem to suggest different mechanisms
for the transient memory storage in the MTL and the persistent
storage in the neocortex. However, due to a lack in any
alternative to the SPH, it is automatically assumed that system
consolidation of memory, like synaptic consolidation, is also
based on structural modifications in synaptic connections
within the neocortex (Wang et al., 2006; Wiltgen et al., 2004).
As claimed by Wiltgen et al. (2004), ‘‘at least some of the
molecules involved in hippocampal plasticity (e.g., PKA, PKC,
MAPK, CREB) may also be required for remote memory
storage in cortical networks.’’ This suggestion is based on the
following two findings:
(i) It is well known that triggering the intracellular signaling
cascade underlying synaptic consolidation in the MTL
requires the activation of NMDA receptors (Nakazawa
et al., 2004; Wittenberg and Tsien, 2002). To study the role
of the NMDA receptors in system consolidation, Cui et al.
(2004) used transgenic mice in which the NMDA receptors
can be temporarily switched off in the forebrain. It was
found that 30-day-switching-off the NMDA receptors (6
months after initial training and at least 2 months prior to
memory retrieval) resulted in severe disruption of fear
memories.
(ii) One of the enzymes essential for hippocampus-dependent
learning is a-calcium-calmodulin kinase II, aCaMKII
(Lisman et al., 2002; Wiltgen et al., 2004; Wang et al.,
2006). The role of this kinase in system memory
consolidation was studied on heterozygous aCaMKII+/
mice (Elgersma et al., 2004; Frankland et al., 2001). These
mice were found to have an impaired spatial and contextual
105
memory when tested 10–50 days after training. It was
concluded that aCaMKII is involved in system memory
consolidation.4
Neither of these two findings can be regarded as evidence for
the use of the same mechanisms for both synaptic consolidation
in the MTL and system consolidation in the neocortex. (i)
Glutamate is the principal excitatory neurotransmitter in the
cortex. Therefore, there are many reasons why inactivation of
NMDA receptors can affect consolidation and/or retrieval of
system memory. (ii) aCaMKII is a multifunctional enzyme and,
even a confirmation of its role in system consolidation cannot
be regarded as compelling evidence that long-term memory
storage in the neocortex is based on protein synthesisdependent modifications in synaptic connections. On the other
hand, different durations for the two types of memory
consolidation, as well as the absence of evidence demonstrating
the requirement of protein synthesis for system consolidation,
support the aforementioned suggestion (see Section 2.3) that
primary synaptic consolidation in the MTL and persistent
system consolidation in the neocortex may have radically
different mechanisms.
2.5. Reconsolidation of memory
As mentioned earlier, newly learned memories go through
an initial fragile stage before being consolidated into stable,
long-term memories. According to the SPH, memory stability
is based on irreversible structural modifications of synaptic
connections. However, in the 1960s and 1970s, a puzzling
phenomenon, seemingly incompatible with the SPH, was
found. In rodents, different amnestic factors (electroconvulsive
shock, hypothermia, head injury, etc.) could destroy wellconsolidated memory when applied directly after memory
retrieval (Mactutus et al., 1979; Misanin et al., 1968; see Sara,
2000 for review). Particularly, Judge and Quartermain (1982)
found that the protein synthesis inhibitor, anisomycin produced
amnesia for well-consolidated avoidance reactions, provided
that it was injected immediately after conditional stimulus.
These findings suggest that retrieval can render consolidated
memory into the initial fragile state and that de novo protein
synthesis is required for memory reconsolidation.
The phenomenon of memory reconsolidation was recently
confirmed in a study on fear memory. The site for fear memory
acquisition is the amygdala, and infusion of anisomycin into the
amygdala directly after training prevents the consolidation of
fear conditioning. The same effect was produced by the
infusion of anisomycin into the amygdala after memory
reactivation, regardless of whether retrieval was performed 1 or
14 days after conditioning (Nader et al., 2000). The authors
concluded that this phenomenon of memory reconsolidation
after retrieval is not ‘‘predicted by traditional theories of
memory consolidation,’’ since it seems unlikely that ‘‘retrieval
4
This conclusion should be regarded with some caution, as it was recently
found that CaMKII contributes to short-term memory, but is not necessary for
long-term memory (Irvine et al., 2005, 2006).
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Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
reverses structural modifications of synaptic connections
induced by learning.’’
The work by Nader et al. (2000) initiated a lot of new studies
in this field. Most of these studies confirmed that traces of
memory, including system memories (Debiec et al., 2002;
Duvarci and Nader, 2004; Frankland et al., 2006; but see
Milekic and Alberini, 2002 for the opposite result), undergo
postretrieval reconsolidation (reviewed by Dudai, 2004; Nader,
2003). But in spite of the discovery of postretrieval
reconsolidation, which seemed to ‘‘overturn the old dogma’’
(Nader, 2003), the SPH was not overturned. Very complex
logical constructions were suggested to bring together the SPH
and memory reconsolidation (see Dudai, 2004 and Millin et al.,
2001, for example). However, these logical constructions can
hardly explain the phenomenon of postretrieval memory
reconsolidation within the bounds of the SPH. Rather, they
demonstrate authors’ unwillingness to go beyond the traditional
hypothesis. Meanwhile, the viewpoint that persistent declarative memory is stored in the brain through structural
modifications in synaptic connections is incompatible with
the phenomenon of memory reconsolidation after retrieval. It
does seem unlikely that each memory reactivation produces at
least a transient reversal of structural modifications in the
synaptic connections formed during memory consolidation.
The existence of the phenomenon of postretrieval reconsolidation of consolidated memory (if this phenomenon does really
exist, see Alberini, 2005; Alberini et al., 2006; Biedenkapp and
Rudy, 2004; Cammarota et al., 2004; Milekic and Alberini,
2002 who suppose that the phenomenon of reconsolidation is
related to recent memory only) requires a radical revision of the
existing concept on the mechanism of the memory storage.
2.6. Neurogenesis in the adult brain
For many years, it was commonly accepted that new neurons
are not produced in the adult mammalian brain. Neuron
stability in the brain was considered to contribute to the stability
of new patterns of neural activity formed over the course of
memory consolidation. As stated by Rakic (1985), ‘‘A stable
population of neurons in primates . . . may be important for the
continuity of learning and memory over a lifetime.’’
The traditional view on the absence of neurogenesis in the
adult brain has been called into question by recent studies
demonstrating neurogenesis in adult rodents and primates,
including humans (Eriksson et al., 1998; Gould et al., 1999a;
Gross, 2000; Kempermann et al., 2004; Kornack and Rakic,
1999; Lledo et al., 2006; Ming and Song, 2005; Schinder and
Gage, 2004). Adult neurogenesis takes place mainly in the
hippocampus. The presence of neurogenesis in the neocortex,
however, is disputable (cf. Gould et al., 1999b and Rakic,
2002). In rats, about 9000 new granule cells are produced each
day in the dentate gyrus of the hippocampus; the number of new
neurons generated each month is about 6% of the total size of
the cell population (Cameron and McKay, 2001). The adultgenerated cells form synaptic connections with other neurons
and, therefore, are integrated in hippocampal circuits (Gross,
2000; Liu et al., 2003; Lledo et al., 2006; Ming and Song, 2005;
Schinder and Gage, 2004). Gross (2000) concluded that the
existence of adult-generated neurons may lead to ‘‘the
development of entirely new circuits with new and previously
unused elements as well as the modulation of older circuits and
connections.’’
