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The Journal of Neuroscience, December 1, 1998, 18(23):10037-10044
Specific and Differential Activation of Mitogen-Activated Protein
Kinase Cascades by Unfamiliar Taste in the Insular Cortex of the
Behaving Rat
Diego E.
Berman1,
Shoshi
Hazvi1,
Kobi
Rosenblum1,
Rony
Seger2, and
Yadin
Dudai1
Departments of 1 Neurobiology and
2 Biological Regulation, The Weizmann Institute of Science,
Rehovot 76100, Israel
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ABSTRACT |
Rats were given to drink an unfamiliar taste solution under
conditions that result in long-term memory of that taste. The insular
cortex, which contains the taste cortex, was then removed and assayed
for activation of mitogen-activated protein kinase (MAPK) cascades by
using antibodies to the activated forms of various MAPKs. Extracellular
responsive kinase 1-2 (ERK1-2) in the cortical homogenate was
significantly activated within <30 min of drinking the taste solution,
without alteration in the total level of the ERK1-2 proteins. The
activity subsided to basal levels within <60 min. In contrast, ERK1-2
was not activated when the taste was made familiar. The effect of the
unfamiliar taste was specific to the insular cortex. Jun N-terminal
kinase 1-2 (JNK1-2) was activated by drinking the taste but
with a delayed time course, whereas the activity of Akt kinase
and p38MAPK remained unchanged. Elk-1, a member of the ternary
complex factor and an ERK/JNK downstream substrate, was activated with
a time course similar to that of ERK1-2. Microinjection of a
reversible inhibitor of MAPK/ERK kinase into the insular cortex shortly
before exposure to the novel taste in a conditioned taste aversion
training paradigm attenuated long-term taste aversion memory without
significantly affecting short-term memory or the sensory, motor, and
motivational faculties required to express long-term taste aversion
memory. It was concluded that ERK and JNK are specifically and
differentially activated in the insular cortex after exposure to a
novel taste, and that this activation is required for consolidation of
long-term taste memory.
Key words:
taste; incidental learning; conditioned taste aversion; long-term memory; insular cortex; mitogen-activated protein kinase; novelty
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INTRODUCTION |
Taste learning in the rat is rapid
and robust. This might be attributable to the fact that rodents
are immersed in a world dominated by chemical information (Revusky and
Garcia, 1970 ; Bures et al., 1988). Behavioral paradigms that tax taste
memory in the rat, when combined with cellular and molecular methods,
offer therefore significant advantages in the analysis of learning and memory (Rosenblum et al., 1993, 1997; Yamamoto et al., 1994; Schafe et
al., 1995; Lamprecht and Dudai, 1997). When a rat encounters an
unfamiliar taste, information flows to the central taste area in the
insular cortex (Braun et al., 1982; Finger, 1987; Hettinger and Frank,
1992) and triggers there molecular changes that subserve the encoding
of taste memory. These changes involve tyrosine phosphorylation of the
2B subunit of the NMDA receptor (Rosenblum et al., 1997), activation of
protein kinase C (Bahar and Dudai, 1997; Yasoshima and Yamamoto, 1997),
cholinergic modulation (Naor and Dudai, 1996), and protein synthesis
(Rosenblum et al., 1993). Specifically, the ability of protein
synthesis inhibitors to block the formation of taste memory in cortex
in the first few hours after sampling a novel taste (ibid.) fits into a
conceptual framework that depicts consolidation of long-term memory as
dependent on modulation of gene expression (Goelet et al., 1986) and
synaptic resculpture (Bailey and Kandel, 1993).
