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The Journal of Neuroscience, September 15, 2000, 20(18):7017-7023
The Role of Identified Neurotransmitter Systems in the Response
of Insular Cortex to Unfamiliar Taste: Activation of ERK1-2 and
Formation of a Memory Trace
Diego E.
Berman,
Shoshi
Hazvi,
Victor
Neduva, and
Yadin
Dudai
Department of Neurobiology, The Weizmann Institute of Science,
Rehovot 76100, Israel
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ABSTRACT |
In the behaving rat, the consumption of an unfamiliar taste
activates the extracellular signal-regulated kinase 1-2 (ERK1-2) in
the insular cortex, which contains the taste cortex. In contrast, consumption of a familiar taste has no effect. Furthermore, activation of ERK1-2, culminating in modulation of gene expression, is obligatory for the encoding of long-term, but not short-term, memory of the new
taste (Berman et al., 1998 ). Which neurotransmitter and neuromodulatory systems are involved in the activation of ERK1-2 by the unfamiliar taste and in the long-term encoding of the new taste information? Here
we show, by the use of local microinjections of pharmacological agents
to the insular cortex in the behaving rat, that multiple neurotransmitters and neuromodulators are required for encoding of
taste memory in cortex. However, these systems vary in the specificity
of their role in memory acquisition and in their contribution to the
activation of ERK1-2. NMDA receptors, metabotropic
glutamate receptors, muscarinic, and  -adrenergic and dopaminergic
receptors, all contribute to the acquisition of the new taste memory
but not to its retrieval. Among these, only NMDA and muscarinic
receptors specifically mediate taste-dependent activation of ERK1-2,
whereas the -adrenergic function is independent of ERK1-2, and
dopaminergic receptors regulate also the basal level of ERK1-2
activation. The data are discussed in the context of postulated novelty
detection circuits in the central taste system.
Key words:
memory; novelty; taste; acetylcholine; glutamate; MAPK
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INTRODUCTION |
Consumption of even a small amount
of an unfamiliar tastant is a salient experience that may suffice to
imprint a long-term memory of the new taste and its hedonic valence
(Bures et al., 1998). This single-trial learning capability has a clear
phylogenetic advantage, e.g., it ensures that poisons, if survived, are
never approached again. We attempt to elucidate how such efficient
learning and robust memory are implemented in the rat brain. A key role in the detection of taste novelty and the encoding of taste memory is
played by the central gustatory area in the insular cortex (IC) (Kiefer
and Braun, 1977; Rosenblum et al., 1993, 1997; Schafe and Bernstein,
1998). We have identified previously multiple molecular mechanisms in
the IC that are specifically turned on by an unfamiliar taste but not
by a familiar one (Rosenblum et al., 1997; Berman et al., 1998).
One of these mechanisms involves differential activation of
mitogen-activated protein kinases (MAPKs), specifically the extracellular signal-regulated kinases 1-2 (ERK1-2) (Berman et al.,
1998). Activation of ERK1-2 develops within half an hour after
consumption of a new taste and triggers modulation of gene expression
that subserves consolidation of memory in the IC (Berman et al.,
1998). Reaction to taste in the behaving organism can be
detected within seconds or even less (Halpern and Tapper, 1971). It is
hence evident that the activation of ERK1-2 in the IC is triggered by
earlier neuronal events that may also control immediate behavior.
Furthermore, this activation is not induced merely by perception of the
sensory attributes of the taste per se, because a familiar taste has no
effect; additional input to cortex that encodes "unfamiliarity" is
required. How is this done? A likely possibility is that certain
neuromodulators, e.g., acetylcholine (Naor and Dudai, 1996; Rosenblum
et al., 1996; Gutierrez et al., 1999), are recruited by the mismatch
between the perceived and the familiar, instruct the IC that some
action is needed to react to the new situation on the one hand, and
register it in memory on the other.
In this study, we have investigated the effect of microinjection into
the IC of antagonists and agonists of identified neurotransmitters and
neuromodulators on the activation of ERK1-2 by unfamiliar taste and on
the encoding of taste memory. Activation of ERK1-2 was selected as a
molecular correlate of memory formation because it leads to activation
of the transcription factor Elk-1 in the IC, and its blockade in the IC
prevents taste memory (Berman et al., 1998). We report here that,
whereas formation of taste memory in the IC can be disrupted by
perturbation of multiple types of receptors for neurotransmitters, only
a subgroup of these receptor types is differentially required in the
acquisition of memory but not in its retrieval. Furthermore, only
glutamatergic [NMDA receptor (NMDAR)-mediated] and cholinergic inputs
function specifically in novelty-dependent activation of ERK1-2 in the
IC. Our data also suggest that the basal activity level of ERK1-2 in
the IC is maintained by a balance between glutamatergic, dopaminergic, and GABAergic inputs.