The continual incorporation of new-born neurons into
existing hippocampal circuits may be a source of the instability
in neural interconnections established in the process of learning
and hippocampus-dependent memory consolidation (see Sections 2.3 and 2.4). The contradiction between the SPH and the
continuous incorporation of new neurons into the hippocampal
circuits was highlighted by Nottebohm (2002) as follows:
‘‘A theory of learning based on synapses did not predict a
need for replacing healthy adult neurons by other neurons of
the same kind, and so something basic must have been
missing. If synaptic plasticity did not predict neuronal
replacement, how must we reconstitute our logic of brain
function so that both phenomena, synaptic plasticity and
spontaneous neuronal replacement, can coexist, conceptually, in a harmonious manner?’’
In contrast to the prediction of the SPH that adult
neurogenesis may cause the erosion of hippocampus-dependent
memory, results obtained by some authors suggest that adult
neurogenesis improves an acquisition and initial consolidation
of new information (Gould et al., 1999c; Gross, 2000; Schinder
and Gage, 2004). This notion was supported by the following
facts. The stimulating effect of environmental enrichment and
physical activity on adult hippocampal neurogenesis improved
hippocampus-dependent learning (Kempermann et al., 1997;
Nilsson et al., 1999; van Praag et al., 1999). On the other hand,
the suppression of cell proliferation in the hippocampus by Xor gamma-irradiation and by chronic treatment with an antimitotic agent, methylazoxymethanol, impaired hippocampusdependent learning (Bruel-Jungerman et al., 2005; Madsen
et al., 2003; Shors et al., 2001; Snyder et al., 2005).
The functional role of hippocampal adult neurogenesis in
learning and memory remains to be established (see Aimone
et al., 2006; Lledo et al., 2006). The most accepted viewpoint is
that adult neurogenesis increases network capacities for the
acquisition of new information (Kempermann, 2002; Schinder
and Gage, 2004; Gross, 2000; Tashiro et al., 2006; Wang et al.,
2006). For example, according to Gross (2000), after
completing memory consolidation in the neocortex, old
hippocampal neurons may die, ‘‘making room for new naive
neurons that would then function similarly in consolidating new
memories.’’
However, it is important to be aware that the SPH does not
predict the necessity of replacing healthy neurons to create
more room for new memories (Nottebohm, 2002; see above).
According to the SPH, acquisition of new information requires
a re-modification of the patterns of synaptic connections – that
is, deleting the synapses related to ‘‘old memories’’ and
creating new synaptic connections, but not the generation of
new neurons. Adult neurogenesis can create more room for
learning new tasks only if memory consolidation occurs not at
the synaptic level, but within individual neurons.
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
2.7. The synaptic plasticity hypothesis does not explain the
specific memory impairments present in Alzheimer’s
disease
Alzheimer’s disease (AD) is a neurodegenerative disease
characterized by the formation of amyloid plaques and
neurofibrillary tangles. AD starts as the specific disease of
memory, while other neurological functions are intact. As
emphasized in a recent review, ‘‘Alzheimer’s disease characteristically produces a remarkably pure impairment of
declarative memory in its earliest stages’’ (Walsh and Selkoe,
2004). Correspondingly, the degeneration of neurons leading to
AD is area-specific. It occurs primarily in the cerebral regions
related to the acquisition and storage of declarative memory
(the hippocampus and entorhinal cortex, amygdala, and
association cortices), but not in the primary sensory and motor
cortices (Price, 2000; Selkoe, 2001). Within the memoryrelated regions, specific neuronal populations are particularly
vulnerable, whereas other neurons are spared. It appears that
degeneration selectively affects those neurons which serve as
carriers of memory traces.
Since AD starts as the specific disease of memory, any
hypothesis on the mechanism of learning and memory
consolidation has to include an explanation of this specificity
(see Small et al., 2001). Why are the neurons involved in
learning and memory storage more vulnerable, versus other
neurons, to the genetic and cardiovascular risk factors for AD?
Guided by the SPH, many authors concentrated on studying
LTP in transgenic mice that develop an AD-like phenotype due
to expression of human mutant tau and/or mutant amyloid b
protein precursor proteins. However, the results of these studies
are extremely inconsistent. Although some studies reported
age-related deficits (although usually not radical) in the
induction and/or maintenance of LTP in transgenic versus
wild-type mice (Chapman et al., 1999; Gureviciene et al., 2004;
Jacobsen et al., 2006; Oddo et al., 2003; Trinchese et al., 2004),
others found no change or even a robust increase of LTP tested
on the hippocampus and prefrontal cortex (Fitzjohn et al., 2001;
Hsia et al., 1999; Jolas et al., 2002; Larson et al., 1999; Roder
et al., 2003). Thus, results obtained in transgenic mice can
hardly be regarded as evidence for a link between decreased
synaptic plasticity tested by changes in LTP and AD-like
phenotype.
Several authors, who did not find any changes of LTP,
reported deficits of basal synaptic functions in amyloid b
protein precursor transgenic mice (Hsia et al., 1999; Fitzjohn
et al., 2001). Correspondingly, biochemical and morphological
analyses of brain tissue taken from AD patients led to
conclusion that synapses in the hippocampus and association
cortices are the initial targets in AD (Davies et al., 1987; Terry
et al., 1991; see Small et al., 2001 and Selkoe, 2002 for
reviews). However, deficits in basal synaptic transmission can
hardly explain why AD starts with specific impairments of
learning and memory because not only memory, but all brain
functions equally depend on synaptic transmission.
One can conclude that the specific impairment of memory in
the earliest stage of AD can hardly be interpreted within the
107
context of the SPH. The specificity of synapses is mainly
determined by the transmitter released from presynaptic
terminals and accepted by receptors of target neurons. Since
synaptic connections newly formed during learning and
memory consolidation are unlikely to use specific ‘‘memory’’
transmitters, it is plausible to suggest that memory consolidation involves not only synaptic, but also intracellular
modifications. In this case, the selective vulnerability of the
memory-related neurons to risk factors for AD can be regarded
as the result of specific intraneural modifications that arise in
the process of memory consolidation (see below).
3. Alternative (genomic) hypothesis of memory
Here I have tried to show that all the ‘‘sins’’ of the SPH are
rooted in its major intrinsic self-contradiction. It is hardly
possible to build stable declarative memory on such a nonstable foundation as synaptic plasticity. The phenomenon of
synaptic plasticity may be used for learning and transient
memory saving. However, persistent memory which lasts
throughout the entire lifespan must be ‘‘etched in stone.’’ The
only ‘‘stone-like’’ molecules in the living cells are the
molecules of DNA. Therefore, it is plausible to hypothesize
that acquired information is persistently stored within
individual neurons through modifications of DNA, and that
these modifications serve as the carriers of elementary
memory traces. This idea (the genomic hypothesis of
memory5) was distinctly proclaimed by Davis and Squire
(1984) and Crick (1984) in their attempt to explain the
persistence of memory (see also Arshavsky, 2003a; Been
and Dietrich, 2004; De Fonzo et al., 2000; Dietrich and Been,
2001; Nottebohm, 2002; Peña de Ortiz and Arshavsky, 2001;
Peña de Ortiz et al., 2004):
‘‘Some long-term memories may last days, weeks, or even
many years. . . . This suggests that the maintenance of longterm memories cannot be based solely on either posttranslational protein modification or the synthesis of new proteins
at or near the time of new learning. This suggestion is based
on observation that brain proteins have a half-life on the
order of days to weeks . . . It is possible that neurons have
genetic commands to maintain those molecular or morphological alterations that occur when memory is initially
established . . .’’ (Davis and Squire, 1984).