The possibility that synaptic remodeling subserves taste memory in the
insular cortex has led us to search for molecular mechanisms that might
link the acquisition of taste information to lasting changes in the
cortical circuits, which are presumed to retain the representation of
taste over time. In this context, mitogen-activated protein kinase
(MAPK) cascades are attractive candidates. MAPKs are families of
Ser/Thr protein kinases, which take part in transmission, classification, and amplification of information embedded in
extracellular signals from the membrane via the cytoplasm to the
nucleus (Cano and Mahadevan, 1995; Seger and Krebs, 1995; Sugden and
Clerk, 1997). In many types of tissues, MAPKs contribute to
proliferation, differentiation, and development (ibid.). In neural
systems, MAPKs were implicated in plasticity and learning. In long-term
facilitation in Aplysia, apMAPK [homolog of the human
extracellular responsive kinase 2 (ERK2)] was shown to be activated by
serotonin (Michael et al., 1998) and translocated into the neuronal
nucleus (Martin et al., 1997). Furthermore, in the same system a
mutation in the phosphorylation sites of apMAPK blocked
learning-related internalization of apCAM (Bailey et al., 1997). ERK
activation was also reported to play a role in conditioning in
Hermissenda (Crow et al., 1998) and in hippocampal long-term
potentiation (LTP) (English and Sweatt, 1996).
We have therefore investigated whether taste-learning experience
modulates the activity of MAPKs in the insular cortex. Here, we
report that activation of MAPKs in the insular cortex of the behaving
rat is correlated with, and obligatory for, normal taste learning in
both incidental and associative situations. The effect is specific to
an unfamiliar (as opposed to familiar) taste and to the insular cortex
and is differential; namely, only ERK1-2 and Jun N-terminal kinase
1-2 (JNK1-2), but not Akt kinase and p38MAPK, are activated.
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MATERIALS AND METHODS |
Animals. Male Wistar rats (~60-d-old, 200-250 gm)
were used. They were caged individually at 22 ± 2°C in a 12 hr
light/dark cycle.
Reagents. Monoclonal anti-diphospho ERK (dpERK)
(Thr183/Tyr185, MAPK-YT) and anti-ERK antibodies were from Sigma (St.
Louis, MO). Polyclonal anti-phospho Akt (pAkt) (Ser473), anti-Akt,
anti-phospho Elk-1 (pElk-1) (Ser383), anti-Elk-1, anti-diphospho
JNK (dpJNK) (Thr183/Tyr185), anti-JNK, anti-diphospho p38MAPK
(dp-p38MAPK) (Thr180/Tyr182), and anti-p38MAPK were from New England
Biolabs (Beverly, MA). Horseradish peroxidase (HRP)-linked protein A
and the enhanced chemiluminescense (ECL) kit were from Amersham
(Buckingshamshire, UK). Goat anti-mouse (IgG) peroxidase conjugate was
from Sigma. PD098059 was from Calbiochem (La Jolla, CA). All other
chemicals were of analytical grade or the highest grade available.
Behavioral procedures. Throughout the study, we used two
types of taste learning situations: incidental (Hebb, 1949) and
associative (Garcia et al., 1955). Incidental learning was used for
most of the molecular analysis of the effect of taste experience on
MAPKs in insular cortex. The rats were exposed once for 10 min to an unfamiliar taste (Rosenblum et al., 1993), followed by decapitation at
the indicated times and tissue processing as described below. The
behavioral consequences of such exposure, i.e., the formation of memory
for the novel taste, was determined in other groups of rats by using
the associative conditioned taste aversion paradigm (CTA) (Revusky and
Garcia, 1970; Bures et al., 1988), either alone or in combination with
latent inhibition (see below) (Lubow, 1989). In CTA, organisms learn to
avoid a novel taste if its ingestion is followed by transient
poisoning. We used the procedure detailed in Rosenblum et al. (1993,
1997). Unless indicated otherwise, saccharin (0.1% w/v, sodium salt)
was used as the unfamiliar taste in training, i.e., the conditioned
stimulus (CS), and injection of LiCl (0.15 M, 2% body
weight, i.p.) as the malaise-inducing agent (the unconditioned
stimulus, US). Rats were pretrained for 3 d to get their
daily water ration once a day for 10 min from two pipettes containing
10 ml of water. On the conditioning day, they were allowed to drink the
saccharin solution instead of water from similar pipettes for 10 min,
and 40 min after the offset of the drinking period they were injected
intraperitoneally with LiCl. Under these conditions, 3 d after
training the conditioned rats preferred water to saccharin at a ratio
of approximately 9:1 in a multiple choice test situation (three
pipettes with 5 ml of saccharin each, three pipettes with 5 ml of water
each), whereas nonconditioned rats preferred saccharin to water. The behavioral data are presented below in terms of aversion index (AI),
defined as {[milliliters of water/(milliliters of water + milliliters of saccharin)] x 100} consumed in the test; 50 is chance
level, and the higher the AI, the more the rats prefer water to the
conditioned taste.
