Molecular Mechanisms Underlying Memory Consolidation of Taste Information in the Cortex

Abstract

The senses of taste and odor are both chemical senses. However, whereas an organism can detect an odor at a relatively long distance from its source, taste serves as the ultimate proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial substances. The automatic reaction to a given taste has been developed during evolution and is well adapted to conditions that may occur with high probability during the lifetime of an organism. However, in addition to this automatic reaction, animals can learn and remember tastes, together with their positive or negative values, with high precision and in light of minimal experience. This ability of mammalians to learn and remember tastes has been studied extensively in rodents through application of reasonably simple and well defined behavioral paradigms. The learning process follows a temporal continuum similar to those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolidation. Moreover, inhibiting protein synthesis in the gustatory cortex (GC) specifically affects the consolidation phase of taste memory, i.e., the transformation of short- to long-term memory, in keeping with the general biochemical definition of memory consolidation. This review aims to present a general background of taste learning, and to focus on recent findings regarding the molecular mechanisms underlying taste-memory consolidation in the GC. Specifically, the roles of neurotransmitters, neuromodulators, immediate early genes, and translation regulation are addressed.

Full text

BEHAVIORAL NEUROSCIENC
E
REVIEW ARTICLE
published: 05 January 2012
doi: 10.3389/fnbeh.2011.00087
Molecular mechanisms underlying memory consolidation
of taste information in the cortex
Shunit Gal-Ben-Ari 1,2 and Kobi Rosenblum1,2*
1Department of Neurobiology, University of Haifa, Haifa, Israel
2Center for Gene Manipulation in the Brain, University of Haifa, Haifa, Israel
Edited by:
Riccardo Brambilla, San Raffaele
Scientific Institute and University, Italy
Reviewed by:
Riccardo Brambilla, San Raffaele
Scientific Institute and University, Italy
Clive R. Bramham, University of
Bergen, Norway
*Correspondence:
Kobi Rosenblum, Department of
Neurobiology and Ethology, Center
for Gene Manipulation in the Brain,
University of Haifa, Mt Carmel, Haifa
31905, Israel.
e-mail: kobir@psy.haifa.ac.il
The senses of taste and odor are both chemical senses. However, whereas an organism
can detect an odor at a relatively long distance from its source, taste serves as the ultimate
proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial
substances. The automatic reaction to a given taste has been developed during evolution
and is well adapted to conditions that may occur with high probability during the lifetime
of an organism. However, in addition to this automatic reaction, animals can learn and
remember tastes, together with their positive or negative values, with high precision and
in light of minimal experience. This ability of mammalians to learn and remember tastes
has been studied extensively in rodents through application of reasonably simple and well
defined behavioral paradigms.The learning process follows a temporal continuum similar to
those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolida-
tion. Moreover, inhibiting protein synthesis in the gustatory cortex (GC) specifically affects
the consolidation phase of taste memory, i.e., the transformation of short- to long-term
memory, in keeping with the general biochemical definition of memory consolidation. This
review aims to present a general background of taste learning, and to focus on recent find-
ings regarding the molecular mechanisms underlying taste–memory consolidation in the
GC. Specifically, the roles of neurotransmitters, neuromodulators, immediate early genes,
and translation regulation are addressed.
Keywords: taste learning, consolidation, gustatory cortex, insular cortex, MAPK, ERK, translation regulation,
conditioned taste aversion
INTRODUCTION
Intake of food and avoidance of poison are crucial to an organ-
ism’s survival in a dynamic environment. The process of deciding
whether food is “safe” or “hazardous” relies heavily on the gusta-
tory and somatosensory systems, which are involved in evaluating
diverse properties of putative foods, such as: chemosensory, e.g.,
modality, intensity; orosensory, e.g., texture, temperature, pun-
gency; and gratification capacity (Rosenblum, 2008;Carleton et al.,
2010).
The sense of taste differs from the other senses in two major
characteristics: (1) Each taste input has dual labeling, one related
to its physical (texture and temperature) and chemical features,
and the other to its hedonic value and safety; (2) Deciding on the
safety aspects of a novel sensation, such as the taste of an unfa-
miliar food, involves a different temporal scale from other senses:
taste association with unconditioned stimulus (US) takes 1–12 h
(Bures et al., 1998;Merhav and Rosenblum, 2008), compared with
a few seconds for responses to other sensations.
Two main strategies are used by various species, including
humans, in responding to various tastes: genetic programming,
i.e., affinity to sweet tastes, aversion to bitter ones, and com-
plex learning mechanisms that involve several forebrain structures
(Rosenblum, 2008). Modification of the basic genetic program-
ming and memories of new tastes and their values are expected
to be mediated, at least in part, by the gustatory cortex (GC;
Yamamoto et al., 1984, 1985;Rosenblum, 2008;Doron and Rosen-
blum, 2010), which is defined according to its cytoarchitectonic
boundaries as the dysgranular part of the insular cortex (IC;
Burwell, 2001). This is in line with its unique anatomical connec-
tions (Figure 1), through which it receives multimodal sensory
inputs, including visceral, gustatory, and somatosensory informa-
tion from sensory thalamic nuclei (Fujita et al., 2010). However,
other brain regions, such as the basolateral amygdala (Bla) and
dorsal hippocampus, have been shown to be activated during novel
taste processing (Yefet et al., 2006;Doron and Rosenblum, 2010),
and also to be necessary for safe taste–memory consolidation (De
la Cruz et al., 2008). Most of the studies of the molecular mecha-
nisms underlying taste memory were performed in mice and rats,
therefore, the present review will focus on these studies.
Taste recognition on the receptor level, as well as taste reactiv-
ity, as defined genetically, are beyond the scope of this review; they
have been extensively covered elsewhere (Frank et al., 2008;Car-
leton et al., 2010). The first objective of this review is to describe
taste-related behavior paradigms, in order to elucidate the mole-
cular and cellular mechanisms underlying learning and memory.
We then provide a detailed analysis of the currently known mole-
cular and cellular mechanisms of taste learning in the GC, which
resides in the IC. We aim to focus mainly on studies during the
last decade; previous studies have been reviewed elsewhere (Bures
et al., 1998;Rosenblum, 2008).
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
FIGURE 1 | Neuroanatomy of the taste system. Chemical stimuli
originating in alimentary sources, upon reaching the oral cavity initiate the
processing of gustatory information (CN, central nucleus; BLA, basolateral
amygdala; NST, nucleus of solitary tract; PBN, parabrachial nucleus; pVPMpc,
parvocellular part of the ventralis postmedial thalamic nucleus of the
thalamus; GC, gustatory cortex). Taste cells, which are broadly tuned to the
diverse taste modalities, are innervated by cranial nerves VII, IX, X, which
project to the primary gustatory nucleus in the brainstem (NST). The NST
sends information to three different systems: the reflex system, the lemniscal
system, and the visceral–limbic system.The reflex system comprises
medullary and reticular-formation neurons, which innervate the cranial motor
nuclei. The lemniscal system consists of projections of the gustatory portion
of the NST to the secondary nucleus situated in the dorsal pons (PBN); this, in
turn, sends axons to the pVPMpc, which ultimately relays gustatory
information to the anterior part of the insular cortex (GC).The visceral–limbic
system refers to a collateral network of connections to the hypothalamus and
limbic areas in the forebrain, which comprises the central gustatory pathway.