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MATERIALS AND METHODS |
Animals. Male Wistar rats (~60 d old, 250-300 gm)
were used. They were caged individually at 22 ± 2°C in a 12 hr
light/dark cycle.
Reagents. Scopolamine, propranolol, bicuculline, and
(R,S)- -methyl-4-carboxyphenylglycine
(MCPG), monoclonal anti-diphospho-ERK (dpERK) (Thr183/Tyr185, MAPK-YT),
anti-ERK antibodies, and goat anti-mouse (IgG) peroxidase conjugate
were from Sigma (St. Louis, MO).
D,L-2-amino-5-phosphonovaleric acid (APV),
muscimol, and R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride [SCH 23390 (SCH)] were from Research Biochemicals (Natick, MA).
2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX) was from Tocris Cookson (Bristol, UK). Horseradish peroxidase (HRP)-linked protein A and the enhanced chemiluminescence (ECL) kit were from Amersham Pharmacia Biotech
(Buckingshamshire, UK). All other chemicals were of analytical grade or
the highest grade available.
Behavioral procedures. We used two types of taste learning
situations: incidental (Thorndike and Rock, 1934) and associative. The
associative learning paradigm was conditioned taste aversion (CTA)
(Revusky and Garcia, 1970; Bures et al., 1988, 1998). In CTA, organisms
learn to avoid a novel taste if its ingestion is followed by transient
malaise. We used the procedure described by Rosenblum et al. (1993,
1997). Unless indicated otherwise, saccharin was used as the unfamiliar
taste, and LiCl (0.15 M, 2% body weight, i.p.)
was used as the malaise-inducing agent. The rats were water deprived
for 24 hr and then pretrained for 3 d to get their daily water
ration once a day for 10 min from a pipette containing 10 ml of water.
On day 4, they were allowed to drink the saccharin solution instead of
water for 10 min. Forty minutes after the offset of the drinking
period, they were injected with LiCl intraperitoneally. Under these
conditions, 3 d after training, the conditioned rats preferred
water to saccharin at a ratio of 9:1 in a multiple choice test
situation (Berman et al., 1998). The conditioned aversion is presented
below as aversion index, defined as [milliliters of
water/(milliliters of water + milliliters of saccharin) × 100],
consumed in the test; hence, 50 indicates equal preference. In the
"incidental learning" paradigm, rats were first water deprived for
24 hr and then pretrained for 3 d to get their water ration from
pipettes during 10 min per day, as above. On day 4, the animals were
exposed for 10 min to the unfamiliar taste, sodium saccharin 0.1% w/v
(Rosenblum et al., 1993; Berman et al., 1998). The rats were then
subjected to either a molecular or a behavioral analysis. For the
molecular analysis, they were killed at the indicated time after taste
consumption, and their IC was removed and processed for determination
of the effect of the incidental exposure to the new taste on the
activation of ERK1-2 (see below). For the behavioral analysis, the
rats were subjected to CTA training 3 d later to determine the
behavioral manifestation of the incidental training. Under this
protocol, the incidental learning situation became the
conditioned stimulus (CS) preexposure phase in a latent inhibition (LI)
experiment (Lubow, 1989). In LI, preexposure to a sensory stimulus
attenuates the effectiveness of that same stimulus to serve as a
conditioned stimulus in subsequent learning. Indeed, the exposure of
rats to an unfamiliar taste several days before CTA training
significantly reduces the acquired aversion to that same taste
(Rosenblum et al., 1997). In other words, the behavioral consequences
of the incidental taste learning situation and their pharmacological modulation were hence determined in a protocol of LI of CTA (LI+CTA), in which CTA training was used as a probe for the efficacy of the
incidental learning that has taken place a few days earlier.
Surgery and microinjection. Rats were anesthetized with 4.8 ml/kg Equithesin (2.12% w/v MgSO4, 10%
v/v ethanol, 39.1% v/v propylene glycol, 0.98% w/v sodium
pentobarbitone, and 4.2% w/v chloral hydrate), restrained in a
stereotactic apparatus (David Kopf Instruments, Tujunga, CA),
and implanted bilaterally with stainless steel guide cannula (23 gauge,
thin wall) aimed 1.0 mm above the gustatory neocortex
[anteroposterior, +1.2 mm relative to bregma; lateral, ±5.5 mm;
ventral, 5.5 mm (Paxinos and Watson, 1986)]. The cannula were
positioned in place with acrylic dental cement and secured by two skull
screws. A stylus was placed in the guide cannula to prevent clogging.