In some experiments, a latent inhibition procedure (Lubow, 1989) was
used to measure familiarity. The combination of CTA and latent
inhibition takes advantage of the fact that CTA is much more effective
if the CS is unfamiliar. In latent inhibition, preexposure to a sensory
stimulus attenuates the effectiveness of that same stimulus as a CS in
subsequent learning. Thus, exposure of rats to an unfamiliar taste
several days before CTA training significantly reduces the acquired
aversion to that same taste (Rosenblum et al., 1993, 1997). In latent
inhibition experiments, the rats were exposed for 10 min to either
saccharin or water (control), in two pipettes of 10 ml each, 3 d
before the second exposure to saccharin, as the CS in CTA training.
Surgery and microinjection. Rats were anesthetized with 5.6 ml/kg Equithesin (2.12% w/v MgSO4, 10% v/v
ethanol, 39.1% v/v propylene glycol, 0.98% w/v sodium pentobarbitone,
4.2% w/v chloral hydrate), restrained in a stereotaxis apparatus
(Kopf), and implanted bilaterally with a stainless steel guide cannula
(23 gauge) 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 cannulas were
positioned in place with acrylic dental cement and secured by two skull
screws. A stylus was placed in the guide cannulas to prevent clogging.
Animals were allowed 1 week to recuperate before being subjected to
experimental manipulations. The stylus was removed from the guide
cannulas, and a 28 gauge injection cannula, extending 1.0 mm from the
tip of the guide cannula, was inserted. The injection cannula was connected via PE20 tubing to a Hamilton microsyringe driven by a
microinfusion pump (CMA/100; Carnegie Medicin). 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.
Homogenization. Rats were decapitated at the indicated times
after the completion of the exposure to the unfamiliar taste. The
insular cortex containing the gustatory cortex, or other brain areas
indicated in Results, were dissected out. For the insular cortex, the
crossing of the rhinal fissure and the medial cerebral artery was used
as a reference point, and cortical tissue 1.5 mm deep, 1.5 mm rostral,
1.0 mm caudal, and 2.0 mm dorsal to it was excised. 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% polyacrylamide) (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
(40-60 µg) was loaded in each lane (Lowry et al., 1951). After the
run, the lanes were also compared by Ponceau staining. After it was
blocked 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. The blots were subsequently 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 proteins were usually
applied first (dpERK, 1:30,000; pElk-1, 1:1000; dpJNK, 1:1000; pAkt,
1:1000; dp-p38MAPK, 1:1000). The blots were then stripped in 0.9% w/v
NaCl, 100 mM Tris-HCl, 1% v/v Tween-20, and 2% w/v SDS,
pH 7.6, four times for 15 min each at room temperature under vigorous
shaking. The blots were then rinsed three times for 10 min in washing
buffer (same stripping buffer with 0.05% Tween-20 instead of
SDS), blocked for 1.5 hr with 1% BSA, and incubated with the
antibodies corresponding to the phosphorylation state-independent forms
of the proteins as described above (ERK, 1:2000; Elk-1, 1:1000; JNK,
1:1000; Akt, 1:1000; p38MAPK, 1:1000). 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 |
Drinking an unfamiliar taste activated ERK1-2 in the
insular cortex
Samples of the insular cortex from rats that were allowed to drink
a solution of unfamiliar taste, i.e., 10 ml of 0.1% saccharin, were
immunoblotted with a specific dpERK1-2 antibody. ERK activation was
detected at 10 min after the offset of drinking saccharin, peaking at 30 min, and subsiding to basal levels within 60 min (Fig.
