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The Journal of Neuroscience, November 1, 1999, 19(21):9570-9578
Auditory Thalamus, Dorsal Hippocampus, Basolateral Amygdala, and
Perirhinal Cortex Role in the Consolidation of Conditioned Freezing to
Context and to Acoustic Conditioned Stimulus in the Rat
Benedetto
Sacchetti,
Carlo
Ambrogi
Lorenzini,
Elisabetta
Baldi,
Giovanna
Tassoni, and
Corrado
Bucherelli
Dipartimento di Scienze Fisiologiche, Viale G.B. Morgagni 63, I-50134 Florence, Italy
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ABSTRACT |
On the basis of previous experimental evidence, it is known that
the auditory thalamus (AT), the dorsal hippocampus (DH), the
basolateral amygdala (BLA), and the perirhinal cortex (PC) are involved
in the mnemonic processing of conditioned freezing. In particular, BLA
and PC appear to be involved both in conditioned stimulus (CS) and
context conditioned freezing. Through AT, the auditory CS is sent to
other sites, whereas DH is involved in context conditioning.
Nevertheless, the existing evidence does not make it possible to assess
AT, DH, BLA, and PC involvement during the consolidation phase of
conditioned freezing. To address this question, fully reversible
tetrodotoxin (TTX) inactivation was performed on adult male Wistar rats
having undergone CS and context fear training. Anesthetized animals
were injected stereotaxically with TTX (either 5 or 10 ng in 0.5 or 1.0 µl of saline, according to site dimensions) at increasing
post-acquisition delays. Context and CS freezing durations were
measured during retention testing, always performed 48 and 72 hr after
TTX administration. The results showed that AT inactivation does not
disrupt consolidation of either contextual or auditory fear memories.
In contrast, inactivation of the other three structures disrupted
consolidation. For the DH, this disruption was specific to contextual
cues and only occurred when inactivation was performed early (up to 1.5 hr) after training. The BLA and PC were shown to be involved in the
consolidation of both contextual and auditory fear. Their involvement
persisted for longer periods of time (2 d for BLA and 8 d for PC).
These findings provide information to build a temporal profile for the post-training processing of fear memories in structures known to be
important for this form of learning. The results are discussed in
relation to previous studies on conditioned freezing and other aversive
conditioned response neural correlates.
Key words:
reversible tetrodotoxin inactivation; CS and context
freezing; consolidation; auditory thalamus; dorsal hippocampus; basolateral amygdala; perirhinal cortex
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INTRODUCTION |
In pavlovian fear conditioning, the
unconditioned stimulus (US), e.g., electrical footshocks, becomes
associated not only with an appropriate conditioned stimulus (CS) but
also with the environment in which the punishment is administered,
i.e., the training context. This means that the conditioned subjects,
for instance rats, will exhibit significant conditioned fear to both CS
and context. Their fear may be conveniently and separately measured as
conditioned freezing duration (Kim and Fanselow, 1992 ; Rudy and
Morledge, 1994; Oler and Markus, 1998; Sacchetti et al., 1999).
When an acoustic CS is used in fear conditioning, several neural sites
are thought to be involved in conditioned freezing learning: the
auditory thalamus (AT), primarily involved in acoustic input processing
(LeDoux et al., 1983, 1986; Romanski and LeDoux, 1992), the dorsal
hippocampus (DH), involved in context conditioning (Kim and Fanselow,
1992; Phillips and LeDoux, 1992; Rudy and Morledge, 1994; Maren, 1998),
the basolateral amygdala (BLA) (Phillips and LeDoux, 1992; Maren and
Fanselow, 1995, 1996; Maren et al., 1996; Muller et al., 1997), and the
perirhinal cortex (PC) (Corodimas and LeDoux, 1995; Suzuki, 1996), the
latter two playing a role in CS and context conditioning. These
functional attributions are based almost exclusively on irreversible
lesions results. The irreversible lesion technique does not make it
possible to define in which of the putative phases of mnemonic
processing (acquisition, consolidation, or storage-retrieval) a given
site plays an active role (Bures and Buresova, 1990). Other, and
possibly more exhaustive, information can be obtained by means of the
reversible inactivation technique. This technique makes it possible to
reversibly inactivate a given neural site during any of the putative
mnemonic phases without interfering with the other ones, thus defining the mnemonic role of a given site phase by phase (McGaugh, 1966; Bures
and Buresova, 1990; Ambrogi Lorenzini et al., 1997, 1998a, 1999).