Animals were allowed 1 week to recuperate before being subjected to
experimental manipulations. The stylus was removed from the guide
cannula, and a 28 gauge injection cannula, extending 1.0 mm from the
tip of the guide cannula, was inserted. The injection cannula were
connected via PE20 tubing to a Hamilton microsyringe driven by a
microinfusion pump (CMA/100; Carnegie Medicin, Stockholm, Sweden).
Microinjection was performed bilaterally in a 1 µl volume per
hemisphere delivered over 1 min. The injection cannula was left in
position before withdrawal for an additional 1 min to minimize dragging
of the injected liquid along the injection tract. The sphere of
diffusion of the injectate was estimated in a set of control animals
microinjected with 1 µl of India ink (Fig.
1) and found to overlap the gustatory area (Kosar et al., 1986). Drugs were dissolved in physiological saline
or in artificial CSF (ACSF), and the appropriate vehicle was used as
control. The particular drug dosages used for microinjection were
selected on the basis of previous in vivo studies
(Quillfeldt et al., 1994; Riedel et al., 1994; Naor and Dudai, 1996;
Riedel, 1996; Rosenblum et al., 1997). In the case of MCPG, we have
explored in preliminary experiments a dose range of 5-50 µg and
selected the higher dose for further investigation.
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Figure 1.
Left, A Nissl-stained frozen
section of the rat brain [coronal cut, +1.2 mm relative to bregma
(Paxinos and Watson; 1986)] depicting the sphere of diffusion of 1 µl of India ink microinjected into the insular cortex as detailed in
Materials and Methods. Right, A scheme of the
corresponding contralateral hemisphere depicting the superimposed
sphere of diffusion in a group of 10 rats (gray)
and the estimated "median" obtained by superimposing the five
smallest dye diffusion spheres (black).
GI, Granular insular cortex; DI,
dysgranular insular cortex; AI, agranular insular
cortex; CPu, caudate-putamen; Par,
parietal cortex; Pir, piriform cortex.
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Homogenization. Rats were decapitated 30 min after the
completion of the exposure to the unfamiliar taste. The insular cortex containing the gustatory cortex was dissected out as described previously (Rosenblum et al., 1997). The tissue was immediately homogenized in a glass-Teflon homogenizer in 200 µl of SDS sample buffer (10% glycerol, 5% -mercaptoethanol, and 2.3% SDS, in 62.5 mM Tris-HCl, pH 6.8) and boiled for 5 min.
Samples were immediately stored at  20°C until further usage.
Western blot analysis. Aliquots in SDS sample buffer were
subjected to SDS-PAGE (8% acrylamide) (Laemmli, 1970) and Western blot
analysis (Burnette, 1981). The amount of protein in each sample was
always determined before loading, and the same amount of protein
(60-100 µg) was loaded in each lane. After the run, the lanes were
also compared by Ponceau staining. After blocking with 1% BSA for 1 hr
at room temperature, the blot was reacted overnight at 4°C or for 2 hr at room temperature with the primary antibody and then incubated for
1 hr at room temperature with HRP-linked protein A or with goat
anti-mouse HRP-linked antibody before exposure to the ECL substrate.
The antibodies directed against the phosphorylated ERK1-2 were usually
applied first (dpERK, 1:30000). The blots were stripped in 0.9% w/v
NaCl, 10 mM Tris-HCl, 0.05% v/v Tween 20, and
2% w/v SDS, pH 7.6, four times for 10 min each at room temperature
under vigorous shaking. The blots were then rinsed three times for 10 min in washing buffer (same stripping buffer without SDS), blocked for
1.5 hr with 1% BSA, and incubated with the antibody anti-ERK1-2
(total ERK1-2, 1:2000). The efficacy of the stripping step was
assessed by omitting the first antibody and verifying the lack of
signals on the blot. Quantification was performed using a computerized
densitometer and image analyzer (Molecular Dynamics, Sunnyvale, CA).
Statistics. Differences among the groups were determined
using one-way ANOVA. For paired comparisons, Scheffe contrast tests were used with an level of 0.05.