1A). The total amount
of ERK1-2 was not affected by drinking the novel taste solution (Fig.
1B). The effect on dpERK1-2 was not restricted to
saccharin; a similar increase in ERK activation was observed in the
insular cortex after sampling other unfamiliar tastes: a solution of
1% NaCl [dpERK (NaCl)/dpERK (water) = 2.0 ± 0.3;
n = 6] or a solution of 1% glycine [dpERK
(glycine)/dpERK (water) = 2.4 ± 0.5; n = 6]. ERK
activation was not detected in the occipital lobe, olfactory bulb,
piriform cortex, or cerebellum (Fig.
2).
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Figure 1.
The effect of gustatory experience on activation
of ERK1-2 in the rat insular cortex. A, Activated
ERK1-2 (dpERK1-2). B, Total ERK1-2. Three types of
experimental groups were used. In group 1, rats were allowed to
drink water. In group 2, rats were allowed to drink a solution of
saccharin, a taste that they had never encountered before (the
unfamiliar taste). In group 3, rats were allowed to drink the saccharin
solution, which in this case was made familiar earlier by allowing them
to drink it once for 10 min 3 d before presenting it again in the
experiment (see Materials and Methods). Several sets of experiments
were conducted in different combinations of the groups. Each graph
depicts a "magnitude ratio," which is the ratio of the combined
intensity of the 42 + 44 kDa bands in one experimental group over
another (groupi/groupj) as a
function of time after the offset of drinking. A,
Filled circles, Data from a set of experiments depicting
group2/group1, i.e., the ratio of
dpERK1-2 in the insular cortex of rats allowed to drink unfamiliar
saccharin solution over that in rats allowed to drink water.
A, Open circles, Data from another set of
experiments depicting
group2/group3, i.e., the ratio of
dpERK1-2 in the insular cortex of rats allowed to drink unfamiliar
saccharin over that in rats allowed to drink familiar saccharin.
Inset, A representative blot of dpERK1-2 at
t = 30 min after drinking water
(W), unfamiliar saccharin
(S), or familiar saccharin
(SF), and quantification of experiments similar
to those depicted in the blot (activation in the water group, 1.0;
n = 9-11 each). The results show that the effect
of taste experience on the activation of ERK1-2 in the insular cortex
is attributable to the unfamiliarity of the taste. B,
Same as in A but depicting the results for total
ERK1-2. (In this and all other figures, values are mean ± SEM,
and *p < 0.05.)
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Figure 2.
The level of activated ERK1-2 and total ERK1-2
in various brain regions 30 min after the exposure to the unfamiliar
taste. A, Activated ERK1-2. B, Total
ERK1-2. IC, Insular cortex; OL,
occipital lobe; OB, olfactory bulb; PC,
piriform cortex; CB, cerebellum. n = 6 in each group.
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A familiar taste had no effect on ERK activation
A single exposure to an unfamiliar taste significantly attenuates
the effectiveness of subsequent CTA training with that same taste
(Rosenblum et al., 1993), as expected from latent inhibition (Lubow,
1989). Such preexposure also essentially abolished the effect of
drinking the saccharin solution on the activation of ERK1-2 in the
insular cortex (Fig. 1A, inset). The
activation of ERK1-2 as a function of time was similar when plotted
either as dpERK (saccharin, unfamiliar)/dpERK (saccharin, familiar) or as dpERK (saccharin, unfamiliar)/dpERK (water) (Fig.
1A). Again, the total amount of ERK1-2 was
unaffected (Fig. 1B).