Concerning the conditioned freezing responses, of the above mentioned
sites only BLA has been investigated by means of the reversible
inactivation technique and this only during acquisition and retrieval
(Helmstetter, 1992; Fanselow and Kim, 1994; Muller et al., 1997).
Therefore, it appears that, as of now, not much is known about the role
played by AT, DH, BLA, and PC in fear mnemonic processing taking place
between acquisition and retrieval, i.e., during consolidation, when the
engram is modified from a short-term one to a long-term one, to be
subsequently stored (McGaugh, 1966; Dudai, 1996; Nadel and Moscovich,
1997).
The aim of the present work is to obtain information on consolidation
processing of CS and context conditioned freezing. As stated above, the
reversible inactivation performed in this mnemonic phase makes it
possible to evaluate the role of a chosen structure in conditioned
freezing consolidation without interfering with either antecedent
(acquisition) or subsequent (storage and/or retrieval) phases. AT, DH,
BLA, and PC are reversibly inactivated bilaterally by means of the
stereotaxic administration of tetrodotoxin (TTX) performed at
increasing post-acquisition delays in rats having undergone fear
conditioning to an acoustic CS and to the context. In this way, it is
possible to follow the chronological evolution of CS and context engram
consolidative processing to address the question of whether or not both
follow the same neural and chronological pattern.
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MATERIALS AND METHODS |
Animals
Seventy-day-old male albino Wistar rats (average body weight of
290 gm) (Morini, S. Polo D'Enza, Italy) were used. The animals were individually housed in stainless steel cages in a room with a
natural light/dark cycle and constant temperature of 20 ± 1°C. The rats had access to food and water ad libitum throughout
the experiment. All animal care and experimental procedures were
conducted in accordance with the Italian legislation and the official
regulations of the European Communities Council on use of laboratory
animals (Directive of November 24, 1986; 86/609/EEC).
Behavioral procedures
Apparatus. A basic Skinner box module (Modular
Operant Cage; Coulbourn Instruments, Allentown, PA) was used to
induce freezing. Box dimensions were 29 × 31 × 26 cm. The
top and two opposite sides were made of aluminum panels. The other two
sides were made of transparent plastic. The floor was made of stainless
steel rods connected to a shock delivery apparatus (Grid Floor Shocker, model E13-08; Coulbourn Instruments Inc.). There was a loudspeaker to
emit acoustic stimuli of known intensity, frequency, and duration. The
apparatus was connected to a stimulus programming device (Scatola di
comando Arco 2340; Ugo Basile) to predetermine number, duration, and
rate of CS-US couplings. The apparatus was placed in an acoustically insulated room (3.5 × 1.8 × 2.1 m), kept at a constant
temperature of 20 ± 1°C. Illumination inside the room was 60 lux.
Context freezing response was measured in the same apparatus that had
been used for conditioning. Freezing response to explicit CS (sound)
was measured in a totally different apparatus from that used for
conditioning. The apparatus was a modified shuttle box apparatus (Ugo
Basile) (20 × 47 × 20 cm). The walls were made of gray
opaque plastic with black vertical stripes (width of 1 cm, spaced 3 cm
apart). The lid was made of transparent plastic and the floor of black
opaque plastic. In the apparatus, there was a loudspeaker to administer
acoustic stimuli to the experimental subjects. The apparatus was
connected to a stimulus programming unit (Automatic Reflex Conditioner
7501; Ugo Basile) to predetermine CS (number of stimuli, duration of
stimuli, and rate of stimulation). The unit could also predetermine
intensity and frequency of the acoustic stimulus. The apparatus was
placed in an acoustically insulated room (3.5 × 3.6 × 2.1 m) kept at a constant temperature of 20 ± 1°C.
Illumination inside the room was 10 lux.