The PBN is connected to the amygdala, the hypothalamus, and the
bed-nucleus of the stria terminalis. All limbic gustatory targets are
interconnected with each other as well as with the PBN and the GC.
BEHAVIOR PARADIGMS FOR THE MEASUREMENT OF TASTE
LEARNING, MEMORY, AND CONSOLIDATION
The molecular mechanisms underlying learning and memory are
the subject of ongoing research. Although learning and memory
are considered to be two different processes, they involve a con-
tinuum of events. Following a discrete event, physical changes
underlying memory encoding and processing of the information
to be stored takes place. Ethologically, this is described as the
acquisition phase; it involves creation of an internal representa-
tion of the novel information. This representation remains labile
for some time, while the process of consolidation takes place. Dur-
ing this process the new memory becomes increasingly resistant
to disruption (Alberini, 2011), which can involve several types of
intervention: behavioral (e.g., Merhav et al., 2006), pharmacolog-
ical (e.g., Rosenblum et al., 1993), or others (Bures et al., 1998).
It has been shown that the consolidation of new memory can be
disrupted by many events, including: blocking synthesis of new
RNA or protein, e.g., by actimomycin D or anisomycin, respec-
tively; disruption of the expression or function of specific proteins;
new learning; brain cooling; seizure, e.g., through electric shock;
brain trauma; and regional brain lesions (Alberini, 2011). During
the consolidation phase, the memory is transformed from short-
term memory (STM), which may last from minutes to hours, to
long-term memory (LTM), which may last from days to a lifetime
(McGaugh, 2000;Kandel, 2001;Dudai, 2004). The time frame of
the “consolidation phase” can vary within a given learning par-
adigm; it depends on the manipulation, and may reflect several
different cellular and molecular processes (Figure 2). One may
ask whether the difference between consolidation and mainte-
nance of memories is an artificial one, since the processes can also
be regarded as continuous processing of the information by varied
molecular and cellular mechanisms within a certain cortical area.
They can also be considered in terms of temporally differential
involvement of several brain structures.
The next phase of memory processing is use or retrieval of
the memory, during which it is susceptible to further changes,
associated with a process of reconsolidation, which mediates its
restabilization. The stability of a memory depends on its age: new
memories are sensitive to post-reactivation disruption, but older
ones are more resistant (Alberini, 2011).
Ethologically, learning is usually classified into non-associative
(habituation and sensitization), associative (relationships between
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
FIGURE 2 | The learning process phases: consolidation is
determined by type of disruption. The learning process is
ethologically divided into consecutive phases of acquisition,
consolidation, retrieval, relearning, and reconsolidation. Whereas
acquisition, retrieval, and relearning are defined in positive terms, the
consolidation and reconsolidation phases are defined in negative terms.
Therefore, the duration of the learning process is variable, and
dependent on the type of experimental perturbation used to determine
consolidation time. The different experimental interferences with
consolidation affect different stages of the molecular mechanisms that
underlie learning and memory formation. Although the same types of
interference may be used to disrupt consolidation and reconsolidation, the
time windows of sensitivity to disruption differ between the two phases of
learning. It is therefore unclear whether the molecular processes that occur
during consolidation are identical to the ones that occur during
reconsolidation.
amounts and events), and incidental learning (learning in the
absence of explicit external reinforcement; Gibb et al., 2006;Mor-
ris, 2006;Miranda et al., 2008;Rosenblum, 2008;Lindquist et al.,
2009). Over the years, different behavioral paradigms have been
developed in order to study the different types of learning, and
also to address the abovementioned temporal phases of memory
formation.
One of the most widespread taste-learning paradigms is the
negative-learning, conditioned taste aversion (CTA) paradigm, in
which an association is formed between a novel taste (serving as a
conditioned stimulus – CS) and malaise (serving as an uncondi-
tioned stimulus – US), resulting in the animal’s subsequent avoid-
ance of the novel food associated with delayed food poisoning
(conditioned response – CR; Garcia et al., 1955;Bures et al., 1998).
The acquisition of CTA is subserved by specific brain regions,
including the IC and the amygdala, although their precise role in
CTA is still unclear (Yamamoto et al., 1994;Lamprecht and Dudai,
1996), and it has been demonstrated that induction of neurotoxic
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
lesions in the IC disrupts acquisition of CTA (Roman et al., 2006;
Roman and Reilly, 2007). Similarly, lesions of the basolateral
region (Bla), but not of the central nucleus of the amygdala, selec-
tively disrupt CTA performance (Nachman and Ashe, 1974;Morris
et al., 1999;St Andre and Reilly, 2007). CTA is commonly used
when a hippocampus-independent form of learning is addressed.
A widely used paradigm of positive-learning is latent inhibition
of CTA (LI-CTA), in which an animal learns that a novel food is
safe, and displays less aversion following CTA than animals sub-
jected to CTA alone (Bures et al., 1998). The LI-CTA paradigm
involves presentation of a novel taste to an animal prior to CTA.
Since this early experience elicits no negative consequences, the
animal displays reduced aversion to the same taste following CTA
(Rosenblum et al., 1993). This modulation of behavior can be
attributed either to reduced strength of the association at the time
of the CTA or to competition during the retrieval phase (Lubow,
1989). LI-CTA is a form of incidental learning that depends on
both the quantity of novel taste consumed and the functionality
of the GC (Rosenblum et al., 1993;Merhav and Rosenblum,2008).
Under certain conditions, CTA can be extinguished (Berman
et al., 2003). Extinction reflects a decrease in the CR in the absence
of reinforcement of a conditioned stimulus. Behavioral evidence
indicates that extinction involves an inhibitory learning mecha-
nism in which the extinguished CR reappears following presenta-
tion of an unconditioned stimulus. However, studies have shown
that the memory was not erased in rats and humans (Lin et al.,
2010).
Taste learning and CTA have several advantages as para-
digms for studying molecular mechanisms underlying learning
and memory. These include: one-trial learning; strong inciden-
tal learning; clear and short learning time; minimal behavioral
manipulation, since the animals can learn in their home cage with
very little interference from other modalities; the sensory input
is clearly defined, and therefore can be quantified in molecular
terms; clearly defined cortical area(s) subserve the learning; and
high reproducibility (Bures et al., 1998;Rosenblum, 2008).
LONG-TERM POTENTIATION IN THE INSULAR CORTEX
The most studied form of neuronal adaptations is Hebbian plastic-
ity, which includes long-term potentiation (LTP), and its recipro-
cal, long-term depression (LTD; Collingridge et al., 2004;Malenka
and Bear, 2004;Feldman, 2009;Pozo and Goda, 2010). Hallmark
features of LTP are that synaptic changes are associative, rapidly
induced, and input specific. These features facilitate reinforce-
ment of active synaptic connections with a given set of sensory
stimuli, thus eliciting an activity-induced increase in synaptic effi-
cacy, which is widely expressed in several pleo- and neocortical
areas. Taken together, these characteristics render LTP an attrac-
tive model for a cellular basis for learning and memory (Bliss and
Collingridge, 1993;Neves et al., 2008;Rosenblum, 2008;Sjostrom
et al., 2008).