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RESULTS |
Perturbation of function of glutamatergic, cholinergic,
-adrenergic, dopaminergic, or GABAergic receptors in the IC shortly
before training impaired the encoding of taste memory
We have microinjected into the IC ligands that are specific for
identified neurotransmitter and neuromodulatory systems shortly before
the first exposure of rats to a novel taste solution and tested the
effect on long-term taste memory. We have targeted the glutamatergic,
cholinergic, dopaminergic, and GABAergic systems, because they were
shown previously to function in the insular cortex (Lopez-Garcia et
al., 1990; Otawa et al., 1995). The -adrenergic system was also
probed because of its presumed role in learning (Cahill et al.,
1994), including in taste paradigms (Mohammed et al., 1986). Two types
of complementary behavioral protocols were used. In the first
(incidental learning, tested in an LI+CTA protocol; see
Materials and Methods), the ligands were applied shortly before the
presentation of a novel taste in a latent inhibition experiment, and
their effect on the efficacy of that same taste as a conditioned taste
in subsequent CTA was determined by measuring CTA memory 3 d after
CTA training. In the second type of protocol (CTA protocol), the
ligands were applied shortly before the presentation of a novel taste
in CTA training, and their effect on CTA memory was determined 3 d
later. The two protocols partially overlap yet complement each other.
The CTA protocol assesses the capability of a taste to become
associated shortly after its consumption with a negative reinforcer and
of the taste aversion association to be remembered in the long term;
the LI+CTA protocol further assesses the capability of a taste per se
to be remembered in the long term. Specifically, in the LI+CTA
protocol, the ligands were microinjected bilaterally 20 min before the
preexposure to the novel taste (10 ml of 0.1% saccharin during 10 min). On the day of CTA training, 3 d after the LI preexposure,
the animals were exposed for the second time to the same taste, and
LiCl injected intraperitoneally was followed 40 min after the offset of
drinking. Animals were tested 3 d later.
The following ligands were each microinjected into the IC: the NMDA
receptor antagonist APV, the metabotropic glutamate receptor (mGluR)
antagonist MCPG, the AMPA/kainate receptor (AMPA/KR) antagonist NBQX,
the muscarinic antagonist scopolamine, the GABAergic antagonist bicuculline, the GABAergic agonist muscimol, the -adrenergic antagonist propranolol, and the dopaminergic
D1/D5 antagonist SCH. We
found out that local microinjection to the IC of antagonists to the
aforementioned glutamatergic receptors, muscarinic acetylcholine receptor, GABA receptors, dopamine
(D1/D5) receptors, and
-adrenergic receptors, as well as of the GABAergic agonist, impaired
the encoding of taste memory as assessed in the LI+CTA protocol (Fig.
2A). As can be seen in
the figure, the ligands were all able to abolish essentially all of the
attenuating effect of LI on subsequent CTA training to the same taste.
In the CTA protocol, all of these ligands attenuated CTA training when
microinjected 20 min before the exposure to saccharin during
conditioning (Fig. 2B). The aversion index of control
rats injected intraperitoneally with saline instead of LiCl in a CTA
protocol was 40 ± 5, whereas that of rats injected intraperitoneally with LiCl in the CTA protocol (and microinjected into
the brain with vehicle only) was 96 ± 3. The ligands used in this
study were able to diminish CTA by 38 ± 6%. This corresponds to
the magnitude of blocking of long-term CTA by LI (Fig.
2A), as well as by other types of pharmacological
inhibition of IC function (Rosenblum et al., 1993; Berman et al.,
1998). It might represent a ceiling effect, unveiling the maximal
contribution of the IC to the overall CTA behavior in our training and
testing protocol. Indeed, the magnitude of blocking was not further
augmented by coinjection of APV plus scopolamine into the cortex (data
not shown).
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Figure 2.
Behavioral effects of the different
neurotransmitter ligands microinjected into the IC. A,
Impairment of latent inhibition by local bilateral microinjection of
the cholinergic antagonist scopolamine (Scop; 50 µg),
the NMDA receptor antagonist APV (10 µg), the GABAergic antagonist
bicuculline (Bic; 20 µg), the AMPA/kainate receptor
antagonist NBQX (5 µg), the -adrenergic receptor antagonist
propranolol (Prop; 20 µg), the GABAergic agonist
muscimol (Mus; 5 µg), the
D1/D5 dopamine receptors antagonist SCH
23390 (SCH; 5 µg), and the metabotropic glutamate
receptor antagonist MCPG (50 µg). Animals were trained and tested in
the LI+CTA protocol as described in Materials and Methods. They were
microinjected with the different ligands 20 min before the preexposure
to the novel taste in the LI phase of the protocol
(n = 6 per group; the control black
bar indicates aversion index value for CTA+LI, and the
dashed bar indicates CTA without LI). B,
Effect of the ligands on CTA acquisition. Animals were microinjected 20 min before CTA training (n = 10) and tested as
detailed in Materials and Methods in the CTA protocol.