Conditioning. On day 1, the rat was gently taken
manually from the home cage, placed in a bucket, and carried from the
housing room to the appropriate soundproofed room. Once
there, it was placed inside the conditioning apparatus. The rat was
left undisturbed for 3 min. After this time, CS as an 800 Hz tone from
a frequency generator, amplified to 75 dB (Phillips and LeDoux, 1992;
Sacchetti et al., 1999) lasting 6 sec was administered seven times, at
30 sec intervals. The last 1 sec of each CS was paired with the US as
electric footshock. US intensity was 0.5 mA, as in previous experiments (Sacchetti et al., 1999). Two minutes after the end of the
stimulation pattern, the rats were brought back to the home cage.
Conditioned freezing measurement. Freezing duration was
measured 48 and 72 hr after TTX or saline administration. To measure contextual freezing, the animals were again placed inside the conditioning apparatus and left there for 3 min. While they were there,
neither electrical nor acoustic stimuli were administered. After that
time, they were brought back to the home cage. Rats' behavior was
recorded by means of a closed circuit television system. To measure CS
freezing, the animals were placed in the other apparatus to avoid the
facilitation of CS retention caused by contextual cues (Balaz et
al., 1982; Corodimas and LeDoux, 1995; Oler and Markus, 1998). Once
inside the apparatus, the animal was left undisturbed for 3 min. After
this time, during a subsequent second 3 min period, a series of seven
acoustic stimuli was administered, identical to those used during the
conditioning session (frequency, intensity, duration, and intervals
between stimuli). By means of a closed circuit television system,
rats' behavior was recorded for the entire 6 min period, after which
the animals were brought back to the home cage. Rats of each group were
divided in two subgroups (four to six animals). As in previous
experiments (Sacchetti et al., 1999), one subgroup was tested for
context freezing on the first day and for CS freezing the day after,
whereas the other followed a specular schedule (context, first day; CS,
second day). This schedule was used to ensure that the exposure of all
the subjects first to context and secondly to CS, or vice versa, would not bias the retention of the two responses (Winocur, 1997).
Freezing (immobility) was defined as the complete absence of somatic
motility, respiratory movements excepted (LeDoux et al., 1983).
Measurements were performed by means of a stopwatch by personnel that
did not known to which experimental group each animal belonged. Total
cumulated freezing time (i.e., total seconds spent freezing during each
3 min period) was measured.
Surgery and drug administration
Functional inactivation of the chosen structure was induced by
the administration of either 5 or 10 ng of TTX (Sigma, Milano, Italy), dissolved in 0.5 or 1.0 µl of saline, respectively,
into points with stereotaxic coordinates obtained from the atlas of Paxinos and Watson (1986). Mean inactivated nervous tissue radius after
TTX administration was estimated at 1 mm for 10 ng and 0.7-0.8 mm for
5 ng of TTX injection (Zhuravin and Bures, 1991; Ambrogi Lorenzini et
al., 1995) (Fig. 1). At least 20 min were
necessary to reach maximal neural inactivation. Inactivation lasted no
less than 120 min, exponentially decreasing and disappearing completely within 24 hr (Zhuravin and Bures, 1991). TTX was injected under general
anesthesia (ketamine, 100 mg/kg, i.p.) at different post-acquisition intervals for each group of animals. Rats were held in the stereotaxic apparatus. The injection needle (outside diameter, 0.3 mm), connected with a short piece of polyethylene tubing to a Hamilton syringe, was
fixed in the electrode holder of the stereotaxic apparatus and
introduced into the target structure. Either 0.5 or 1.0 µl of the
solution was injected over a 1-2 min period, and the needle was left
in place for another 1 min before it was slowly withdrawn.
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Figure 1.
Extension of TTX inactivation of PC, BLA, DH, and
AT, estimated on the basis of injection sites ( , end of
needle tracks) and on known characteristics of TTX diffusion (see
Materials and Methods). Plates adapted from the atlas of Paxinos and
Watson (1986).
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TTX was bilaterally injected in all experiments. Control group rats
were injected bilaterally with saline.
Detailed methods
Shocked and not shocked control animals. Two control
groups of animals not submitted to surgery (eight rats in each group) underwent the same conditioning procedure, one receiving the electric footshocks and the other not receiving the electric footshocks. Retention testing was performed 4 and 5 d after acquisition trial.