‘‘The time span of human memory (without obvious
rehearsal) is often a matter of years, sometimes even tens
of years. Yet . . . almost all the molecules in our bodies, with
the exception of DNA, turn over in a matter of days, weeks
or at the most a few months . . . Several possible solutions of
the problem suggest themselves. For example, memory
might be coded in alterations to particular stretches of
chromosomal DNA’’ (Crick, 1984).
5
In previous publications, the term ‘‘chemical hypothesis of memory’’ was
used instead of ‘‘genomic hypothesis’’ (Arshavsky, 2003a,b; Peña de Ortiz and
Arshavsky, 2001).
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There are two attempts to specify the genomic hypothesis of
memory. One of them suggests that persistent memory storage
occurs either via the mechanism of somatic DNA recombination similar (although not necessary identical) to V(D)J
recombination in cells of the immune system (Arshavsky,
2003a,b, 2006a; Peña de Ortiz and Arshavsky, 2001; Peña de
Ortiz et al., 2004) or via the meiotic mechanism of DNA
recombination acting in an early stage of postnatal development
(Dietrich and Been, 2001; Been and Dietrich, 2004). Some
experimental data supporting the hypothesis on using somatic
V(D)J-like DNA recombination for the memory storage have
been obtained (Colón-Cesario et al., 2006; McGowan et al.,
2004; Peña de Ortiz et al., 2003; Ren and Peña de Ortiz, 2002;
Wang et al., 2003). In particular, it was found that a blockade of
enzymes participating in the process of somatic DNA
recombination impairs learning and memory consolidation.
Although these results cannot be regarded as compelling
evidence for the genomic mechanism of memory, they may
stimulate further investigation in this direction.
The other version of the genomic hypothesis suggests that
the persistence of memory is based on epigenetic modifications
(Holliday, 1999; Levenson and Sweatt, 2005, 2006; Levenson
et al., 2006). It is known that DNA molecules associate with
proteins (histones) to form chromatin. Epigenetic modifications
alter the structure of the chromatin due to chemical changes to
the DNA or histones without changing the DNA nucleotide
sequence. Changes to the chromatin structure exert a profound
effect on the cell-specific pattern of gene expression and, as a
result play an important role in cell differentiation, including
neuron differentiation (Hsieh and Gage, 2005; Levenson and
Sweatt, 2006). Epigenetic modifications produced by a brief
signaling event can be very stable and maintained throughout
the entire lifespan of a cell. Therefore, it was hypothesized that
epigenetics may be used as a mechanism for persistent memory
consolidation. Experimental support for this hypothesis came
from studies by Sweatt and coworkers, who found increased
histone acetylation and phosphorylation in hippocampal
neurons of rats during consolidation of contextual fear memory
(Chwang et al., 2006; Levenson et al., 2004).
Although the idea that traces of declarative memory are
stored at the level of modified DNA molecules has obtained
little recognition, the genomic hypothesis of memory seems to
be promising. Here, I will illustrate that the aforementioned
problems faced by the SPH can be overcome within the
genomic hypothesis:
(1) The modified genes would provide a stable basis for the
storage of memory, as presumed DNA changes arising in the
process of memory consolidation cannot be reversed or
altered. When describing the consolidation of memory from
a labile to stable state, Dudai (2004) used the term which he
named Lady Macbeth’s Principle: ‘‘What’s done cannot be
undone.’’ This principle can hardly be applied to synaptic
rewiring, which can be altered and undone, but is completely
applicable to DNA modifications. Memory traces coded in
modified DNA can be only deleted from the brain upon the
death of the neurons storing those memory traces.
(2) The genomic hypothesis of memory suggests that different
mechanisms are used for memory storage and retrieval. This
is the reason why memory engrams are resistant to synaptic
activity. Neuron excitation (regardless of how strong it is)
does not affect once-produced DNA modifications.
(3) and (4) The genomic hypothesis does not suggest the same
mechanism (i.e., rewiring of synaptic connections) for
learning and for permanent memory storage. Therefore, it
does not assume that memory retrieval results from
reactivating the same neural assemblies involved in the
primary encoding of the information. This means that the
differences between ‘‘synaptic memory’’ and ‘‘system
memory’’ (their different localizations, the different
temporal characteristics of their consolidation, and the fact
that the former depends on protein synthesis – whereas the
latter does not) do not contradict the genomic hypothesis
(unlike the SPH, which is contradicted on all accounts).
(5) As highlighted above, the reconsolidation of system
memory (if this phenomenon does exist) contradicts the
SPH and requires its radical revision. In contrast, the
phenomenon of memory reconsolidation is not crucial to
the genomic hypothesis. One can suggest that the proteins
produced by modified genes, which serve as carriers of
memory traces, may be depleted during retrieval, necessitating the production of new proteins for memory
restoration. This notion, while speculative, may help to
make sense of such puzzling phenomena as postretrieval
memory reconsolidation. A direct prediction following
from this notion is that inhibitors of protein synthesis
(which completely block memory consolidation when
administered after learning) should cause only a temporary
amnesia when applied after memory reactivation. Indeed,
some studies have found that inhibitors of protein synthesis
applied directly after retrieval do produce a temporary loss
of memory, which then recovers spontaneously (Anokhin
et al., 2002; Judge and Quartermain, 1982; Lattal and Abel,
2004; Power et al., 2006; but see Debiec et al., 2002;
Duvarci and Nader, 2004 for the opposite result). These
findings suggest that, while the inhibition of protein
synthesis after learning interferes with memory consolidation, the inhibition of protein synthesis after memory
reactivation results in a transient retrieval deficit and does
not interfere with the engram.
(6) It is difficult to discuss the role of adult neurogenesis in
learning and memory, since the literature on this issue is full
of both conceptual and experimental contradictions (see
Leuner et al., 2006). The prevalent viewpoint is that
incessant renewal of adult hippocampal neurons is
necessary to delete old memories after their permanent
consolidation within the neocortex, to make room for the
acquisition of new memories. As emphasized above, the
SPH does not predict the necessity of replacing healthy
neurons to create more room for new memories. According
to this hypothesis, the acquisition of new information
requires a re-modification of the patterns of synaptic
connections – deleting the synapses related to ‘‘old
memories’’ and creating new synaptic connections. In
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
contrast, adult neurogenesis can create more room for
acquisition of new information if memory is consolidated at
the intracellular – genomic – level, but not at the synaptic
level.
(7) The genomic hypothesis provokes a new approach to
understanding the etiology of AD as specific disease of
memory. The idea that traces of declarative memory are
stored at the genomic level suggests that modified pattern of
gene expression can produce new proteins that were not
expressed during embryogenesis and early postnatal
development. If these proteins migrate to the neuron
surface, they must be recognized by the immune system as
‘‘non-self’’ antigens. It was suggested that the immune
reaction against one’s own neurons serving as carriers of
memory traces are prevented by the blood–brain barrier,
which protects the brain from the entry of immunoglobulins
and strongly restricts the penetration of T lymphocytes
(Arshavsky, 2003a, 2006a; Peña de Ortiz and Arshavsky,
2001; Peña de Ortiz et al., 2004). Results of numerous
studies have shown that all risk factors for AD – both
cardiovascular (atherosclerosis, hypertension, stroke, etc.)
and genetic (mutations of the amyloid precursor protein and
presenilin 1 and 2 genes, as well as the inheritance of the E4
allele of the apolipoprotein E gene) – lead to the destruction
of the blood–brain barrier (de la Torre, 2004; Iadecola,
2004; Jellinger and Attems, 2005; Jeynes and Provias,
2006; Sadowski et al., 2004; Zlokovic, 2005). In experiments on transgenic mice developing an AD-like phenotype, it was found that impairments of the blood–brain
barrier emerged prior any signs of neuron degeneration and
memory deficits (Ujiie et al., 2003). Within the outline of
the genomic hypothesis, AD can be interpreted as an
autoimmune disease associated with blood–brain barrier
impairments (see Arshavsky, 2006a for detail).6 This
interpretation explains why the process of neuron degeneration during AD, at least in its earliest stages, specifically
affects the neurons implicated in the consolidation and
storage of memory traces. As to a loss of mental functions
and motor disability that develop in later stages of AD, they
can result from secondary non-specific inflammation (Zipp
and Aktas, 2006).