C, Effect of the ligands on CTA retrieval. Animals were
trained and microinjected with the drugs 20 min before the test session
in the CTA protocol, 3 d after the conditioning
(n = 11). Aversion Index is defined
as [milliliters of water/(milliliters of water + milliliters of
saccharin) × 100]. Injection volume is 1 µl/hemisphere.
An aversion index of 50 indicates equal-preference level.
Ctrl, Control animals microinjected into the IC with
vehicle only. Included for comparison is also the aversion index of
sham-conditioned controls, i.e., rats injected in training with saline
intraperitoneally instead of LiCl intraperitoneally, and microinjected
into the IC with vehicle only (43 ± 3, horizontal solid
line ± dashed lines).
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The drugs microinjected into the IC did not serve as reinforcers
in CTA
We were concerned with the possibility that the drugs
microinjected into the IC might themselves induce visceral malaise, because a variety of drugs, including neurotransmitter antagonists, may
induce malaise when administered systemically (MacMahon et al., 1981;
Asin and Montana, 1989; Bures and Buresova, 1989). Although the drugs
in our study were locally microinjected into the IC, and, moreover,
this was done before the taste was presented, i.e., in a backward
conditioning situation that is not expected to lead to efficient
associations, we could not exclude the possibility that subtle malaise might develop that lingers
throughout and after the time during which the tastant is consumed and
become associated with the experienced taste. Furthermore, association of drug-induced malaise with taste may under appropriate conditions overshadow the association of LiCl with the taste in the CTA protocol. Therefore, we have monitored the amount of saccharin consumed by rats
that had been microinjected with each of the ligands 20 min before the
onset of drinking, in the absence of LiCl intraperitoneal injection 40 min after the offset of drinking (Naor and Dudai, 1996), and compared
it with the amount of saccharin consumed in a first re-presentation of
the tastant 3 d later. If microinjection of a specific drug into
the IC produced malaise, we would expect consumption of saccharin on
its re-presentation 3 d later to be lower. This was not the case.
The values for the control (vehicle microinjected into the IC) were
8.9 ± 0.5 versus 8.6 ± 0.4 ml, respectively. The
corresponding values for scopolamine, propranolol, SCH, APV, MCPG,
NBQX, and bicuculline were 9.0 ± 0.4 versus 9.2 ± 0.5, 9.1 ± 0.5 versus 8.8 ± 0.8, 9.0 ± 0.9 versus 8.9 ± 0.9, 9.1 ± 0.6 versus 9.4 ± 0.8, 8.8 ± 0.3 versus
8.9 ± 0.5, 9.2 ± 0.5 versus 9.0 ± 0.3, and 8.9 ± 0.9 versus 9.5 ± 1.0. Hence, we did not detect any evidence
for reinforcing properties of the ligands used when microinjected into
the IC under the conditions used by us in this study.
AMPA/KR antagonist and GABA receptor agonist impaired both
acquisition and retrieval of taste memory
The effect of a drug administrated during training on performance
in a CTA memory test may be attributable to effects either on
acquisition or on sensory or motor faculties essential for the
behavioral performance of the task. In the latter case, the performance
in a retrieval test is also expected to be impaired. To test the role
of the different neurotransmitter-neuromodulator systems in retrieval,
we microinjected the drugs 20 min before the test. CTA retrieval was
only affected by the microinjection of NBQX and muscimol (Fig.
2C).
Perturbation of cholinergic, glutamatergic, dopaminergic, and
GABAergic receptor function blocked taste-induced MAPK activation in
the IC
As shown previously, drinking an unfamiliar taste specifically and
differentially activates ERK1-2 in the insular cortex of the behaving
rat (Berman et al., 1998). To test the effect of the different
neurotransmitter ligands on taste-induced ERK1-2 kinase activation,
animals were microinjected with the antagonists into the IC 20 min
before the exposure to the novel taste. Thirty minutes after the offset
of drinking, the time in which ERK activation is maximal (Berman et
al., 1998), the IC was excised, homogenized, and immunoblotted with
antibodies that specifically recognize the double-phosphorylated,
activated form of ERK1-2. As can be seen in Figure
3A, taste-induced MAPK
activation was blocked by the microinjection of scopolamine, APV, MCPG,
NBQX, SCH, and muscimol. The total amount of ERK protein remained
unaltered in all treatments.
