Molecular Mechanisms of Memory Storage in Aplysia
ROBERT D. HAWKINS1,2*, ERIC R. KANDEL1,2,3,4, AND CRAIG H. BAILEY1,2,4
1Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University,
2New York State Psychiatric Institute,3Howard Hughes Medical Institute, and4Kavli Institute for Brain
Sciences, 1051 Riverside Drive, New York, NY 10032
suggest that experience-dependent modulation of synaptic
strength and structure is a fundamental mechanism by
which these memories are encoded, processed, and stored
within the brain. In this review, we focus on recent advances
in our understanding of the molecular mechanisms that
underlie short-term, intermediate-term, and long-term forms
of implicit memory in the marine invertebrate Aplysia cali-
fornica, and consider how the conservation of common
elements in each form may contribute to the different tem-
poral phases of memory storage.
Cellular studies of implicit and explicit memory
Modern studies in cognitive neuroscience have shown
that memory is not a unitary process but consists of several
forms that can be grouped into at least two general catego-
ries each with its own rules (Squire and Zola-Morgan, 1991;
Polster et al., 1991). Explicit, or declarative, memory is the
conscious recall of knowledge about people, places, and
things, and it is particularly well developed in the vertebrate
brain. Implicit, or nondeclarative, memory is memory for
motor skills and other tasks and is expressed through per-
formance, without conscious recall of past experience; it
includes simple associative forms, such as classical condi-
tioning, and nonassociative forms, such as sensitization and
habituation. These two forms of memory have been local-
ized to different neural systems within the brain (Milner,
1985). As first shown by the neuropsychological studies of
the patient H.M., explicit memory is critically dependent on
structures in the medial temporal lobe of the cerebral cortex,
including the hippocampal formation. Implicit memory in-
volves the cerebellum, the striatum, the amygdala, and in
the simplest cases, the sensory and motor pathways re-
cruited for particular perceptual or motor skills utilized
during the learning process. As a result, implicit memory
can also be studied in a variety of simple reflex systems,
including those of higher invertebrates, whereas explicit
forms can best (and perhaps only) be studied in mammals.
In the mammalian brain, the cellular and molecular
changes that underlie both forms of memory are difficult to
study because the effects are often modest and the contri-
bution of individual synapses to the learning process is not
yet well defined. To bridge this gap, the more tractable
nervous systems of higher invertebrates have proven useful
for the analysis of behavioral problems and have enhanced
our knowledge about the synaptic loci and mechanisms that
underlie various elementary forms of learning and memory
(Carew and Sahley, 1986; Byrne, 1987; Hawkins et al.,
1993). One such model system is the gill- and siphon-
withdrawal reflex of the marine invertebrate Aplysia cali-
fornica. This reflex exhibits several forms of learning,
including dishabituation, sensitization, and classical con-
ditioning, that have many of the behavioral features of
learning in mammals, suggesting that learning in Aplysia
and mammals may share common mechanisms (Pinsker
et al., 1970; Carew et al., 1971, 1981, 1983; Hawkins et
al., 1986, 1989, 1998; Colwill et al., 1988a, b; Walters,
Recent studies of a variety of memory processes, ranging
Received 28 March 2006; accepted 20 April 2006.
* To whom correspondence should be addressed. E-mail: rdh1@
azolepropionic acid; AMPAR, AMPA receptor; C/EBP, CCAAT-box-
enhanced binding protein; CamKII, calcium/calmodulin-dependent protein
kinase type II; CPEB, cytoplasmic polyadenylation element binding pro-
tein; CRE, cAMP-responsive element; CREB, cAMP response element
binding protein; CS, conditioned stimulus; EPSP, excitatory postsynaptic
potential; LTF, long-term facilitation; LTP, long-term potentiation;
MAPK, mitogen-activated protein kinase; NMDA, N-methyl-D-aspartate;
PKA, protein kinase A; PKC, protein kinase C; PSP, postsynaptic poten-
tial; STF, short-term facilitation.
Reference: Biol. Bull. 210: 174–191. (June 2006)
© 2006 Marine Biological Laboratory
A contribution to The Biological Bulletin Virtual Symposium
on Marine Invertebrate Models of Learning and Memory.
in complexity from simple forms of implicit memory in
invertebrates to more complex forms of explicit memory in
mammals, suggest that changes in the strength and structure
of synaptic connections contribute critically to these diverse
forms of memory storage (Kandel, 2001). For both implicit
and explicit memory, two general types of storage mecha-
nisms have been described: short-term memory lasting min-
utes and long-term memory lasting days, weeks, or longer.
This temporal distinction in behavior is reflected in specific
forms of synaptic plasticity that underlie each form of
behavioral memory as well as in specific molecular require-
ments for each of these two forms of synaptic plasticity. The
short-term forms involve the covalent modifications of pre-
existing proteins by a variety of kinases and are expressed
as alterations in the effectiveness of pre-existing connec-
tions. By contrast, in addition to PKA and MAPK, the
long-term form also requires CREB-mediated gene expres-
sion and new mRNA and protein synthesis. Moreover, the
long-term form often is associated with the growth of new
synaptic connections. For both implicit and explicit memory
storage, the synaptic growth is thought to represent the final
and self-sustaining change that stabilizes the long-term pro-
cess. In addition to short- and long-term memory, a family
of intermediate processes that last one or more hours and
often require translation but not transcription can be pro-
duced by various training protocols using repeated or pro-
In this review, we discuss and compare critical synaptic
sites and the underlying cellular and molecular mechanisms
of short- and intermediate-term (Fig. 1) and long-term (Fig.