4. Concluding remarks
At present, the Hebbian hypothesis of synaptic plasticity is
practically the only hypothesis on cellular mechanisms of
memory that is widely recognized. All current knowledge on
learning and the initial stage of memory consolidation (synaptic
consolidation) is based on this hypothesis. However, due to the
lack of rival hypotheses, the SPH has been used not only to
explain learning and initial memory consolidation, but also for
6
Recently the idea on the autoimmune origin of AD was advocated by
D’Andrea who studied hippocampal and entorhinal tissues from AD patients by
using polyclonal anti-Ig antibodies. As compared to the age-matched controls, a
significant increase in Ig staining was detected in both parenchyma and
individual neurons of AD tissue (D’Andrea, 2003, 2005).
109
permanent (system) consolidation. The major objective of this
paper is to illustrate that this approach to understanding longterm declarative memory faces a series of conceptual and
experimental problems that are unlikely to be resolved within
the context of the SPH. All these problems are rooted in the
attempt to use the intrinsically unstable phenomenon of
synaptic plasticity to explain the mechanism of stable memory,
which can be stored in the brain throughout decades and even
an entire lifespan. Potentially permanent declarative memory
requires a different mechanism – one that can provide more
stability than synaptic plasticity, which is based on transient
changes in gene transcription and protein synthesis.
Here, I advocate the alternative, genomic hypothesis, which
suggests that memory traces are stored within individual
neurons through genomic modifications. The advantage of this
hypothesis is that genomic modifications forming in the process
of memory consolidation cannot be altered or undone. In other
words, this hypothesis suggests that memory consolidation is
akin to the irreversible steps that occur in the process of cell
differentiation (see Nottebohm, 2002; Levenson et al., 2006;
Levenson and Sweatt, 2006). The genomic hypothesis of
declarative memory is part of a more general hypothesis on the
role of cellular and network mechanisms in performing
complex cognitive functions closely linked to consciousness
(Arshavsky, 2001, 2003a,c, 2006b). This hypothesis suggests
that cognitive functions are performed not by neural networks
consisting of simple neurons (see Introduction), but by
networks consisting of ‘‘complex’’ neurons that are carriers
of ‘‘elementary cognition’’ – in particular, carriers of
elementary traces of declarative memory.
The main criticism of the genomic hypothesis (particularly,
of the version developed by Peña de Ortiz and Arshavsky, see
above) is that it does not offer any mechanistic explanation for
memory retrieval. In fact, this criticism implies that the
commonly accepted SPH offers such a mechanism – namely,
the reactivation of neuronal assemblies which are formed in the
process of learning. I think this argument is not fear. As shown
above, memory retrieval cannot occur through the reactivation
of the same neuronal assemblies which are involved in initial
learning, because of the different localization of these two
processes. Here, I would like to point out the principle
impediment to understanding a mechanism of memory retrieval
– an impediment that is related to any hypothesis of declarative
memory. By definition, the retrieval of declarative memory in
humans is a conscious recollection of facts and events. This
means that the question about the mechanism of memory
retrieval is tightly linked to the much more fundamental
question about the cellular mechanisms of consciousness. It is
futile to hope that understanding memory retrieval can be
possible without addressing the nature of consciousness, which
remains beyond the scope of modern neuroscience. Therefore,
this paper does not pretend to discuss the mechanism for
retrieving declarative memory. Rather, its objective is: (i) to
emphasize the monopoly of the pure connectionist approach on
understanding memory consolidation and storage, (ii) to show
the main limitations of this approach, and (iii) to stimulate
alternative, cellular-oriented approaches to the problem.
110
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
References
Abraham, W.C., Williams, J.M., 2003. Properties and mechanisms of LTP
maintenance. Neuroscience 9, 463–474.
Aimone, J.B., Wiles, J., Gage, F.G., 2006. Potential role for adult neurogenesis
in the encoding of time in new memories. Nat. Neurosci. 9, 723–727.
Alberini, C.M., 2005. Mechanisms of memory stabilization: are consolidation
and reconsolidation similar or distinct processes? Trends Neurosci. 28, 51–
56.
Alberini, C.M., Milekic, M.H., Tronel, S., 2006. Mechanisms of memory
stabilization and de-stabilization. Cell. Mol. Life Sci. 63, 999–1008.
Anagnostaras, S.G., Maren, S., Fanselow, M.S., 1999. Temporally graded
retrograde amnesia of contextual fear after hippocampal damage in rats:
within-subjects examination. J. Neurosci. 19, 1106–1114.
Anokhin, K.V., Tiunova, A.A., Rose, S.P., 2002. Reminder effects – reconsolidation or retrieval deficit? Eur. J. Neurosci. 15, 1759–1765.
Arshavsky, Y.I., 2001. Role of individual neurons and neural networks in
cognitive functioning of the brain: a new insight. Brain Cogn. 46,
414–428.
Arshavsky, Y.I., 2003a. Cellular and networks properties in the functioning of
the nervous system: from central pattern generators to cognition. Brain Res.
Rev. 41, 229–267.
Arshavsky, Y.I., 2003b. Long-term memory: does it have a structural or
chemical basis? Trends Neurosci. 26, 465–466.
Arshavsky, Y.I., 2003c. When did Mozart become a Mozart? Neurophysiological insight into behavioral genetics. Brain Mind 4, 327–339.
Arshavsky, Y.I., 2006a. Alzheimer’s disease, brain immune privilege and
memory: a hypothesis. J. Neural. Transm. 113, 1697–1707.
Arshavsky, Y.I., 2006b. ‘‘Scientific roots’’ of dualism in neuroscience. Prog.
Neurobiol. 79, 190–204.
Bahrick, H.P., 1984. Semantic memory content in permastore: fifty years
of memory for Spanish learned in school. J. Exp. Psychol. Gen. 113,
1–29.
Bahrick, H.P., Bahrick, P.O., Wittlinger, R.P., 1975. Fifty years of memories for
names and faces. J. Exp. Psychol. Gen. 104, 54–75.
Bailey, C.H., 1999. Structural changes and the storage of long-term memory in
Aplysia. Can. J. Physiol. Pharmacol. 77, 738–747.
Bailey, C.H., Kandel, E.R., Si, K., 2004. The persistence of long-term memory;
a molecular approach to self-sustaining changes in learning-induced synaptic growth. Neuron 44, 49–57.
Bailey, D.J., Kim, J.J., Sun, W., Thompson, R.F., Helmstetter, F.J., 1999.
Acquisition of fear conditioning in rats requires the synthesis of mRNA
in the amygdala. Behav. Neurosci. 113, 276–282.
Bayley, P.J., Gold, J.J., Hopkins, R.O., Squire, L.R., 2005. The neuroanatomy of
remote memory. Neuron 46, 799–810.
Bayley, P.J., Squire, L.R., 2005. Failure to acquire new semantic knowledge in
patients with large medial temporal lobe lesions. Hippocampus 15, 273–
280.