An MEK inhibitor impaired CTA memory in the insular cortex
To determine whether the activation of ERKs was not only
correlated but also obligatory for taste learning, we locally
microinjected an inhibitor of MEK (MAPK/ERK kinase), PD098059 (Alessi
et al., 1995; Dudley et al., 1995), into the insular cortex 30 min
before exposure to the novel taste in the context of CTA training. As seen in Figure 3, the MEK inhibitor
impaired long-term CTA memory tested 72 or 120 hr after training,
without significantly affecting memory at 3 hr after training
(short-term memory) (Lamprecht and Dudai, 1997). The MEK inhibitor also
attenuated the effect of preexposure to the novel taste in an
incidental learning situation, assayed in the latent inhibition
paradigm (see Materials and Methods). Thus, the AI of rats
microinjected with PD098059 into the insular cortex 30 min before
preexposure to saccharin 3 d prior to CTA training, and tested
3 d after training, was 90 ± 4 versus 75 ± 5 in
controls microinjected into the insular cortex with ACSF (p < 0.05) and 97 ± 4 in untreated
controls subjected to CTA training in the absence of a latent
inhibition training (n = 6-7 each). The inhibitor had
no effect on saccharin preference in noncontingent controls: the AI of
rats microinjected into the insular cortex with PD098059 30 min before
exposure to saccharin in the absence of subsequent LiCl intraperitoneal
injection, and tested for saccharin versus water preference 72 hr
later, was 43 ± 5 compared with 40 ± 5 in rats subjected to
the same protocol but microinjected into the insular cortex with ACSF
instead of PD098059 and 44 ± 4 in naive untreated rats
(n = 6 per group). These data, combined with the data
of Figure 3, also indicate that the MEK inhibitor blocks ~40% of CTA
memory at 72 or 120 hr, an effect comparable in magnitude to that of
inhibitors of protein synthesis in the insular cortex (Rosenblum et
al., 1993).
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Figure 3.
Impairment of CTA by local microinjection of the
reversible MEK inhibitor PD098059 into the insular cortex. AI values
are plotted versus time after training. Each group of animals was
tested only once at the indicated time. Filled circles,
Rats microinjected with 1 µl of 30 µM PD089059 per
hemisphere into the insular cortex 30 min before CTA training;
open circles, rats microinjected with 1 µl of ACSF
plus 1% DMSO (n = 6 each). Inset,
Spatial and temporal specificity of the inhibitor effect.
A, Control animals. B, PD098059
microinjected 2 mm above the stereotaxic coordinates used for injection
into the insular cortex. C, PD098059 microinjected into
the insular cortex 30 min before the first memory test.
n = 8 in each group.
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The MEK inhibitor also did not impair retrieval of long-term CTA memory
once formed, implying no effect on sensory, motivational, or motor
abilities required for CTA expression (Fig. 3, inset). The
effect on CTA was not observed when the inhibitor was injected 2 mm
above the insular cortex (Fig. 3, inset). When
PD098059-microinjected animals were retrained in a CTA paradigm (this
time using 1% glycine as the novel taste) 1 week after the completion
of the first CTA experiment, they displayed normal CTA (AI, 96 ± 4 vs 97 ± 5, control vs PD098059-injected animals), indicating
that the effect of the inhibitor was transient and reversible and that
the insular cortex suffered no long-term damage.
To confirm that PD098059 was indeed capable of blocking taste-induced
ERK activation in the insular cortex in vivo, we
microinjected the inhibitor 30 min before the exposure of the animals
to the novel taste, removed the insular cortex 30 min later, and
immunoblotted its homogenate as described above. We found that the
inhibitor blocked the taste-induced increase in ERK activity in
vivo (Fig. 4).
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Figure 4.