Long-term potentiation has been described in several brain
areas, including the hippocampus and the cortex, and in
conjunction with taste learning, (Escobar et al., 1998, 2002;
Ramirez-Lugo et al., 2003;Chen et al., 2006;Alme et al.,
2007;Bramham, 2007;McGeachie et al., 2011;Rodriguez-Duran
et al., 2011). It was demonstrated that tetanic stimulation of
the basolateral amygdaloid nucleus (Bla) induced N-methyl-d-
aspartate (NMDA)-dependent but metabotropic glutamate recep-
tor (mGluR)-independent LTP in the IC (Escobar et al., 1998,
2002;Jones et al., 1999). It is important to note that IC–LTP and
CTA both involve similar molecular mechanisms in the IC, such
as NMDA receptor (NMDAR) dependence, activation of ERK1/2,
and induction of immediate early genes (IEGs), including Zif268,
Fos, Arc, and Homer (Jones et al., 1999;Rodriguez-Duran et al.,
2011).
However, it remains to be more robustly proven that LTP-like
mechanisms in the IC subserve taste learning. It was shown that
induction of LTP in the Bla–IC projection prior to CTA enhanced
CTA retention (Escobar and Bermudez-Rattoni, 2000). In addi-
tion, it was shown that on the one hand, intracortical microinfu-
sion of brain-derived neurotrophic factor (BDNF) induced LTP in
the Bla–IC projection of adult rats (Escobar et al., 2003), and on
the other hand, that intracortical microinfusion of BDNF prior to
CTA training enhanced retention of this task (Castillo et al., 2006).
In a follow-up study, Rodriguez-Duran et al. (2011) have shown
that when the paradigm was reversed, i.e., CTA was performed
prior to LTP induction in the Bla–IC projection, CTA training
prevented the subsequent induction of LTP in the Bla–IC pro-
jection for at least 120 h after CTA training. In addition, they
showed that CTA training produced a persistent change in the
possibility of inducing subsequent LTP in the Bla–IC projection in
a protein-synthesis-dependent manner, and inferred that changes
in the possibility of inducing subsequent synaptic plasticity con-
tributed to the formation and persistence of aversive memories
(Rodriguez-Duran et al., 2011).
Long-term potentiation consists of two phases on the molecu-
lar level: induction, which triggers potentiation, and maintenance,
which sustains the potentiation over time. Many molecules have
been shown to be involved in the induction phase of LTP, but
very few have been implicated in the maintenance phase. Since
the working hypothesis is that LTP is the cellular mechanism
underlying LTM storage, the molecular mechanisms relevant to the
maintenance phase are highly important. To the best of our knowl-
edge, to date, only a single molecule, protein kinase Mζ(PKMζ),
has been found to be necessary for maintenance in both the hip-
pocampus (spatial learning) and the IC (CTA): local injection of
ZIP, a PKMζselective inhibitor, into the hippocampus resulted
in reversal of LTP maintenance in vivo and loss of 1day old spa-
tial memory (Pastalkova et al., 2006). Similarly, its injection into
the GC resulted in reversal of long-term CTA memory in a dose-
dependent manner,whereas other serine/threonine protein kinase
inhibitors are capable of interference with long-term memory for-
mation, but are ineffective once the memory has been established
(Shema et al., 2009, 2011).
Protein kinase Mζis the brain-specific atypical protein kinase C
(PKC) isoform,which unlike full-length PKC isoforms,is a cleaved
form comprising the independent catalytic domain of PKCζ, and
is a second messenger-independent kinase. PKMζis constitutively
active in sustaining LTP maintenance, and studies have shown
that it mediates synaptic potentiation specifically during the late
phase of LTP. LTP induction increases new PKMζsynthesis, leading
to enhanced synaptic transmission. The mechanism underlying
L-LTP and spatial memory maintenance by PKMζis thought
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
to involve AMPA receptor phosphorylation and trafficking, with
subsequent changes in the amplitude of excitatory postsynaptic
potential (EPSP) concomitant with dendritic translation regulated
by PKMζphosphorylation (and inhibition) of Pin1 (Sacktor, 2008;
Vlachos et al., 2008;Navakkode et al., 2010;Parvez et al., 2010;von
Kraus et al., 2010;Westmark et al., 2010;Mei et al.,2011;Sajikumar
and Korte, 2011).
NEUROTRANSMITTERS IN THE GUSTATORY CORTEX
INVOLVED IN TASTE LEARNING
The working hypothesis is that an organism relies on its sensory
system, specifically, in the present context, the sense of taste, to
create an internal representation of a given physical or chem-
ical stimulus. The sensory information is converted into neu-
ronal activity that subserves the various phases of learning, i.e.,
acquisition, consolidation, and retrieval. Information regarding
physical/chemical properties and the significance of a given taste
reaches the GC via several different neurotransmitters, and elicits
the release of several neurotransmitter systems in the GC, where
relevant receptors are expressed as well. Several molecular changes
in the GC have been found to be correlated with novel taste learn-
ing at various time points after exposure to a novel taste. The
molecules involved include acetylcholine (ACh), dopamine, nora-
drenaline, gamma-aminobutyric acid (GABA), glutamate, and
various neuropeptides (Figure 3;Rosenblum et al., 1995, 1996,
1997;Berman et al., 2000;Belelovsky et al., 2005, 2009;Koh and
Bernstein, 2005;Merhav et al., 2006;Banko et al., 2007;Costa-
Mattioli et al., 2007;Elkobi et al., 2008;Merhav and Rosenblum,
2008;Barki-Harrington et al., 2009b;Doron and Rosenblum,2010;
Sweetat et al., 2011). However, only the muscarinic-cholinergic
and NMDARs have been extensively studied with regard to their
roles in taste–memory acquisition, consolidation, and retention
(Jones et al., 1999;Gutierrez et al., 2003;Nunez-Jaramillo et al.,
2008;Rosenblum, 2008).
GLUTAMATE
Physical and chemical taste information is transferred from the
oral cavity to the cortex via fast neurotransmission, mediated by
the neurotransmitter glutamate, the main excitatory neurotrans-
mitter in the mammalian CNS (Rosenblum, 2008;Rondard et al.,
2011). Since the prominence of a given taste is hypothesized to
be mediated via activation of the neuromodulatory system (e.g.,
Kaphzan et al., 2006),it is possible that the interaction between the
two systems produces a long-term taste–memory trace; it is also
likely that it coincides on specific neurons and probably molecules
that can serve as coincidence detectors of the sensory input and its
meaning (Kaphzan et al., 2006).
The glutamate receptor family comprises four types of
receptors: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propi-
onic acid (AMPA), N-methyl-d-aspartic acid (NMDA), kainate,
and mGluRs. AMPA, NMDA, and kainate receptors are ionotropic
receptors, i.e., they can produce complex fast ion influx-mediated
changes in the neuron, whereas mGluRs produce slow sec-
ond messenger-mediated changes in the neuron by activating
G-protein-coupled receptors (GPCRs; Rondard et al., 2011).
Glutamate and dopamine have been implicated in off-line
processing and memory consolidation following CTA, by means
of in vivo microdialysis and capillary electrophoresis (Guzman-
Ramos et al., 2010). In their study, Guzman-Ramos et al.