Been, W., Dietrich, A., 2004. DNA recombination, memory storage and
learning. In: Parisi, V., De Fonzo, V., Aluffi-Pentini, F. (Eds.), Dynamical Genetics. Research Signpost, India, pp. 365–380.
Benson, D.L., Colman, D.R., Huntley, G.W., 2001. Molecules, maps and
synapse specificity. Nat. Rev. Neurosci. 2, 899–909.
Biedenkapp, J.C., Rudy, J.W., 2004. Context memories and reactivation:
constraints on the reconsolidation hypothesis. Behav. Neurosci. 118,
956–964.
Blair, T.H., Schafe, G.E., Bauer, E.P., Rodrigues, S.M., LeDoux, J.E., 2001.
Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear
conditioning. Learn. Mem. 8, 229–242.
Bliss, T.V., Lømo, T., 1973. Long-lasting potentiation of synaptic transmission
in the dentate area of the anaesthetized rabbit following stimulation of the
perforant path. J. Physiol. (Lond.) 232, 331–356.
Bontempi, B., Laurent-Demir, C., Destrade, C., Jaffard, R., 1999. Timedependent reorganization of brain circuitry underlying long-term memory
storage. Nature 400, 671–675.
Broadbent, N.J., Squire, L.R., Clark, R.E., 2006. Reversible hippocampal
lesions disrupt water maze performance during both recent and remote
memory tests. Learn. Mem. 13, 187–191.
Bruel-Jungerman, E., Laroche, S., Rampon, C., 2005. New neurons in the
dentate gyrus are involved in the expression of enhanced long-term memory
following environmental enrichment. Eur. J. Neurosci. 21, 513–521.
Cameron, H.A., McKay, R.D., 2001. Adult neurogenesis produces a large
pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–
417.
Cammarota, M., Bevilaqua, L.R., Medina, J.H., Izquierdo, I., 2004. Retrieval
does not induce reconsolidation of inhibitory avoidance memory. Learn.
Mem. 11, 572–578.
Chapman, P.F., White, G.L., Jones, M.W., Cooper-Blacketer, D., Marshall, V.J.,
Irizarry, M., Younkin, L., Good, M.A., Bliss, T.V., Hyman, B.T., Younkin,
S.G., Hsiao, K.K., 1999. Impaired synaptic plasticity and learning in aged
amyloid precursor protein transgenic mice. Nat. Neurosci. 2, 271–276.
Cheek, D.B., LeCron, L.M., 1968. Clinical Hypnotherapy. Grune a. Stratton,
New York.
Chklovskii, D.B., Mel, B.W., Svoboda, K., 2004. Cortical rewiring and information storage. Nature 431, 782–788.
Chwang, W.B., O’Riordan, K.J., Levenson, J.M., Sweatt, J.D., 2006. ERK/
MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn. Mem. 13, 322–328.
Colón-Cesario, M., Wang, J., Ramos, X., Garcı́a, H.G., Dávila, J.J., Laguna, J.,
Rosado, G., Peña de Ortiz, S., 2006. An inhibitor of DNA recombination
blocks memory consolidation, but not reconsolidation, in context fear
conditioning. J. Neurosci. 26, 5524–5533.
Crick, F., 1984. Memory and molecular turnover. Nature 312, 101.
Cui, Z., Wang, H., Tan, Y., Zaia, K.A., Zhang, S., Tsien, J.Z., 2004. Inducible
and reversible NR1 knockout reveals crucial role of the NMDA receptor in
preserving remote memories in the brain. Neuron 41, 781–793.
D’Andrea, M.R., 2003. Evidence linking neuronal cell death to autoimmunity in
Alzheimer’s disease. Brain Res. 982, 19–30.
D’Andrea, M.R., 2005. Add Alzheimer’s disease to the list of autoimmune
diseases. Med. Hypoth. 64, 458–463.
D’Angelo, E., Rossi, E., Gall, D., Prestory, F., Nieus, T., Maffei, A., Sola, E.,
2005. Long-term potentiation of synaptic transmission at the mossy fibergranule cell relay of cerebellum. Prog. Brain Res. 148, 69–80.
Davies, C.A., Mann, D.M., Sumpter, P.Q., Yates, P.O., 1987. A quantitative
morphometric analysis of the neuronal and synaptic content of the frontal
and temporal cortex in patients with Alzheimer’s disease. J. Neurol. Sci. 78,
151–164.
Davis, H.P., Squire, L.R., 1984. Protein synthesis and memory: a review.
Psychol. Bull. 96, 518–559.
Debiec, J., LeDoux, J.E., Nader, K., 2002. Cellular and systems reconsolidation
in the hippocampus. Neuron 36, 527–538.
De Fonzo, V., Bersani, E., Aluffi-Pentini, F., Parisi, V., 2000. A new look at the
challenging world of tandem repeats. Med. Hypoth. 54, 750–760.
de la Torre, J.C., 2004. Alzheimer’s disease is a vasocognopathy: a new term to
describe its nature. Neurol. Res. 26, 517–524.
De Paola, V., Holtmaat, A., Knott, G., Song, S., Wilbrecht, L., Caroni, P.,
Svoboda, K., 2006. Cell type-specific structural plasticity of axonal
branches and boutons in the adult neocortex. Neuron 49, 861–875.
Dietrich, A., Been, W., 2001. Memory and DNA. J. Theor. Biol. 208, 145–149.
Dudai, Y., 2004. The neurobiology of consolidations, or, how stable is the
engram? Annu. Rev. Psychol. 55, 51–86.
Duvarci, S., Nader, K., 2004. Characterization of fear memory reconsolidation.
J. Neurosci. 24, 9269–9275.
Eccles, J.C., 1972. Possible synaptic mechanism subserving learning. In:
Karcmar, A.G., Eccles, J.C. (Eds.), Brain and Human Behavior.
Springer-Verlag, New York, pp. 39–61.
Eichenbaum, H., 1997. Declarative memory: insights from cognitive neurobiology. Annu. Rev. Psychol. 48, 547–572.
Elgersma, Y., Sweatt, J.D., Giese, K.P., 2004. Mouse genetic approaches to
investigating calcium/calmodulin-dependent protein kinase II function in
plasticity and cognition. J. Neurosci. 24, 8410–8415.
Engert, F., Bonhoeffer, T., 1999. Dendritic spine changes associated with
hippocampal long-term synaptic plasticity. Nature 399, 66–70.
Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C.,
Peterson, D.A., Gage, F.H., 1998. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317.
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
Fitzjohn, S.M., Morton, R.A., Kuenzi, F., Rosahl, T.W., Shearman, M., Lewis, H.,
Smith, D., Reynolds, D.S., Davies, C.H., Collingridge, G.L., Seabrook, G.R.,
2001. Age-related impairment of synaptic transmission but normal long-term
potentiation in transgenic mice that overexpress the human APP695SWE
mutant form of amyloid precursor protein. J. Neurosci. 21, 4691–4698.
Fligstein, D., Barabasz, A., Barabasz, M., Trevisan, M.S., Warner, D., 1998.
Hypnosis enhances recall memory: a test of forced and non-forced conditions. Am. J. Clin. Hypn. 40, 297–305.
Frankland, P.W., Bontempi, B., 2005. The organization of recent and remote
memories. Nat. Rev. Neurosci. 6, 119–130.
Frankland, P.W., Bontempi, B., Talon, L.E., Kaczmarek, L., Silva, A.J., 2004.
The involvement of the anterior cingulate cortex in remote contextual fear
memory. Science 304, 881–883.