Inhibition of taste-dependent ERK1-2 activation
by PD098059 in the insular cortex. A, A representative
blot of samples of insular cortex of animals subjected to different
manipulations. Water, Animals drinking 10 ml of water;
Sacch, animals exposed to 10 ml of saccharin;
PD+Sacch, animals injected with PD098059 30 min before
the exposure to saccharin. Rats were killed 30 min after each
treatment, and the samples were blotted with anti-diphospho ERK1-2
antibodies. B, Summary of data from experiments like
those in A. Open bar, Animals exposed to
water; filled bar, animals exposed to saccharin;
shaded bar, animals microinjected into the insular
cortex with PD098059 and 30 min later presented with saccharin.
n = 4 per group.
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Elk-1, an ERK downstream substrate, was also activated by
taste experience
Elk-1 is a member of the ternary complex factor, which
together with the serum response factor (SRF) forms a multiprotein complex at the serum response element (SRE) of the c-fos promoter (Hipskind et al., 1991; Treisman, 1995). Elk-1 is rapidly
phosphorylated in response to activation of ERKs, JNKs, and p38MAPK
(Whitmarsh et al., 1995, 1997). Phosphorylation of Elk-1 increases its
ability to form a ternary complex with SRE and SRF and ultimately to
activate c-fos transcription (Janknecht et al., 1994; Gille et al.,
1995). We therefore decided to check whether this member of the
transcription factor family undergoes activation in the rat insular
cortex after sampling a novel taste. By using a specific anti-phospho
Elk-1 (Ser383) antibody, we found a taste-induced increase in the level of phosphorylation of Elk-1 (Fig. 5),
which correlated temporally with the increase of ERK activity.
Activation of Elk-1 was abolished by familiarity with the taste (Fig.
5) and was not detected in the cerebellum, occipital lobe, olfactory
bulb, and piriform cortex (data not shown).
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Figure 5.
Activation of Elk-1 in the insular cortex as a
function of time after sampling a saccharin solution as an unfamiliar
taste. Magnitude ratio is expressed as pElk-1 (saccharin)/pElk-1
(water) (filled circles), Elk-1 (saccharin)/Elk-1
(water) (open circles), or pElk-1 (saccharin)/pElk-1
(familiar saccharin) (filled square,
t = 30 min). In the latter case, the saccharin
solution was made familiar by preexposure, as detailed in the legend to
Figure 1. n = 8-12 per time point.
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Taste experience also activated JNK1-2 but not Akt kinase
or p38MAPK
JNK (also known as SAPK) was also shown to activate Elk-1
and increase c-Fos induction after exposure of cells to different agents, such as UV radiation, cytokines, and growth factors (Gille et
al., 1995; Whitmarsh et al., 1995; Su and Karin, 1996; Yang et al.,
1998). By using phospho-specific anti-JNK antibodies, we observed
activation of JNK1-2 60 min after drinking the taste solution,
subsiding to basal level within an additional 60 min (Fig.
6). The total amount of JNK remained
unaltered (Fig. 6).
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Figure 6.
Activation of JNK1-2 in the insular cortex as a
function of time after sampling a novel taste. Magnitude ratio is
expressed as dpJNK (saccharin)/dpJNK (water) or JNK (saccharin)/JNK
(water), respectively (combined values for both bands in each case).
Inset, A representative blot at t = 60 min after drinking. Filled circles, Diphospho-JNK;
open circles, total JNK. n = 9-12
per time point.
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In contrast, Akt, a serine-threonine kinase (PKB) activated by the
phosphoinositide 3-kinase (PI3-K) cascade (Marte and Downward, 1997;
Downward, 1998), and p38MAPK, the vertebrate HOG homolog (Su and Karin,
1996), were not activated in the insular cortex after drinking the
unfamiliar taste (Fig. 7). The total
amount of these two signaling kinases was not altered as well (Fig.
7).
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Figure 7.
The effect of gustatory experience on Akt and
p38MAPK in the insular cortex. A, The level of
phospho-Akt (pAkt) and total Akt as a function of
time after drinking saccharin or water. Filled circles,
pAkt; open circles, total Akt. Inset, A
representative blot at t = 30 min after drinking.