(2010) demonstrated the occurrence of an amygdala-dependent
dopamine and glutamate reactivation within the IC, about 45 min
after the stimuli association. Furthermore, blockade of dopamin-
ergic D1 and/or NMDARs before the off-line activity impaired
long- but not STM, which suggests dependence on protein syn-
thesis (Guzman-Ramos et al., 2010). In addition, dopamine and
NMDA can synergistically activate extracellular signal-regulated
kinase (ERK)/Mitogen-activated protein kinase (MAPK) signal-
ing, which is necessary for the formation of long-term taste
memory (Kaphzan et al., 2006, 2007).
Activation of NMDARs has been shown to be necessary for
attenuation of the neophobic taste response in both the IC
(Figueroa-Guzman et al., 2006) and the Bla (Figueroa-Guzman
and Reilly, 2008). Acute microinfusions of MK-801, a non-
competitive NMDAR antagonist, into both brain regions revealed
that although there was no effect on the initial magnitude of the
neophobic response, attenuation of gustatory neophobia was pre-
vented. Similarly, microinfusion of mGlu5-selective antagonist,
3-[2-methyl-1,3-thiazol-4yl)ethynyl]pyridine (MTEP), at 0, 1, or
5μg into the rat IC or Bla prior to CTA resulted in enhanced
CTA performance in the case of the Bla, indicated by robust CTA
followed by slower extinction than in control animals, in a dose-
dependent manner. Interestingly, MTEP microinfusion into the
IC resulted in less robust aversion following CTA, in addition to
enhanced extinction, in a dose-dependent manner (Simonyi et al.,
2009). Previous studies that employed systemic administration
of mGlu antagonists before CTA conditioning have demonstrated
that activation of mGlu5, but not of mGlu1 receptors, was required
for CTA learning (Schachtman et al., 2003). In addition, attenua-
tion of CTA can be attained by microinjectionof a broad-spectrum
mGlu antagonist into the Bla (Yasoshima et al., 2000) or the IC
(Berman et al., 2000).
mGlu5 receptors interact with NMDARs, and the two modu-
late one another’s function in several brain regions in a mutually
positive manner: stimulation of either receptor potentiates the
other (Fowler et al., 2011). The two receptors are physically con-
nected with each other through anchor proteins: mGlu5 receptor
binds Homer proteins (Fagni et al., 2004),NMDAR interacts with
postsynaptic density (PSD)-95, and Homer and PSD-95 can be
clustered by Shank – all three of which are PSD proteins (Nais-
bitt et al., 1999;Tu et al., 1999). NMDA and mGlu5 can act
synergistically to activate a number of proteins such as MAPKs,
calcium/calmodulin-dependent protein kinase II (CaMKII), and
CREB (Mao and Wang, 2002;Yang et al., 2004).
A plethora of studies using genetic, pharmacological, physi-
ological, and biochemical approaches have indicated the critical
roles played by mGlu5 and NMDA in both the IC and the hip-
pocampus in acquisition and consolidation, but not retrieval,
of memory of aversive tasks, specifically in avoidance learning
and CTA (Schachtman et al., 2003;Cui et al., 2005;Gravius
et al., 2005;Izquierdo et al., 2006;Simonyi et al., 2007, 2009;
Barki-Harrington et al., 2009a;Nunez-Jaramillo et al., 2010).
In a recent follow-up study employing co-administration of an
mGlu5-receptor-positive allosteric modulator, 3-cyano-N-(1,3-
diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), and an NMDAR
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
FIGURE 3 | Molecular mechanisms underlying taste learning
in the gustatory cortex: schematic simplified representation
assuming the different molecular events take place within
the same neuron. Glutamate/neuromodulators (Ach, dopamine)
reach the postsynaptic site and affect the neuron through specific
receptors (NMDAR, AMPAR, mGluR, muscarinic receptors, dopamine
receptors, e.g., D1). The receptors are linked to scaffold proteins that form the
postsynaptic density (PSD), e.g., MAGUKs, Shank, Homer. MAGUKs are
linked through distal scaffolding proteins (DSP) to CamKII.The complexes of
receptors and PSD proteins activate signal transduction and hub molecules,
which in turn activate transcription and translation regulation.This chain of
events, according to our current understanding, results in a new cellular
steady state. It is currently unknown whether all molecular processes
depicted occur within a single neuron – a question that remains to be further
explored. A, neuromodulators/glutamate; B, receptors; C, scaffold proteins; D,
signal transduction and hub molecules; E, translation regulation; F,
transcription. Key: neuromodulators – white hexagon; glutamate – white
ellipse; receptors of neurotransmitters/neuromodulators – blue;
representatives of major protein kinases and phosphatases that may have
short-term (CamKIIα) or long-term effects-green; protein translation
machinery – purple; transcription factors – coral; immediate early genes – red;
second messenger – orange. *CaMKII is known to phosphorylate PSD-95 and
SAP-97, but it remains to be clarified whether it phosphorylates PSD-93 and
SAP-102 as well. In addition, CamKII is well known to activate cytoplasmic
polyadenylation element binding protein (CPEB) in other brain regions and in
connection with other forms of learning, thereby affecting protein translation.
**The BDNF pathway has been simplified; other proteins participate in this
pathway.
antagonist, MK-801, it was shown that NMDA and mGlu5 inter-
acted functionally in CTA-conditioned rats. Whereas CDPPB
administered by itself prior to the conditioning trial had no effect
on CTA or hippocampus-dependent step-down inhibition, co-
administration of the two compounds resulted in attenuation of
learning deficits in both tasks (Fowler et al., 2011).
There is ample evidence in the literature for the importance of
NMDAR, specifically its regulatory NR2B subunit, in taste learn-
ing. For example, CTA conditioning-induced long-lasting tyro-
sine phosphorylation of NR2B specifically in the IC (Rosenblum
et al., 1995). Furthermore, local administration of (2R)-amino-5-
phosphonovaleric acid (APV), a reversibly selective competitive
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
inhibitor of NMDAR, to the IC prior to CTA conditioning
impaired CTA memory in a brain-region- and time-dependent
manner (Rosenblum et al., 1995, 1996, 1997). In addition, whereas
exposure to a novel taste, e.g., saccharin, increased phosphoryla-
tion in the NMDAR subunits, repeated doses of saccharin at the
same concentration, which rendered the taste familiar, led to a dra-
matic decrease in the levels of serine phosphorylation of NR2A and
NR2B subunits (Nunez-Jaramillo et al., 2008).
NR2B phosphorylation in the IC is not only correlated with
but is necessary for taste learning, as has been demonstrated
through pharmacological and genetic approaches: local admin-
istration of the tyrosine kinase inhibitor, genistein, to the IC
prevented the increase in phosphorylation of NR2B on tyrosine
1472, and attenuated taste–memory formation (Barki-Harrington
et al., 2009b). Additionally,whereas novel taste exposure has been
recently demonstrated to induce intracellular redistribution of
NR2A and NR2B subunits in the IC (Nunez-Jaramillo et al., 2008),
microinjection of genistein to the IC altered this learning-induced
distribution pattern of NMDAR, highlighting the importance of
NR2B tyrosine phosphorylation after learning in determination
of NMDAR distribution (Barki-Harrington et al., 2009b).
In another study, transgenic (Tg) mice over-expressing the
NR2B subunit specifically in the forebrain (which includes the IC)
were shown to have enhanced CTA, as well as slower extinction
rates, although aversion levels were similar in Tg and wild-type
(Wt) mice 30 days after the CTA conditioning. However, under
the LI-CTA paradigm, the Tg mice did not differ from Wt mice
in their aversion levels, and in a paradigm of two-taste LI-CTA
(second order conditioning, in which the mice are exposed to
both novel and familiar tastes) the Tg mice showed attenuation of
enhanced CTA (Li et al., 2010).