Frankland, P.W., Ding, H.K., Takahashi, E., Suzuki, A., Kida, S., Silva, A.J.,
2006. Stability of recent and remote contextual fear memory. Learn. Mem.
13, 451–457.
Frankland, P.W., O’Brien, C., Ohno, M., Kirkwood, A., Silva, A.J., 2001.
Alpha-CaMKII-dependent plasticity in the cortex is required for permanent
memory. Nature 411, 309–313.
Gould, E., Reeves, A.J., Fallah, M., Tanapat, P., Gross, C.G., Fuchs, E., 1999a.
Hippocampal neurogenesis in adult Old World primates. Proc. Natl. Acad.
Sci. U.S.A. 96, 5263–5267.
Gould, E., Reeves, A.J., Graziano, M.S., Gross, C.G., 1999b. Neurogenesis in
the neocortex of adult primates. Science 286, 548–552.
Gould, E., Tanapat, P., Hastings, N.B., Shors, T.J., 1999c. Neurogenesis in
adulthood: a possible role in learning. Trends Cogn. Sci. 3, 186–192.
Green, J.P., 1999. Hypnosis, context effects, and the recall of early autobiographical memories. Int. J. Clin. Exp. Hypn. 47, 284–300.
Greenberg, R.M., Kellner, C.H., 2005. Electroconvulsive therapy: a selected
review. Am. J. Geriatr. Psychiatry 13, 268–281.
Grenier, F., Timofeev, I., Steriade, M., 2003. Neocortical very fast oscillations
(ripples, 80–200 Hz) during seizures: intracellular correlates. J. Neurophysiol. 89, 841–852.
Gross, C.G., 2000. Neurogenesis in the adult brain: death of a dogma. Nat. Rev.
Neurosci. 1, 67–73.
Grutzendler, J., Kasthuri, N., Gan, W.B., 2002. Long-term dendritic spine
stability in the adult cortex. Nature 420, 812–816.
Gureviciene, I., Ikonen, S., Gurevicius, K., Sarkaki, A., van Groen, T., Pussinen,
R., Ylinen, A., Tanila, H., 2004. Normal induction but accelerated decay of
LTP in APP + PS1 transgenic mice. Neurobiol. Dis. 15, 188–195.
Hebb, D.O., 1949. The Organization of Behavior. Wiley, New York.
Holliday, R., 1999. Is there an epigenetic component in long-term memory? J.
Theor. Biol. 200, 339–341.
Hsia, A.Y., Masliah, E., McConlogue, L., Yu, G.Q., Tatsuno, G., Hu, K.,
Kholodenko, D., Malenka, R.C., Nicoll, R.A., Mucke, L., 1999. Plaqueindependent disruption of neural circuits in Alzheimer’s disease mouse
models. Proc. Natl. Acad. Sci. U.S.A. 96, 3228–3233.
Hsieh, J., Gage, F.H., 2005. Chromatin remodeling in neural development and
plasticity. Curr. Opin. Cell Biol. 17, 664–671.
Iadecola, C., 2004. Neurovascular regulation in the normal brain and in
Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360.
Igaz, L.M., Vianna, M.R., Medina, J.H., Izquierdo, I., 2002. Two time periods of
hippocampal mRNA synthesis are required for memory consolidation of
fear-motivated learning. J. Neurosci. 22, 6781–6789.
Irvine, E.E., Vernon, J., Giese, K.P., 2005. AlphaCaMKII autophosphorylation
contributes to rapid learning but is not necessary for memory. Nat. Neurosci.
8, 411–412.
Irvine, E.E., von Hertzen, L.S., Plattner, F., Giese, K.P., 2006. aCaMKII
autophosphorylation: a fast track to memory. Trends Neurosci. 29, 459–465.
Jacobsen, J.S., Wu, C.C., Redwine, J.M., Comery, T.A., Arias, R., Bowlby, M.,
Martone, R., Morrison, J.H., Pangalos, M.N., Reinhart, P.H., Bloom, F.E.,
2006. Early-onset behavioral and synaptic deficits in a mouse model of
Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 103, 5161–5166.
Jellinger, K.A., Attems, J., 2005. Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease. J. Neurol. Sci. 229, 37–41.
Jeynes, B., Provias, J., 2006. The possible role of capillary cerebral amyloid
angiopathy in Alzheimer lesion development: a regional comparison. Acta
Neuropathol. (Berl.) 112, 417–427.
111
Jolas, T., Zhang, X.S., Zhang, Q., Wong, G., Del Vecchio, R., Gold, L., Priestley,
T., 2002. Long-term potentiation is increased in the CA1 area of the
hippocampus of APP(swe/ind) CRND8 mice. Neurobiol. Dis. 11, 394–409.
Judge, M.E., Quartermain, D., 1982. Characteristics of retrograde amnesia
following reactivation of memory in mice. Physiol. Behav. 28, 585–590.
Kandel, E.R., 2000. Cellular mechanisms of learning and the biological basis of
individuality. In: Kandel, E.R., Schwartz, J.H., Jessel, T.M. (Eds.), Principles of Neural Science. 4th ed. McGraw-Hill, New York, pp. 1247–1279.
Kandel, E.R., 2001. The molecular biology of memory storage: a dialog
between genes and synapses. Biosci. Rep. 21, 565–611.
Kempermann, G., 2002. Why new neurons? Possible functions for adult
hippocampal neurogenesis. J. Neurosci. 22, 635–638.
Kempermann, G., Kuhn, H.G., Gage, F.H., 1997. More hippocampal neurons in
adult mice living in an enriched environment. Nature 386, 493–495.
Kempermann, G., Wiskott, L., Gage, F.H., 2004. Functional significance of
adult neurogenesis. Curr. Opin. Neurobiol. 14, 186–191.
Koch, C., Laurent, G., 1999. Complexity and the nervous system. Science 284,
96–98.
Kornack, D.R., Rakic, P., 1999. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc. Natl. Acad. Sci. U.S.A. 96,
5768–5773.
Lamprecht, R., LeDoux, J.E., 2004. Structural plasticity and memory. Nat. Rev.
Neurosci. 5, 45–54.
Larson, J., Lynch, G., Games, D., Seubert, P., 1999. Alterations in synaptic
transmission and long-term potentiation in hippocampal slices from young
and aged PDAPP mice. Brain Res. 840, 23–35.
Lattal, K.M., Abel, T., 2004. Behavioral impairments caused by injections of the
protein synthesis inhibitor anisomycin after contextual retrieval reverse with
time. Proc. Natl. Acad. Sci. U.S.A. 101, 4667–4672.
LeDoux, J., 2003. The self: clues from the brain. Ann. N. Y. Acad. Sci. 1001,
295–304.
Leuner, B., Gould, E., Shors, T.J., 2006. Is there a link between adult
neurogenesis and learning? Hippocampus 16, 216–224.
Levenson, J.M., O’Riordan, K.J., Brown, K.D., Trinh, M.A., Molfese, D.L.,
Sweatt, J.D., 2004. Regulation of histone acetylation during memory
formation in the hippocampus. J. Biol. Chem. 279, 40545–40559.
Levenson, J.M., Roth, T.L., Lubin, F.D., Miller, C.A., Huang, I.C., Desai, P.,
Malone, L.M., Sweatt, J.D., 2006. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J. Biol. Chem.
281, 15763–15773.
Levenson, J.M., Sweatt, J.D., 2005. Epigenetic mechanisms in memory formation. Nat. Rev. Neurosci. 6, 108–118.
Levenson, J.M., Sweatt, J.D., 2006. Epigenetic mechanisms: a common theme
in vertebrate and invertebrate memory formation. Cell. Mol. Life Sci. 63,
1009–1016.