B, The level of diphospho-p38MAPK
(dp-p38MAPK) and total p38MAPK as a function of
time after drinking saccharin or water. Filled circles,
dp-p38MAPK; open circles, total p38MAPK.
Inset, A representative blot at t = 30 min after drinking. In both A and B,
n = 11-15 per time point.
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DISCUSSION |
We have approached the role of MAPKs in taste learning in the
insular cortex of the behaving rat by using two methodologies. One was
correlation of MAPK activation, quantified by immunoblotting, with a
behavioral experience. The other was inference of function from
dysfunction, using local microinjections into the insular cortex of a
reversible MAPK-kinase inhibitor. We found that the ERK signaling
cascade in the insular cortex is necessary for taste learning and that
the ERK, as well as the JNK cascade, is activated in the insular cortex
by a taste experience that results in long-term taste memory. In
contrast, other MAPKs, Akt/PKB, and p38MAPK, were unaffected. Together,
the data show that MAPK cascades are activated specifically and
differentially in taste learning in the insular cortex and that at
least part of this activation is obligatory for long-term, but not
short-term, taste memory. Several laboratories have provided evidence
that the insular cortex plays a role in taste learning and memory
(Braun et al., 1972; Dunn and Everitt, 1988; Bermudez-Rattoni and
McGaugh 1991, Gallo et al., 1992; Kiefer and Orr, 1992; Rosenblum et
al., 1993, 1997; Schafe and Bernstein, 1998). The fine delineation of
the insular cortex subregion(s) required for CTA learning, and a robust
correspondence with neuronal layers directly implicated in the
processing of taste attributes by electrophysiological analysis, must
yet be clearly established (Lasiter and Glanzman 1982; Neard et al., 1996). The role of the insular cortex in CTA is especially important in
situations in which the conditioned taste is unfamiliar (Yamamoto et
al., 1994; Rosenblum et al., 1997). Anatomical, cytotoxic, or metabolic
lesions of insular cortex inflicted during the acquisition of taste
information in CTA training usually do not abolish subsequent CTA
memory, but rather attenuate it considerably (Gallo et al., 1992;
Rosenblum et al., 1993, 1997; Yamamoto et al., 1994). This is
consistent with our data showing that inhibition of MEK activity in the
insular cortex during the taste acquisition phase of CTA training
results in a marked reduction, but not elimination, of long-term CTA
memory (see Results). The present findings thus corroborate the notion
that the insular cortex participates in the processing and storage of
information about new taste experiences and identify molecular cascades
that take part in the aforementioned processes.
Investigations of MAPKs in the nervous system often focus on cell
cultures or relatively simple preparations (for review, see Seger and
Krebs, 1995; Su and Karin, 1996). In cultured mammalian neurons, the
activation of ERKs is regulated by membrane depolarization and calcium
influx (Rosen et al., 1994), G-protein-coupled receptors (Sugden
and Clerk, 1997), and cytoskeletal reorganization (Irigoyen et al.,
1997). It is also regulated by muscarinic agonists in oligodendrocyte
progenitors (Larocca and Almazan, 1997). ERK pathways were implicated
in long-term facilitation and in apCAM learning-related internalization
in Aplysia sensory neurons (Bailey et al., 1997; Martin et
al., 1997; Michael et al., 1998), and in classical conditioning in
Hermissenda (Crow et al., 1998). Activation of p42MAPK was reported to take place in brain slices in area CA1 during hippocampal LTP, a candidate plasticity mechanism in the mammalian brain (English and Sweatt, 1996). However, to the best of our knowledge, no studies were reported on the role of the MAPK signaling cascades in learning in
vertebrates. Here, we show that activation of MAPK signaling cascades
is correlated with and critical for long-term storage of
experience-dependent information in the cortex of the behaving rat in
natural learning situations.