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Figure 3.
Effect of various ligands microinjected into the
IC on ERK1-2 activation. A, Effect on taste-induced
ERK1-2 activation. Top, representative blots of
activated (dpERK1-2) and total ERK1-2
(ERK) from animals microinjected with the
different neurotransmitter ligands 20 min before exposure to saccharin
(black and gray bars) and water
(white bar). Bottom, Quantification of
the results from the blots (n = 10 per group). The
level of dpERK1-2 in animals microinjected with ACSF and exposed to
saccharin (black bar) is used as standard. Ratio of
activation is presented as dpERK experimental/dpERK saccharin.
B, Effect of the ligands on the basal level of ERK1-2
activation. Top, Representative blots of dpERK1-2 and
ERK1-2 from animals microinjected with the ligands and exposed to
water 20 min later. Bottom, Quantification of the
results from the blots (n = 12). The level of
dpERK1-2 in animals microinjected with ACSF and exposed to water
(black bar) is used as standard. Ratio of activation is
presented as dpERK experimental/dpERK water. W, Water;
S, saccharin.
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The basal level of activation of ERK1-2 in the IC depends on the
AMPA, mGluR, dopaminergic, and GABAergic receptors
Which neurotransmitter system(s) is responsible for keeping the
basal activity of MAPK in cortex? To answer this question, we
microinjected the antagonists into the IC 20 min before drinking a
familiar taste (tap water). The IC was then excised and treated as
above. Only the microinjection of NBQX, MCPG, SCH 23390, and muscimol
decreased the basal level of MAPK activation, whereas bicuculline
increased it (Fig. 3B). No changes were observed in the
total amount of ERKs.
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DISCUSSION |
When a rat samples an unfamiliar foodstuff, but not when it
consumes a familiar one, molecular mechanisms are mobilized in the
insular cortex, which probably encode the saliency of the event on the
one hand and trigger long-term memory of the new taste on the other.
Among these is activation of the ERK1-2 cascade, culminating in
modulation of gene expression in cortical neurons (Berman et al.,
1998). The activation of ERK1-2 attains maximal values within 30 min
and subsides to "resting level" within 60 min. It is not
attributable merely to the perception of the taste; reacting to the
same taste on a subsequent presentation, when it is already familiar,
does not affect ERK1-2 activity. Hence, information in addition to
that encoded in the sheer sensory percept must instruct the cortex that
the taste is novel and activate ERK1-2. Furthermore, rats react to
taste within seconds or even less (Halpern and Tapper, 1971), whereas
the aforementioned molecular manifestation of novelty detection
displays a kinetics with a  1/2 of many
minutes. It is therefore of interest to identify the pathways upstream
of the ERK1-2 cascade that inform the cortical circuits about the
novelty of the sensory input. The objective of the work presented in
this paper was to contribute toward the identification of such
pathways, as well as of their contribution to the formation of
long-term memory of the new taste for which the activation of ERK1-2
is obligatory. This was done by introducing into the insular cortex,
shortly before the consumption of a new taste, specific antagonists or
agonists of identified neurotransmitter and neuromodulator systems and
testing their effect on the activation of ERK1-2 and taste memory.
Our results show that, although multiple neurotransmitter systems
in the IC are necessary for incidental taste learning and CTA learning,
they do differ in the specificity of their effect on memory (Fig.
2A,B). Glutamatergic (AMPA, NMDA,
mGlu), -adrenergic, cholinergic (muscarinic), dopaminergic
(D1/D5), and
GABAA receptors are all required for the
acquisition of taste information. However, the AMPA and the GABAergic
systems are also obligatory for retrieval of taste information, turning
it likely that they play a role either in both acquisition and
retrieval, or, more likely, also in other processes related to the
perception of taste and the reaction to it. The results also show that
the activation of ERK1-2 in the insular cortex by unfamiliar taste is
specifically dependent on the activation of muscarinic acetylcholine
receptors (mAChRs) and NMDAR (Fig.
3A,B).