Linch, M.A., 2004. Long-term potentiation and memory. Physiol. Rev. 84, 87–
136.
Lisman, J., Schulman, H., Cline, H., 2002. The molecular basis of CaMKII
function in synaptic and behavioural memory. Nat. Rev. Neurosci. 3, 175–
190.
Liu, S., Wang, J., Zhu, D., Fu, Y., Lukowiak, K., Lu, Y.M., 2003. Generation of
functional inhibitory neurons in the adult rat hippocampus. J. Neurosci. 23,
732–736.
Lledo, P.M., Alonso, M., Grubb, M.S., 2006. Adult neurogenesis and functional
plasticity in neuronal circuits. Nat. Rev. Neurosci. 7, 179–193.
Luria, A.R., 1968. The Mind of a Mnemonist. Basic Books, New York.
Luria, A.R., 1976. The Neuropsychology of Memory. Winston, New York.
Mactutus, C.F., Riccio, D.C., Ferek, J.M., 1979. Retrograde amnesia for old
(reactivated) memory: some anomalous characteristics. Science 204, 1319–
1320.
Madsen, T.M., Kristjansen, P.E., Bolwig, T.G., Wortwein, G., 2003. Arrested
neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119, 635–642.
Malenka, R.C., Bear, M.F., 2004. LTP and LTD: an embarrassment of riches.
Neuron 44, 5–21.
Maletic-Savatic, M., Malinow, R., Svoboda, K., 1999. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity.
Science 283, 1923–1927.
112
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
Manns, J.R., Eichenbaum, H., 2006. Evolution of declarative memory. Hippocampus 16, 795–808.
Maroun, M., Yaniv, D., Richter-Levin, G., 2001. Plasticity in local neuronal
circuits. In vivo evidence from rat hippocampus and amygdala. In: Hölscher,
C. (Ed.), Neuronal Mechanisms of Memory Formation. Cambridge University Press, Cambridge, MA, pp. 137–145.
Martin, S.J., Grimwood, P.D., Morris, R.G., 2000. Synaptic plasticity and
memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–
711.
McGaugh, J.L., 2000. Memory – a century of consolidation. Science 287, 248–
251.
McGowan, P.O., Hope, T., Kelsoe, G.H., Meck, W.H., Williams, C.L., 2004.
Recombination activating gene 1 (RAG1) may have a novel function in
brain. In: Proceedings of the Soc. Neurosci. 34th Annual Meeting, 32221.
Mel, B.W., 2002. Have we been hebbing down the wrong path? Neuron 34,
175–177.
Milekic, M.H., Alberini, C.M., 2002. Temporally graded requirement for
protein synthesis following memory reactivation. Neuron 36, 521–525.
Millin, P.M., Moody, E.W., Riccio, D.C., 2001. Interpretations of retrograde
amnesia: old problems redux. Nat. Rev. Neurosci. 2, 68–70.
Milner, B., Squire, L.R., Kandel, E.R., 1998. Cognitive neuroscience and the
study of memory. Neuron 20, 445–468.
Ming, G.L., Song, H., 2005. Adult neurogenesis in the mammalian central
nervous system. Annu. Rev. Neurosci. 28, 223–250.
Misanin, J.R., Miller, R.R., Lewis, D.J., 1968. Retrograde amnesia produced by
electroconvulsive shock after reactivation of a consolidated memory trace.
Science 160, 554–555.
Nader, K., 2003. Memory traces unbound. Trends Neurosci. 26, 65–72.
Nader, K., Schafe, G.E., LeDoux, J.E., 2000. Fear memories require protein
synthesis in the amygdala for reconsolidation after retrieval. Nature 406,
722–726.
Nagerl, U.V., Eberhorn, N., Cambridge, S.B., Bonhoeffer, T., 2004. Bidirectional activity-dependent morphological plasticity in hippocampal neurons.
Neuron 44, 759–767.
Nakazawa, K., McHugh, T.J., Wilson, M.A., Tonegawa, S., 2004. NMDA
receptors, place cells and hippocampal spatial memory. Nat. Rev. Neurosci.
5, 361–372.
Nilsson, M., Perfilieva, E., Johansson, U., Orwar, O., Eriksson, P.S., 1999.
Enriched environment increases neurogenesis in the adult rat dentate gyrus
and improves spatial memory. J. Neurobiol. 39, 569–578.
Nottebohm, F., 2002. Why are some neurons replaced in adult brain? J.
Neurosci. 22, 624–628.
Oddo, S., Caccamo, A., Shepherd, J.D., Murphy, M.P., Golde, T.E., Kayed, R.,
Metherate, R., Mattson, M.P., Akbari, Y., LaFerla, F.M., 2003. Tripletransgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421.
Parker, E.S., Cahill, L., McGaugh, J.L., 2006. A case of unusual autobiographical remembering. Neurocase 12, 35–49.
Peña de Ortiz, S., Arshavsky, Y.I., 2001. DNA recombination as a possible
mechanism in declarative memory: a hypothesis. J. Neurosci. Res. 63, 72–
81.
Peña de Ortiz, S., Colón, M., Arshavsky, Y.I., 2004. Genomic theory of
declarative memory. In: Parisi, V., De Fonzo, V., Aluffi-Pentini, F.
(Eds.), Dynamical Genetics. Research Signpost, India, pp. 345–364.
Peña de Ortiz, S., Colón, M., Carrasquillo, Y., Ren, K., Padilla, B., Silva, R.,
Arshavsky, Y.I., 2003. Experience-dependent expression of the gene encoding terminal deoxynucleotidyl transferase in the mouse brain. Neuroreport
14, 1141–1144.
Penfield, W., 1958. Some mechanisms of consciousness discovered during
electrical stimulation of the brain. Proc. Natl. Acad. Sci. U.S.A. 44, 51–66.
Power, A.E., Berlau, D.J., McGaugh, J.L., Steward, O., 2006. Anisomycin
infused into the hippocampus fails to block ‘‘reconsolidation’’ but impairs
extinction: the role of re-exposure duration. Learn. Mem. 13, 27–34.
Price, D.L., 2000. Aging of the brain and dementia of the Alzheimer type. In:
Kandel, E.R., Schwartz, J.H., Jessel, T.M. (Eds.), Principles of Neural
Science. 4th ed. McGraw-Hill, New York, pp. 1149–1161.
Quartz, S.R., Sejnowski, T.J., 1997. The neural basis of cognitive development:
a constructivist manifesto. Behav. Brain Sci. 20, 537–556.
Rakic, P., 1985. Limits of neurogenesis in primates. Science 227, 1054–1056.
Rakic, P., 2002. Neurogenesis in adult primate neocortex: an evaluation of the
evidence. Nat. Rev. Neurosci. 3, 65–71.
Ren, K., Peña de Ortiz, S., 2002. Nonhomologous DNA end joining in the
mature rat brain. J. Neurochem. 80, 949–959.
Roder, S., Danober, L., Pozza, M.F., Lingenhoehl, K., Wiederhold, K.H., Olpe,
H.R., 2003. Electrophysiological studies on the hippocampus and prefrontal
cortex assessing the effects of amyloidosis in amyloid precursor protein 23
transgenic mice. Neuroscience 120, 705–720.
Rosenbaum, R.S., Kohler, S., Schacter, D.L., Moscovitch, M., Westmacott, R.,
Black, S.E., Gao, F., Tulving, E., 2005. The case of K.C.: contributions of a
memory-impaired person to memory theory. Neuropsychologia 43, 989–1021.