GABA AND ACh
Although the involvement of glutamate receptors in the process-
ing of taste learning in the GC has been extensively studied,
other neurotransmitters have been implicated as well. Novel tastes
have been shown to increase ACh levels in the rat IC, whereas a
familiar taste did not (Miranda et al., 2000). Furthermore, phar-
macological inactivation of the nucleus basalis magnocellularis, a
cholinergic and GABAergic source in the basal forebrain, impaired
CTA acquisition (Miranda and Bermudez-Rattoni, 1999). How-
ever,retrieval was not impaired by this manipulation. In addition,
cholinergic activity mediated by muscarinic receptors in the IC
has been shown to be necessary for acquisition and consolida-
tion of contextual memory of inhibitory avoidance (Miranda and
Bermudez-Rattoni, 2007).
Inhibitory GABAergic interneurons have been recently demon-
strated to be activated in response to novel taste learning in
a layer-specific manner hours after taste learning, which sug-
gests that these neurons are involved not only in acquisition, but
also in off-line processing and consolidation of taste informa-
tion (Doron and Rosenblum, 2010). Electrophysiological studies
in anesthetized rats revealed that excitatory propagation in the IC
was primarily regulated by AMPA and GABAAreceptors (Fujita
et al., 2010). Another electrophysiological study in rat-cortex slices,
which employed multiple-whole-cell patch-clamp recording from
layer V GABAergic interneurons and pyramidal cells of rat IC,
demonstrated that carbachol, a cholinergic agonist, increased the
amplitude of unitary inhibitory postsynaptic currents (uIPSCs)
in interneuron-to-interneuron synapses with higher paired-pulse
ratios. However, the same compound induced dose-dependent
suppression of uIPSCs in fast spiking of pyramidal cell synapses.
This attenuation was mitigated by atropine, a muscarinic ACh
receptor antagonist (Yamamoto et al., 2010), and the authors
inferred that “carbachol facilitates GABA release in interneuron
synapses with lower release probability, and cholinergic modula-
tion of GABAergic synaptic transmission is differentially regulated
depending on postsynaptic neuron subtypes.” It is important to
note that neurons projecting from one brain-region involved in
taste learning to another (Figure 1) are inherently excitatory, how-
ever, neurons within a certain brain region may be inhibitory
as well. The roles of inhibitory cortical neurons are yet to be
determined.
POSTSYNAPTIC DENSITY-95
Postsynaptic density-95 (PSD-95), a membrane-associated guany-
late kinase (MAGUK), is the major scaffolding protein in the
excitatory PSD and a potent regulator of synaptic strength (Chen
et al., 2011). It has been recently shown that 3 h following novel
taste learning, expression levels of this protein were specifically
elevated in the GC. This elevation has been shown to be necessary
for acquisition of novel taste memory, but not for its retrieval, and
it has not been observed in response to a familiar taste (Elkobi
et al., 2008). Moreover, there was a correlative increase in PSD-95
association with tyrosine-phosphorylated NR2B following novel
taste learning (Barki-Harrington et al., 2009b). A study concerning
spatial learning, which is both hippocampus- and IC-dependent,
has shown that water-maze training induced a translocation of
NMDARs and PSD-95 to lipid raft membrane microdomains,
concomitant with increased NR2B phosphorylation at tyrosine
1472 in the rat IC (Delint-Ramirez et al., 2008), similarly to
novel taste learning, as mentioned above (Barki-Harrington et al.,
2009b).
PSD-95 and other MAGUK family proteins, SAP-97 and PSD-
93, have been shown to interact with NMDAR, thereby regulating
its function, e.g., all three inhibited NR2B-mediated endocyto-
sis (Lavezzari et al., 2003). The MAGUK family proteins have
been shown to mediate NMDAR clustering and/or trafficking by
association with NMDAR NR2 subunits via their C-terminal glu-
tamate serine (aspartate/glutamate) valine motifs. In addition, the
MAGUK proteins interacted differentially with different NMDAR
subtypes, comprised of differing receptor subunit combination
(Cousins et al., 2008). Specifically, PSD-95 interacted with both
NR2A and NR2B (Kornau et al., 1995),and this interaction could
be modulated by either serine or tyrosine phosphorylation.
For example, CaMKII phosphorylated PSD-95 on serine
residue, causing dissociation of NR2A, but not of NR2B from the
NMDA–PSD-95 complex. In addition, PSD-95 itself functioned
as a negative regulator of the tyrosine kinase Src, for which it
served as a contact point to the NMDAR, thus enabling its reg-
ulation (Kalia et al., 2006). Moreover, phosphorylation of NR2A
and NR2B and their associated proteins by Src or Fyn was found
in some cases to enhance their association with PSD-95 (Rong
et al., 2001;Zalewska et al., 2005). Other tyrosine kinases shown
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
to interact with PSD-95 include c-Abl and Pyk2: the former regu-
lated synaptic clustering of PSD-95 (de Arce et al., 2010); the latter
underwent PSD-95-induced postsynaptic clustering and activa-
tion (Bartos et al., 2010). It has been suggested that the role of the
PSD-95–NMDA complex is to protect NR2 subunits from under-
going cleavage by calcium-dependent proteases, and thereby to
provide a mechanism for regulating NMDAR expression (Dong
et al., 2004).
THE ROLE OF THE MAPK/ERK PATHWAY IN THE GUSTATORY
CORTEX
Mitogen-activated protein kinases are a family of serine/threonine
kinases implicated in regulation of cell proliferation and differenti-
ation (Seger and Krebs, 1995;Belelovsky et al.,2007). Three major
groups of MAPKs have been identified in mammalian cells: extra-
cellular signal-regulated kinase (ERK), c-jun N-terminal kinase
(JNK), and p38 MAP kinase. High levels of the ERK isoforms,
ERK1 (p44 MAPK) and ERK2 (p42 MAPK), have been detected in
neurons in the mature CNS (Fiore et al., 1993). ERK activity has
been shown to be crucial for several forms of learning and mem-
ory, including fear conditioning, CTA memory, spatial memory,
step-down inhibitory avoidance, and object recognition memory.
In a study in which several pharmacological agents were locally
injected into the rat IC, it was found that NMDARs, mGluRs,
muscarinic, beta-adrenergic, and dopaminergic receptors were
all implicated in acquisition of the new taste memory, but not
in its retrieval, although these neurotransmitter/neuromodulator
systems differed in their role in acquisition. In addition, it was
demonstrated that of all the receptors studied, only NMDA and
muscarinic receptors specifically mediated taste-dependent acti-
vation of ERK1–2, whereas dopaminergic receptors regulated the
basal level of ERK1–2 activation (Berman et al., 2000). Several
studies have demonstrated the differential role of ERK1 and 2 in
cell growth and proliferation and synaptic plasticity. For exam-
ple, ERK1 knockout mice displayed enhancement of striatum-
dependent long-term memory, in conjunction with facilitation of
LTP in the nucleus accumbens, indicating the importance of ERK2
(Mazzucchelli et al., 2002;Vantaggiato et al., 2006).
ERK activation occurs downstream to neurotransmitter release
and activation of the forebrain cholinergic neurons during and
immediately after acquisition of an inhibitory avoidance response.