That the taste input did not induce massive, nondiscriminative
activation of MAPKs signaling cascades in cortex is evident from the
observation that the stress-related p38MAPK pathway, as well as the Akt
pathway involving the PI3 kinase cascade, were not affected. The
activation of the ERK pathway might involve nuclear substrates
[although an effect on a cytoplasmic substrate cannot be excluded
(Bailey et al., 1997)]. Indeed, we found that a nuclear target of
ERKs, the transcription factor Elk-1, underwent activation during
exposure of rats to a novel taste, and this activation was temporally
correlated with that of ERK. Activation of Elk-1 was recently shown to
result from electrical stimulation of the glutamatergic corticostriatal
pathway in the rat brain (Sgambato et al., 1998). ERKs, as well as JNKs
and p38MAPK, are differentially targeted to the ETS-domain of Elk-1,
resulting in a specific activation of the transcription factor,
depending on the stimulating input (Yang et al., 1998). Because we did
not observe a temporal correlation between Elk-1 and JNK activation, nor any correlation with p38MAPK, we conclude that in the insular cortex, taste-dependent Elk-1 activation depends on ERKs. As to JNKs,
their taste-dependent activation in the insular cortex might be related
to cytoskeletal reorganization (Irigoyen et al., 1997), potentially
reflecting some cellular remodeling processes.
All in all, our data indicate that novel, potentially salient taste
information activates selected sets of intracellular signaling cascades
in the insular cortex. Combinatorial stimulation of MAPKs cascades
might lead to a differential activation of transcription factors,
resulting in specific modulation of gene transcription. For example,
the interplay between ERKs and JNKs activation could result in a
differential expression of the c-Fos and c-Jun transcription factors,
members of the AP-1 transcriptional complex (Karin, 1996). Specifically, we propose that activation of the ERK signaling cascade
is related to the encoding of novelty and/or saliency during
acquisition and to the initiation of long-term storage of some aspects
of taste memory in the insular cortex. The contextual encoding of
novelty and saliency in the insular cortex during the encounter with
the unfamiliar taste, and the encoding of information about it, is
expected to involve neuromodulatory systems, e.g., the cholinergic
basal forebrain input (Naor and Dudai, 1996). A plausible model is that
activation of the cholinergic basal forebrain system, and the
subsequent release of acetylcholine in the cortex, leads to activation
of muscarinic receptors that trigger ERK activation via PKC (Bahar and
Dudai, 1997; Yasoshima and Yamamoto, 1997) or PYK2 (Lev et al.,
1995). Calcium influx via NMDA receptors, which are necessary for the
encoding (but not the retrieval) of taste memory in the insular cortex
(Rosenblum et al., 1997), might also act synergistically with the
cholinergic-dependent signal transduction cascades to activate ERKs.
The present findings could be construed as being in line with the
hypothesis that modulation of gene expression, protein synthesis, and
growth-related processes are involved in long-term experience-dependent plasticity in the nervous system (Goelet et al., 1986; Bailey and
Kandel, 1993). However, we do not know yet whether the changes that we
detect in MAPKs activation in the insular cortex indeed culminate in
modulation of gene expression and growth processes that are causally
related to the encoding of memory in that brain region. Furthermore,
substantial support for an obligatory role of gene expression in the
formation of long-term memory stems from the observation that
antibiotics that inhibit protein synthesis also inhibit memory
consolidation (Davis and Squire, 1984; Montarolo et al., 1986).
However, antibiotics, such as anisomycin, which is extensively used as
a consolidation blocker, are also potent activators of MAPKs (Kyriakis
et al., 1994). It is still to be determined whether the effects of
antibiotics on long-term memory in vivo is
attributable to their interaction with MAPKs, with the translational
apparatus, or both.
| |
FOOTNOTES |
Received June 3, 1998; revised Sept. 3, 1998; accepted Sept. 10, 1998.
This work was supported by grants from the Carl Dominic Center for
Brain Research, the Abramson Fund, and the Reich Fund. We thank Raphael
Lamprecht and Sima Lev for helpful comments on this manuscript.
Correspondence should be addressed to Dr. Yadin Dudai, Department of
Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
| |
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Top
Abstract
Introduction