Ross, R.S., Eichenbaum, H., 2006. Dynamics of hippocampal and cortical
activation during consolidation of a nonspatial memory. J. Neurosci. 26,
4852–4859.
Routtenberg, A., Rekart, J.L., 2005. Post-translational protein modification as
the substrate for long-lasting memory. Trends Neurosci. 28, 12–19.
Sadowski, M., Pankiewicz, J., Scholtzova, H., Li, Y.S., Quartermain, D., Duff,
K., Wisniewski, T., 2004. Links between the pathology of Alzheimer’s
disease and vascular dementia. Neurochem. Res. 29, 1257–1266.
Sara, S.J., 2000. Retrieval and reconsolidation: toward a neurobiology of
remembering. Learn. Mem. 7, 73–84.
Schinder, A.F., Gage, F.H., 2004. A hypothesis about the role of adult
neurogenesis in hippocampal function. Physiology (Bethesda) 19, 253–261.
Scoville, W.B., Milner, B., 1957. Loss of recent memory after bilateral
hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21.
Selkoe, D.J., 2001. Alzheimer’s disease: genes, proteins, and therapy. Physiol.
Rev. 81, 741–766.
Selkoe, D.J., 2002. Alzheimer’s disease is a synaptic failure. Science 298, 789–
791.
Shors, T.J., Miesegaes, G., Beylin, A., Zhao, M., Rydel, T., Gould, E., 2001.
Neurogenesis in the adult is involved in the formation of trace memories.
Nature 410, 372–376.
Si, K., Giustetto, M., Etkin, A., Hsu, R., Janisiewicz, A.M., Miniaci, M.C., Kim,
J.H., Zhu, H., Kandel, E.R., 2003a. A neuronal isoform of CPEB regulates
local protein synthesis and stabilizes synapse-specific long-term facilitation
in Aplysia. Cell 115, 893–904.
Si, K., Lindquist, S., Kandel, E.R., 2003b. A neuronal isoform of the aplysia
CPEB has prion-like properties. Cell 115, 879–891.
Silva, A.J., 2003. Molecular and cellular cognitive studies of the role of synaptic
plasticity in memory. J. Neurobiol. 54, 224–237.
Small, D.H., Mok, S.S., Bornstein, J.C., 2001. Alzheimer’s disease and Abeta
toxicity: from top to bottom. Nat. Rev. Neurosci. 2, 595–598.
Snyder, J.S., Hong, N.S., McDonald, R.J., Wojtowicz, J.M., 2005. A role for adult
neurogenesis in spatial long-term memory. Neuroscience 130, 843–852.
Squire, L.R., 1992. Memory and the hippocampus: a synthesis from findings
with rats, monkeys, and humans. Psychol. Rev. 99, 195–231.
Squire, L.R., Clark, R.E., Knowlton, B.J., 2001. Retrograde amnesia. Hippocampus 11, 50–55.
Squire, L.R., Kandel, E.R., 1999. Memory: From Mind to Molecules. Sci. Am.
Library, New York.
Squire, L.R., Slater, P.C., Chace, P.M., 1976. Reactivation of recent or remote
memory before electroconvulsive therapy does not produce retrograde
amnesia. Behav. Biol. 18, 335–343.
Sweatt, J.D., 2003. Mechanisms of Memory. Elsevier, Amsterdam.
Tashiro, A., Sandler, V.M., Toni, N., Zhao, C., Gage, F.H., 2006. NMDAreceptor-mediated, cell-specific integration of new neurons in adult dentate
gyrus. Nature 442, 929–933.
Taubenfeld, S.M., Milekic, M.H., Monti, B., Alberini, C.M., 2001. The consolidation of new but not reactivated memory requires hippocampal C/
EBPbeta. Nat. Neurosci. 4, 813–818.
Teixeira, C.M., Pomedli, S.R., Maei, H.R., Kee, N., Frankland, P.W., 2006.
Involvement of the anterior cingulate cortex in the expression of remote
spatial memory. J. Neurosci. 26, 7555–7564.
Terry, R.D., Masliah, E., Salmon, D.P., Butters, N., DeTeresa, R., Hill, R.,
Hansen, L.A., Katzman, R., 1991. Physical basis of cognitive alterations in
Alzheimer’s disease: synapse loss is the major correlate of cognitive
impairment. Ann. Neurol. 30, 572–580.
Y.I. Arshavsky / Progress in Neurobiology 80 (2006) 99–113
Teskey, G.C., Valentine, P.A., 1998. Post-activation potentiation in the neocortex of awake freely moving rats. Neurosci. Biobehav. Rev. 22, 195–207.
Thomas, G.M., Huganir, R.L., 2004. MAPK cascade signaling and synaptic
plasticity. Nat. Rev. Neurosci. 5, 173–183.
Thompson, P.J., 1991. Memory function in patients with epilepsy. Adv. Neurol.
55, 369–384.
Toni, N., Buchs, P.A., Nikonenko, I., Bron, C.R., Muller, D., 1999. LTP
promotes formation of multiple spine synapses between a single axon
terminal and a dendrite. Nature 402, 421–425.
Treffert, D.A., Christensen, D.D., 2005. Inside the mind of a savant. Sci. Am.
293, 108–113.
Trinchese, F., Liu, S., Battaglia, F., Walter, S., Mathews, P.M., Arancio, O.,
2004. Progressive age-related development of Alzheimer-like pathology in
APP/PS1 mice. Ann. Neurol. 55, 801–814.
Ujiie, M., Dickstein, D.L., Carlow, D.A., Jefferies, W.A., 2003. Blood–brain
barrier permeability precedes senile plaque formation in an Alzheimer
disease model. Microcirculation 10, 463–470.
van Praag, H., Christie, B.R., Sejnowski, T.J., Gage, F.H., 1999. Running
enhances neurogenesis, learning, and long-term potentiation in mice. Proc.
Natl. Acad. Sci. U.S.A. 96, 13427–13431.
Walsh, D.M., Selkoe, D.J., 2004. Deciphering the molecular basis of memory
failure in Alzheimer’s disease. Neuron 44, 181–193.
113
Wang, H., Hu, Y., Tsen, J.Z., 2006. Molecular and systems mechanisms of
memory consolidation and storage. Prog. Neurobiol. 79, 123–135.
Wang, J., Ren, K., Pérez, J., Silva, A.J., Peña de Ortiz, S., 2003. The
antimetabolite ara-CTP blocks long-term memory of conditioned taste
aversion. Learn. Mem. 10, 503–510.
Wiltgen, B.J., Brown, R.A., Talton, L.E., Silva, A.J., 2004. New circuits for old
memories: the role of the neocortex in consolidation. Neuron 44, 101–108.
Wittenberg, G.M., Tsien, J.Z., 2002. An emerging molecular and cellular
framework for memory processing by the hippocampus. Trends Neurosci.
25, 501–505.
Yi, J.J., Ehlers, M.D., 2005. Ubiquitin and protein turnover in synapse function.
Neuron 47, 629–632.
Zipp, F., Aktas, O., 2006. The brain as a target of inflammation: common
pathways link inflammatory and neurodegenerative diseases. Trends Neurosci. 29, 518–527.
Zlokovic, B.V., 2005. Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci. 28, 202–208.
Zola-Morgan, S.M., Squire, L.R., 1990. The primate hippocampal formation:
evidence for a time-limited role in memory storage. Science 250, 288–290.
Zuo, Y., Lin, A., Chang, P., Gan, W.B., 2005. Development of long-term
dendritic spine stability in diverse regions of cerebral cortex. Neuron 46,
181–189.