ERK plays a major role in learning, by promoting cellular integra-
tion of divergent downstream effectors that may trigger differing
responses, depending upon which subsets of scaffolding anchors,
target proteins, and regulatory phosphatases are involved (Giovan-
nini, 2006). MEK–ERK, the upstream kinase of ERK, is a crucial
signal transduction cascade in synaptic plasticity and memory
consolidation (Sweatt, 2001), and its inhibition affected both early
and late phases of LTP in the hippocampus (Rosenblum et al.,
2002).
Extracellular signal-regulated kinase activation was shown to
be correlated with novel taste learning, although the amount of
protein remained unchanged (Berman et al., 1998;Belelovsky
et al., 2005). In addition, the expression of LTP in the GC was
ERK-dependent, and operated in a positive feedback mode (Jones
et al., 1999). In a recent study,it was shown that bilateral injection
of U0126, a specific MEK inhibitor, to the GC prior to learning
resulted in inhibition of ERK1/2, as well as attenuation of CTA
(Rosenblum, 2008) and blockade of learning-induced elevation of
PSD-95 3 h following taste learning (Elkobi et al., 2008).
The various MAPKs are activated within differing time periods
after novel taste learning; ERK activation appears to begin a few
minutes up to 1 h following novel taste consumption (Rosenblum,
2008). It has been shown that novel taste consolidation requires
the elevation of ERK1/2 activity in the IC 20 min after taste con-
sumption. However, JNK1/2 was activated 1 h after novel taste
learning, whereas p38 was not modified at any of the examined
time points (Berman et al., 1998). Interestingly, the time scale of
ERK activation was species-specific; it was shown to differ between
mice and rats (Swank and Sweatt,2001). ERK expression following
taste learning is not only time-restricted, but also space-restricted;
it was activated in the GC, but not in the hippocampus, after
the same length of time following learning (Yefet et al., 2006).
The various MAPKs also differed in BDNF-induced activation:
intrahippocampal microinfusion of BDNF that aimed to induce
LTP resulted in rapid phosphorylation of ERK and p38, but not of
JNK (Ying et al., 2002). These effects were observed in the dentate
gyrus, but not in other examined hippocampal regions, and were
shown to be MEK–ERK-dependent.
Whereas the upstream regulation of ERK in the GC is well
studied, our knowledge regarding its downstream targets remains
fragmentary. MAPK substrate, ELK-1, a transcription factor regu-
lating immediate early expression of genes via the serum response
element (SRE) DNA consensus site (Besnard et al.,2011), has been
shown to be phosphorylated in a time frame similar to that of
ERK activation after novel taste learning, and neurotransmitters
required for induction of LTM are also required for ELK-1 phos-
phorylation in the GC in response to taste learning (Berman et al.,
2003). Further studies are needed to identify other possible targets
of ERK and their mechanisms of action underlying taste processing
in the GC.
THE ROLE OF TRANSLATION REGULATION IN
TASTE–MEMORY CONSOLIDATION
The distinctive biochemical characteristic of memory consolida-
tion is its dependence on synthesis of functional proteins in the
relevant brain regions (Davis and Squire, 1984). Indeed, local
application of anisomycin, a protein-synthesis inhibitor, to specific
brain regions affected CTA in a dose-, site-, and time-dependent
manner (Rosenblum et al., 1993;Meiri and Rosenblum, 1998).
For instance, local application of anisomycin to the GC atten-
uated CTA and taste learning under the LI paradigm (Rosen-
blum et al., 1993); however, the same treatment had no effect
on STM (Houpt and Berlin, 1999), which suggests that short-term
taste memory is independent of protein synthesis. Temporally,
taste learning is sensitive to protein-synthesis inhibitor(s) from
just before learning until up to 100 min afterward (Rosenblum,
2008). In addition, extinction of CTA is dependent on func-
tional protein synthesis in the prefrontal cortex (Akirav et al.,
2006). It is generally accepted that protein translation affects
LTM consolidation by modulation of synaptic strength, since
protein-synthesis inhibitors prevented transformation of early
LTP to late LTP. However, other modifications of intrinsic neuronal
properties also subserve learning-related behavioral changes. For
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
example, learning-induced reduction in the postburst after hyper-
polarization (AHP) lasts for days after completion of training,
and is implicated in maintenance of learned skills. It has been
recently demonstrated that synaptic activation-induced short-
term postburst AHP reduction in hippocampal and pyramidal
neurons could be transformed to a protein-synthesis-dependent
long-term AHP reduction that persisted for long time periods
(Cohen-Matsliah et al., 2010). Such learning-inducedAHP reduc-
tion has been shown to be maintained by persistent activation
of PKC and ERK in piriform cortex neurons (Seroussi et al.,
2002;Cohen-Matsliah et al., 2007), but has been found to be
CaMKII-independent (Liraz et al., 2009).
Translation consists of three phases: initiation, elongation, and
termination. Of these, the initiation phase is the most tightly
regulated, and is affected by phosphorylation of initiation fac-
tors (IFs) and ribosomal proteins (Proud, 2000). Initiation in
eukaryotes serves as the rate-limiting step in protein synthesis,
and therefore serves as an important target for translational con-
trol (Costa-Mattioli et al., 2009). There is considerable evidence in
the literature that increased initiation results in enhanced learning,
and vice versa. In knockout mice lacking the translation repres-
sor eukaryotic initiation factor 4E-binding protein (4EBP2; Banko
et al., 2007) or with reduced phosphorylation of eukaryotic initi-
ation factor 2α(eIF2α;Costa-Mattioli et al., 2007), and therefore
with enhanced initiation, no differences in taste recognition in
parallel to enhanced CTA learning were observed; furthermore,
other types of learning and plasticity in the consolidation phase
were enhanced as well. Conversely, knockout mice lacking either
S6K1 or S6K2, characterized by reduced initiation rates,exhibited
impaired taste learning (Antion et al., 2008). In a model analo-
gous to CTA in the chick, eukaryotic translation initiation factor
2B (eIF2B) was found to be both correlated with and necessary for
taste–memory consolidation (Tirosh et al., 2007).
The second phase of translation, elongation, requires activ-
ity of elongation factors (EFs). Eukaryotic elongation factor 2
(eEF2) mediated ribosomal translocation (Ryazanov and Davy-
dova, 1989) and was phosphorylated on Thr56 by a spe-
cific Ca2+/calmodulin-dependent kinase. Phosphorylation of this
kinase inhibited its activity and led to general inhibition of protein
synthesis (Nairn and Palfrey,1987). It has been shown that follow-
ing novel taste learning, eEF2 phosphorylation was increased in the
GC, indicating attenuation of translation elongation (Belelovsky
et al., 2005). This finding, which is counter-intuitive, implies that
the situation is more complex than implied by the simple model
of “the more IFs, the better the taste learning” (Rosenblum, 2008).
Nevertheless, there was increased initiation in the same samples,
manifested as increased phosphorylation levels of ERK and S6K1
(Belelovsky et al., 2005).
Therefore, we have proposed a putative mechanism, by which
increased initiation concomitant with decreased elongation in
the same neurons in the GC might increase expression levels of
mRNAs that are poorly initiated. This was reflected, for example,
in the case of phosphorylation of the αsubunit of eIF2 (eIF2 α),
which, in turn, led to suppression of general translation (Hinneb-
usch et al., 2000), concomitant with stimulation of translation of
ATF4 (Lu et al., 2004;Vattem and Wek, 2004),which is required for
late phase LTP and LTM (Bartsch et al., 1995;Chen et al., 2003).