2) memory storage that have been identified by neurobio-
logical studies of elementary forms of implicit memory in
Sensitization and Classical Conditioning of the Gill-
Withdrawal Reflex in Aplysia: Two Elementary Forms
of Implicit Memory Storage
The nervous system of Aplysia contains only about
20,000 large, identifiable nerve cells, clustered into 10 ma-
jor ganglia. The ability to identify individual neurons and
record their activity has made it possible to define the major
components of the neuronal circuits of specific behaviors
and to delineate the critical sites and underlying mecha-
nisms used to store memory-related representations.
The molecular mechanisms contributing to implicit mem-
ory storage have been most extensively studied for the gill-
and siphon-withdrawal reflex of Aplysia (Kandel, 2001). As
is true for other types of defensive reflexes, the gill- and
siphon-withdrawal reflex can be modified by several differ-
ent forms of implicit learning. We begin by focusing on
sensitization, an elementary form of nonassociative learning
by which an animal learns about the properties of a single
noxious stimulus and enables the formation of a learned fear
response. When a light touch is applied to the siphon of the
snail, the snail responds by withdrawing its gill and siphon.
This response is enhanced when the animal is given a
noxious, sensitizing stimulus. As with other forms of de-
fensive behaviors, the memory for sensitization of the with-
drawal reflex is graded, and repeated tail shocks lead to a
longer-lasting memory: A single tail shock produces short-
term sensitization that lasts for minutes, whereas repeated
tail shocks given at spaced intervals produce long-term
sensitization that lasts for up to several weeks (Castellucci
et al. 1986). The reflex also exhibits classical conditioning,
an associative form of learning by which an animal learns
about the predictive relationship between two stimuli. En-
hancement of the withdrawal reflex is greater and longer
lasting if the siphon is touched just before the noxious,
sensitizing stimulus (paired training), compared to unpaired
training or training with either stimulus alone (Carew et al.,
1981, 1983; Antonov et al., 2001).
The simplicity of the neuronal circuit underlying these
behavioral modifications— including direct monosynaptic
connections between identified mechanoreceptor sensory
neurons and their follower cells (Castellucci et al., 1970)—
has allowed the analysis of the short- and long-term mem-
ory for sensitization to be reduced to the cellular and mo-
lecular level. This monosynaptic sensory-to-motor neuron
connection, which is thought to be glutamatergic (Dale and
Kandel, 1993; Trudeau and Castellucci, 1993; Conrad et al.,
1999), can be reconstituted in dissociated cell culture. A
number of studies in our laboratory and elsewhere have
demonstrated that this simplified in vitro model system
reproduces what is observed during behavioral training if
the tail shocks are replaced with brief applications of sero-
tonin (5-HT), a modulatory transmitter normally released by
sensitizing stimuli in the intact animal (Glanzman et al.,
1989; Mackey et al., 1989; Marinesco and Carew, 2002). A
single brief application of 5-HT produces a short-term
change in synaptic effectiveness (short-term facilitation, or
STF), whereas repeated and spaced applications produce
changes in synaptic strength that can last for more than a
week (long-term facilitation, or LTF) (Montarolo et al.,
1986). The facilitation is also larger and longer lasting if the
presynaptic sensory neuron fires action potentials just be-
fore the serotonin application, analogous to classical condi-
tioning (Eliot et al., 1994; Bao et al., 1998; Schacher et al.,
Cellular and Molecular Mechanisms Underlying
Short- and Intermediate-Term Forms of Implicit
Short-term facilitation of synaptic connections involves
enhanced transmitter release from the sensory neurons
Serotonin released in vivo during sensitization or applied
directly to cultured neurons binds to cell surface receptors
MECHANISMS OF MEMORY STORAGE
on the sensory neurons and promotes the production of the
diffusible second messenger cAMP by activating the en-
zyme adenylyl cyclase. This increase in internal concentra-
tion of cAMP results in short-term behavioral sensitization
lasting minutes and correlates with an increase in synaptic
strength of the sensory-to-motor neuron connection referred
to as short-term facilitation. This facilitation is partially due
to the enhanced release of the transmitter glutamate by the
sensory neuron onto its follower cells and is accompanied
by an increase in excitability of the sensory neuron attrib-
utable to the depression of specific sets of potassium chan-
nels (Klein et al., 1982; Castellucci et al., 1986; Dale et al.,
1988). In addition, the changes in cAMP and Ca2?levels
triggered by the activation of serotonin receptors and ionic
short- and intermediate-term synaptic plasticity contributing to learning in Aplysia involve different combina-
tions of pre- and postsynaptic molecules including (1) presynaptic PKA, (2) presynaptic Ca2?and CamKII, (3)
presynaptic PKC, (4) postsynaptic Ca2?and CamKII, and (5) recruitment of pre- and possibly postsynaptic
molecules to new sites.
Mechanisms of short- and intermediate-term memory formation in Aplysia. Different forms of
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