Furthermore, our data indicate that the activation level of ERK1-2
in vivo in cortex is itself modulated in the resting level by a glutamatergic, dopaminergic, and GABAergic balance; in contrast, the muscarinic and -adrenergic input, as well as glutamatergic input
mediated via the NMDA receptor system, do not affect the basal level of
ERK activation in the IC. The activity-dependent regulation of MAPKs in
the nervous system has been investigated in several types of
preparations (English and Sweatt, 1996; Atkins et al., 1998; Berman et
al., 1998; Kaminska et al., 1999; Robertson et al., 1999; Winder et
al., 1999; Rosenblum et al., 2000), but only little is known on the
involvement of identified neuromodulatory and neurotransmitter systems
in MAPK activation in identified brain regions in the context of memory
formation in the behaving organism. Atkins et al. (1998) reported that
systemic administration of the NMDA receptor channel blocker MK-801
attenuated hippocampal MAPK activation during fear conditioning in the
rat. Our results on the role of metabotropic glutamate receptors,
muscarinic receptors, and dopamine receptors in MAPK activation in the
IC are in agreement with those of Robertson et al. (1999) in
hippocampal slices. However, we did not observe coupling of the
-adrenergic receptors to ERK1-2 activation in IC, as reported in
the hippocampus by Robertson et al. (1999) and Winder et al. (1999). In
cultured mammalian neurons, activation of ERKs was reported to be
regulated by membrane depolarization and calcium influx (Rosen et al.,
1994), G-protein-coupled receptors (Sudgen and Clerk, 1997;
Lopez-Ilasca, 1998), and AMPA receptors (Hayashi et al., 1999). ERKs
were also found to be modulated by GABA in immature cerebral granule
cells (Fiszman et al., 1999) and by dopamine and glutamate in
hippocampal slices (Otani et al., 1999) and in rat cortical neurons
(Wang and Durkin, 1995; Das et al., 1997; Vincent et al., 1998). As to
the involvement of intracellular signaling cascades, Robertson et al.
(1999) suggested that dopaminergic and -adrenergic modulation of
MAPK takes place via the cAMP-dependent protein kinase signaling
pathway, whereas muscarinic, glutamatergic-metabotropic, NMDA, and
AMPA-mediated regulation of MAPK involves multiple types of
calcium-mediated signaling. Rosenblum et al. (2000) have reported
recently that, in primary cortical cultures and in the COS-7 model
system expressing muscarinic receptor subtypes, the muscarinic agonist
carbachol activates ERKs in Src-, phosphoinositide-3 kinase-, and
calcium- dependent mechanisms; furthermore, on the basis of their own
as well as earlier data they proposed that MAPK is an intracellular "coincidence detector" of information mediated by cholinergic and
glutamatergic inputs. All in all, the available data indicate that
there is no shortage of potential intracellular signaling mechanisms
that could mediate the effect of the neurotransmitter and
neuromodulators on ERK1-2 activation observed by us in the IC;
however, in the present study, we focused only on the intercellular signaling involved in ERK1-2 activation, in its potential role in
memory formation.
A major question is, how are the neuromodulatory systems such as
the cholinergic and the noradrenergic systems informed that the taste
input is novel? Novelty detection is expected to require some type of
fast internal comparator that matches the on-line (sensory) information
with off-line (memory) information and triggers an appropriate cascade
of events only if a mismatch is detected. In our case, the process
includes recruitment of neuromodulatory pathways, e.g., cholinergic,
resulting in activation of ERK1-2, subsequent modulation of gene
expression, and ultimately long-term alterations in the cortical
circuits that encode the new information. A potential candidate for a
fast internal comparator is a corticothalamo-brainstem system,
which may share properties with the model proposed by Ahissar (Ahissar
et al., 1997; Ahissar, 1998) for the mammalian somatosensory system.
Hence, the thalamus may compare on-line sensory information encoded in
the brainstem with taste memory representations retained in the IC, and
when a mismatch is identified, trigger behavioral response on the one
hand, and initiate memory encoding in the IC on the other. An
additional, potentially complementary circuit may involve the amygdala.