The suggested mechanism could perform a switch-like function in
expressing a specific set of mRNAs within a restricted time window
in a cellular microdomain/s such as the synapse.
MAMMALIAN TARGET OF RAPAMYCIN
Some of the correlative changes that follow novel taste or
CTA paradigms have been observed in proteins that are either
direct or indirect targets of the mammalian target of rapamycin
(mTOR), also known as FKBP-12-rapamycin-associated protein
(FRAP), which consists of two TOR complexes (TORC) that dif-
fer in rapamycin sensitivity. TORC1 mediated rapamycin-sensitive
TOR-shared signaling to the translation machinery, the transcrip-
tion apparatus, and other targets (Loewith et al., 2002;Hay and
Sonenberg, 2004), and its blockade by rapamycin interfered with
translation of specific subpopulations of mRNA (Raught et al.,
2001). Downstream targets of mTOR include ribosomal protein
kinase (S6K1) and EF 1A and 2 (eEF1A and eEF2), which are
mostly involved in ribosome recruitment to mRNA, and regula-
tion of both the initiation and elongation phases of translation
(Hay and Sonenberg, 2004).
There is considerable evidence for the importance of the
mTOR pathway in various forms of synaptic plasticity. In Aplysia,
rapamycin application prevented long-term facilitation (Casadio
et al., 1999), and in the rat hippocampal CA1 region, rapamycin
blocked high-frequency stimulation (HFS) and BDNF-induced
LTP ( Tang et al., 2002). In addition, mTOR-dependent activation
of dendritic S6K1 was shown to be necessary for the induc-
tion phase of protein-synthesis-dependent synaptic plasticity
(Cammalleri et al., 2003).
It has been recently shown that following novel taste learn-
ing, two temporal waves of mTOR activation occurred in the GC
(Belelovsky et al., 2009). Furthermore, it was shown that PSD-95
elevation in the GC 3 h following taste learning, which is neces-
sary for LTM (Elkobi et al., 2008), was prevented following local
application of rapamycin to the GC. Another study has shown, by
means of HFS, an interesting interplay between ERK and mTOR
pathways induced at CA3–CA1 synapses: whereas HFS induced
LTP as well as translational proteins regulated by mTOR, the for-
mer induction was blocked by use of ERK inhibitors (Tsokas et al.,
2007). Moreover, this study showed ERK to be not only correlated
with, but necessary for mTOR stimulation by HFS via interac-
tion with phosphoinositide-dependent kinase 1 (PDK1) and Akt,
which are upstream to mTOR.
Other studies that used genetic and pharmacological
approaches in the CA1 region of the hippocampus showed that
activation of mTORC1 facilitated initiation of protein transla-
tion through phosphorylation and inhibition of eukaryotic initi-
ation factor 4E (eIF4E)-binding proteins (4E-BP), which inhibit
complex formation. Phosphorylation of eIF4E on Ser209 is ERK-
dependent and was closely linked with translation of specific
mRNA subpopulations (Panja et al., 2009). Thus, it is currently
accepted that ERK and mTORC1 synergistically regulate eIF4E and
translation initiation in LTM and synaptic plasticity. It has been
recently shown that Pin1 inhibited protein-synthesis induced by
glutamatergic signaling, and it was suggested that eIF4E and 4E-
BP1/2 mediated an increase in dendritic translation induced by
Pin 1 inhibition (Westmark et al., 2010).
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
It is important to note that other mechanisms have been impli-
cated in translational control of long-lasting synaptic plasticity and
memory, e.g., micro-RNA regulation (miRNA), and it is highly
likely that they participate, at least in part, in taste learning as well.
However, it remains to be clarified whether this is indeed the case.
IMMEDIATE EARLY GENES AND CONVERGENCE OF CS/US
Immediate early genes, activated transiently and rapidly by vari-
ous cellular stimuli, are regulated at the transcription level. They
provide a first response to these stimuli, in advance of protein
synthesis. Many of the IEGs are transcription factors or other
DNA-binding proteins (Plath et al., 2006). Expression levels of
IEGs have been shown to increase in neuronal populations that
subserve stimulus encoding in response to various kinds of behav-
iors (Campeau et al., 1991;Guzowski et al., 2005;Mattson et al.,
2008;Koya et al.,2009). Several such IEGs have been implicated in
taste memory, including cFOS, Activity-regulated cytoskeleton-
associated protein (Arc/Arg3.1), Homer, and BDNF (Saddoris
et al., 2009;Doron and Rosenblum, 2010), and have been shown
to be elevated following other forms of learning as well. The afore-
mentioned IEGs belong to a subclass termed effector neuronal
IEGs, which mediate NMDAR-regulated phenotypic changes in
the brain (Kaufmann and Worley, 1999). Many of these have been
immunohistochemically detected in dendrites (Lyford et al., 1995;
Tsui et al., 1996).
ARC AND HOMER
Arc and Homer are NMDAR-dependent markers for plasticity
(Guzowski et al., 2001). Arc has been shown to play an impor-
tant role in consolidation of synaptic plasticity and memories
as an effector molecule downstream of many signaling pathways
(Shepherd and Bear, 2011). It mediates synaptic homeostatic scal-
ing of AMPA receptors, via a mechanism of interaction with the
endocytosis machinery which, in turn, regulates AMPA receptor
trafficking (Chowdhury et al., 2006;Plath et al., 2006;Shepherd
et al., 2006). Additionally, Arc affects cytoskeletal dynamics, as local
injection of Arc antisense into the dentate gyrus 2 h following LTP
induction resulted in reversal of LTP, as well as dephosphorylation
of actin depolymerization factor/cofilin, and loss of nascent fila-
mentous actin (F-actin) at synaptic sites (Messaoudi et al., 2007;
Bramham et al., 2010). In turn, these changes are instrumental in
regulation of spine morphology by increasing spine density (Pee-
bles et al., 2010). A recent electrophysiological study has shown
that Arc synthesis was regulated by ERK–MNK signaling dur-
ing LTP consolidation in the dentate gyrus in live rats. Although
mTORC1 is activated following HFS stimulation, its pharmaco-
logical inhibition revealed that it is not essential for Arc synthesis
and LTP (Panja et al., 2009).
Homer1 is a PSD scaffolding protein, involved in the regulation
of synaptic metabotropic receptor function; it has been implicated
in structural changes occurring at synapses during long-lasting
neuronal plasticity and development (Xiao et al., 1998). Both Arc
and Zif268 are required for generation of mRNA-dependent LTP.
Additionally, intrahippocampal microinfusion of BDNF resulted
in selective upregulation of Arc mRNA and protein, in addition to
rapid and extensive delivery of Arc mRNA transcripts to granule
cell dendrites (Ying et al., 2002).
A recent study has elegantly exploited the fact that Arc and
Homer1a show differential temporal expression patterns in acti-
vated neurons (Guzowski et al., 2001): it was used to mark neu-
ronal ensembles in the GC and Bla that participated in processing
novel taste information. Using in situ hybridization, Saddoris
et al. (2009) showed that repeated exposure to a novel taste
(sucrose) within the time frame required for temporal differen-
tiation of Arc/Homer1a resulted in increased IEG activity, as well
as increased overlap of activated neuronal populations in the GC.