It interconnects with both the IC and the brainstem and fits to compare
the new with the familiar and to signal the saliency of the novel
situation (Lamprecht and Dudai, 2000). The amygdala was shown recently
to be capable of modulating the ability of the IC to form taste
memory (Escobar and Bermudez-Rattoni, 2000) and is involved in the
cholinergic modulation of that memory (Gutierrez et al., 1999). The
novelty-induced activation of ERK1-2 detected by us, is, according to
this type of model, a mechanism downstream of the neuromodulatory
input, which itself is downstream of the on-line-off-line mismatch
detection that is triggered by the novel taste perception. It is
plausible to assume that glutamatergic input encodes taste information
in the IC, whereas multiple neuromodulatory systems are engaged by the
"novelty detection circuits." Among these neuromodulatory systems,
the cholinergic input activates ERK1-2, whereas the -adrenergic system functions independent of the ERK1-2 cascade. Acetylcholine, dopamine, GABA, and glutamate are released by activity in the IC
(Lopez-Garcia et al., 1990). Cholinergic input has been shown to play
an obligatory role in the encoding of taste aversion memory (Naor and
Dudai, 1996; Gutierrez et al., 1999). Noradrenaline was implicated in
the encoding and consolidation of other types of emotionally charged
memories (Crow and Wendlandt, 1976; Cahill et al., 1994;
Przybyslawski et al., 1999).
A highly simplified scheme compiling the available data on the
potential involvement of identified neurotransmitters and
neuromodulators in the modification by novel taste experience of IC
synapses is presented in Figure 4. Many
questions remain open, such as which molecular mechanisms are activated
by the noradrenergic input, or, more generally, what is the default
response of the brain to taste perception. Is every tastant considered
unfamiliar unless proven otherwise? In other words, are the
neuromodulatory systems that trigger memory formation in the IC, all or
part, activated by the identification of taste unfamiliarity or
inhibited by the recognition of taste familiarity? The elucidation of
these and similar questions requires analysis of the cellular response
to familiar and unfamiliar tastes in cortex, thalamus, brainstem, and
possibly other stations in the central taste circuits, such as
amygdala. The identification of neurotransmitters and neuromodulators that are obligatory for the response to novelty and the encoding of
taste memory should contribute to our understanding of the interaction
and function of the circuits involved.
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|
Figure 4.
A highly simplified scheme of some elements in the
processes that might subserve the encoding of taste memory in the IC.
In the absence of taste input (Basal), the
balance between the resting levels of glutamate (Glu;
acting via AMPA/KR and mGluR), GABA, and dopamine (DA;
via D1/D5 receptors) regulates the basal
level of ERK1-2 activation. When a new taste is consumed, a
hypothetical novelty detection system, e.g., thalamocortico-brainstem
circuits (Ahissar et al., 1997, Ahissar, 1998), compares the on-line
stimulus with taste representations in memory. According to this model,
if a meaningful mismatch is detected, a signal is sent to the
cholinergic and noradrenergic systems, resulting in release of
acetylcholine and noradrenaline in the IC. Acquisition involves, in
addition to glutamatergic transmission via the metabotropic and AMPA
receptors, glutamatergic transmission via the NMDA receptor, as well as
cholinergic and noradrenergic input. Acetylcholine activates ERK1-2,
whereas noradrenaline functions in this system independent of ERK1-2.
Activation of ERK1-2 culminates in modulation of gene expression and
ultimately in long-term representational changes. The yet unidentified
novelty detection circuit may overlap with the IC circuits, which are
altered by taste experience, and may also involve brain areas not
mentioned in the scheme, e.g., amygdala (Schafe and Bernstein, 1996;
Escobar and Bermudez-Rattoni, 2000). In retrieval, glutamatergic
transmission that is essential for activation of the memory circuits
and expression of the recalled behavior is mediated in the now-modified
synapse (bold contours) via the AMPA/KR, whereas the
NMDA, muscarinic, and noradrenaline receptors are no more
obligatory.
ERK activation remains unaltered by the
retrieved information; its resting activity level is still regulated as
in Basal above. The scenario in which some of the
effects of the indicated neurotransmitters and neuromodulators on MAPK
are mediated via interneurons that ultimately use different
transmitters is omitted for the sake of simplicity. For further
details, see Results. A/K, AMPA/KR;
AD, -adrenergic receptor; LTM,
long-term memory; PP, biphosphorylated, hence activated,
ERK1-2.
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FOOTNOTES |
Received Feb. 15, 2000; revised June 23, 2000; accepted June 26, 2000.
We thank Ehud Ahissar, Amir Bahar, and Roni Seger for discussions, and
the Carl and Micaela Einhorn-Dominic Center for Brain Research for support.
Correspondence should be addressed to Dr. Yadin Dudai, Department of
Neurobiology and Institute for Brain Research, The Weizmann Institute
of Science, Rehovot 76100, Israel. E-mail: yadin.dudai{at}weizmann.ac.il.
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ABSTRACT
INTRODUCTION