In addition, they showed that odor cues associated with sucrose,
but not with water, elicited potentiation of IEG activity in the GC
similar to that of sucrose itself, independently of Bla. Such cell
populations, responsive to both CS (taste) and US (odor), are held
to be critical for further plasticity.
Another study employed compartmental analysis of temporal
gene transcription fluorescence in situ hybridization (catFISH) for
Arc, relying on complete translocation of Arc from the nucleus to
the cytoplasm over 30 min. This study, which applied Arc catFISH
following a sucrose-conditioned odor preference test involving
nine odor-taste pairings, showed, in contrast to the findings of
Saddoris et al. (2009), that such a flavor experience paradigm
induced a fourfold increase in the percentage of cells activated
by both taste and odor stimulations in the Bla, but not in the IC
(Desgranges et al., 2010). Furthermore, the authors showed that
in odor-conditioned rats the number of cells responsive to one
stimulus was unchanged. An earlier study, which used catFISH
for Arc as well, also found that following CTA, specific Bla neu-
ronal populations were responsive to both CS and US (Barot et al.,
2008). Furthermore, this study demonstrated that when the LI-
CTA paradigm was used, no coincident activation was detected.
The identity of the cells expressing coincident activation remains
to be further characterized.
BRAIN-DERIVED NEUROTROPHIC FACTOR
Brain-derived neurotrophic factor has emerged as a potent medi-
ator both of synaptic plasticity on the cellular level, and of the
interaction of an organism with its environment on the behavioral
level (Moguel-Gonzalez et al., 2008).Along with its tyrosine kinase
receptor TrkB, BDNF plays a critical role in activity-dependent
plasticity processes, such as LTP,learning, and memory (Ma et al.,
2011). Several studies have examined the effect of BDNF in the
CTA paradigm. As mentioned above, BDNF-induced enhance-
ment of CTA retention (Castillo et al., 2006), and this effect
recently has been demonstrated to be dependent on activation
of MAPK and phosphatidylinositol-3-kinase (PI-3K) in the IC
(Castillo and Escobar, 2011). Furthermore, local administration of
BDNF into the IC immediately after similar anisomycin adminis-
tration performed prior to CTA training has been shown to reverse
the anisomycin-induced CTA memory deficits almost to control
levels. Taken together, these results imply that BDNF is a protein-
synthesis-dependent memory enhancer (Moguel-Gonzalez et al.,
2008).
Although BDNF is an IEG, the time scale of its mRNA expres-
sion is somewhat longer than those of Arc or Homer. For instance,
BDNF mRNA expression in the rat IC peaked 6h after CTA, and
began to return to base level after 8 h (Ma et al., 2011). Sur-
prisingly, this study found that BDNF levels in the Bla remained
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Gal-Ben-Ari and Rosenblum Molecular mechanisms of taste memory
unchanged, but an increase was observed in the central nuclei of
the amygdala (CeA), peaking at 4 h. The authors showed that phos-
phorylated TrkB levels were elevated in the CeA long before the
CTA-induced BDNF synthesis started, indicating a rapid activity-
dependent BDNF release, presumably independent of protein
synthesis. These data suggest that BDNF secretion and synthe-
sis may be spatially and temporally involved in CTA memory
formation. These authors also demonstrated that BDNF secre-
tion and synthesis were necessary for STM and LTM, respectively,
and, in addition, that BDNF injected into the CeA enhanced the
CTA memory. Furthermore, in another study it was shown that
a human naturally occurring polymorphic variant of BDNF in
knock-in mice (Val66Met) caused impairments in CTA extinc-
tion, but not in its acquisition or retention, whereas in humans,
homozygosity to this variant is associated with altered hippocam-
pal volume, hippocampal-dependent memory impairment, and
susceptibility to neuropsychiatric disorders. On the cellular level,
this polymorphism was associated with alterations in intracellu-
lar trafficking and activity-dependent secretion of Wt BDNF in
neurosecretory cells and cortical neurons (Yu et al., 2009).
FUTURE DIRECTIONS
In all, a more thorough understanding of the molecular mech-
anisms underlying taste memory and of the functioning of the
corresponding regulatory processes in relevant neurons that sub-
serve taste-learning processing circuits should help to elucidate
many important basic aspects of neuronal function. The main
future questions and the directions of future research might be
more general in their nature, reflecting the potential development
of knowledge and understanding in the field of biological mech-
anisms of learning and memory, or they might address questions
specific to the taste systems in the mammalian/human brain.
For example, dissection of the temporal dynamics of any mem-
ory – acquisition/consolidation and the establishment of remote
memory retrieval, relearning, and reconsolidation – which was
outlined in Figure 2 can be misleading. It is clear that acquisition
and retrieval are well defined in time. However, the consolidation
phase is defined mainly in negative rather than positive terms; it is
sensitive to various disruptions at different time points following
acquisition, and the connections between the various molecu-
lar entities involved in the process of taste learning are not well
described. In Figure 3 we outline some of the processes known to
be taking place in the GC following novel taste learning. This off-
line processing of information in the brain may represent a more
continuous rather than a phasic process. However, the mechanisms
and molecular/cellular participants in these processes are yet to be
identified (Figure 3). It is clear that in order to better understand
the consolidation or off-line processes, it is necessary to enhance
the measurements of the biochemical factors that are correlated
with and necessary for taste learning, and to improve their reso-
lution to a few cubic micrometers or to cellular/subcellular levels.
The tools for this kind of in vivo single-cell analysis have been
dramatically improved recently, and will be used to obtain better
descriptions of the molecular and cellular mechanisms underlying
learning and memorizing processes. Moreover, we and others will
aim to identify the specific circuit or neuronal ensemble involved
in creation and maintenance of any given memory and its value.
Other aims, more specific to the taste system, will be to under-
stand the neuronal mechanisms underlying the taste–memory
condition of waiting “on hold” for many hours, with its physi-
cal and chemical information as a conditioned stimulus, pending
arrival of the unconditioned stimulus or the digestive information
that will enable the taste to be tagged as safe or dangerous. This spe-
cific and unique ability of taste-learning beautifully represents the
flexibility of the neuronal system underlying learning and memory
processes, and can also teach us about the limits of the neuronal
systems abilities to create simple and associative memories.
ACKNOWLEDGMENTS
This work was supported by DIP (RO 3971/1-1), ISF (1305/08),
and European Union Seventh Framework Program EUROSPIN
(Contract HEALTH-F2-2009-241498) grants for Kobi Rosenblum.
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any
commercial or financial relationships
that could be construed as a potential
conflict of interest.
Received: 29 August 2011; accepted: 12
December 2011; published online: 05 Jan-
uary 2012.
Citation: Gal-Ben-Ari S and Rosen-
blum K (2012) Molecular mecha-
nisms underlying memory consolida-
tion of taste information in the cor-
tex. Front. Behav. Neurosci. 5:87. doi:
10.3389/fnbeh.2011.00087
Copyright © 2012 Gal-Ben-Ari and
Rosenblum. This is an open-access arti-
cle distributed under the terms of
the Creative Commons Attribution Non
Commercial License, which permits non-
commercial use, distribution, and repro-
duction in other forums, provided the
original authors and source are credited.
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