Post-acquisition AT inactivation. AT functional inactivation
was induced by injection of 5 ng of TTX into points with the following
stereotaxic coordinates: anteroposterior (AP),  5.6; lateral (L), 3.3;
and ventral (V), 5.8 according to Paxinos and Watson (1986) (Figs. 1,
2). Different groups of animals were
injected at diverse post-acquisition delays. A total of 65 rats were
randomly divided into six groups: TTX-injected (T) and saline-injected (S) at three different post-acquisition delays of 0.25, 1.5, and 6 hr. Because of inadequate morphological evidence, 10 animals were
excluded. The remaining 55 animals made up the following groups, each
group ranging between 8 and 11 animals: T-0.25, S-0.25, T-1.5, S-1.5,
T-6, and S-6.
Post-acquisition DH inactivation. As described previously
(Ambrogi Lorenzini et al., 1996), DH functional inactivation was induced by the injection of 10 ng of TTX into points with the following
stereotaxic coordinates: AP, 4.1; L, ±2.5; and V, 3.1 according to
Paxinos and Watson (1986) (Figs. 1, 2). Different groups of animals
were injected at diverse post-acquisition delays. A total of 84 rats
were randomly divided into eight groups: TTX-injected and
saline-injected at four different post-acquisition delays of 0.25, 1.5, 6, and 24 hr. Because of inadequate morphological evidence, 12 animals
were excluded. The remaining 72 animals made up the following groups,
each group ranging between 8 and 11 animals: T-0.25, S-0.25, T-1.5,
S-1.5, T-6, S-6, T-24, and S-24.
Post-acquisition BLA inactivation. BLA functional
inactivation was induced by the injection of 5 ng of TTX into points
with the following stereotaxic coordinates: AP, 3; L, ±4.8; and V, 8.7 according to Paxinos and Watson (1986) (Figs. 1, 2). Different groups of animals were injected at diverse post-acquisition delays. A
total of 141 rats were randomly divided into 14 groups: TTX-injected and saline-injected at seven different post-acquisition delays of 0.25, 1.5, 6, 24, 48, 96, and 192 hr. Because of inadequate morphological
evidence, 14 animals were excluded. The remaining 127 animals made up
the following groups, each group ranging between 8 and 11 animals:
T-0.25, S-0.25, T-1.5, S-1.5, T-6, S-6, T-24, S-24, T-48, S-48, T-96,
S-96, T-192, and S-192.
Post-acquisition PC inactivation. As described previously
(Ambrogi Lorenzini et al., 1998b), partial PC functional inactivation, centered between anterior and posterior PC limits, was induced by
injection of 5 ng of TTX into points with the following stereotaxic coordinates: AP, 2.6; L, ±6.1; and V, 7 according to Paxinos and
Watson (1986) (Figs. 1, 2). Different groups of animals were injected
at diverse post-acquisition delays. A total of 158 rats were randomly
divided into 16 groups: TTX-injected and saline-injected at eight
different post-acquisition delays of 0.25, 1.5, 6, 24, 48, 96, 192, and
384 hr. Because of inadequate morphological evidence, 18 animals were
excluded. The remaining 140 animals made up the following groups, each
group ranging between 8 and 11 animals: T-0.25, S-0.25, T-1.5, S-1.5,
T-6, S-6, T-24, S-24, T-48, S-48, T-96, S-96, T-192, S-192, T-384, and
S-384.
Statistical analysis
One-way ANOVA, mixed ANOVAs, with treatment (TTX and saline) and
different post-acquisition delays as a between-subjects variable and
context and CS freezing as a within-subjects variable, and Newman-Keuls multiple comparisons test were used.
Morphology
At the end of the experiments, injected sites were
histologically verified. Rats were deeply anesthetized and
intracardially perfused with saline, followed by 4% formaldehyde.
Brains were cut with a freezing microtome, and injection needle tracks
were identified in Nissl-stained serial sections (Fig. 2). Subjects whose histological evidence was not adequate were excluded from data processing.
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RESULTS |
All groups of animals were divided into two subgroups, which were
respectively measured for CS or context freezing in the 2 d of
testing (see Materials and Methods). Because there were no significant
statistical differences between subgroups, it was possible to
statistically elaborate the cumulated freezing results (to CS and to
the context) of the first and second day, so that final statistical
analysis was performed on groups of rats ranging between 8 and 12 animals.
Control groups
All control saline-injected groups (Figs.
3-7)
showed conditioned responses quantitatively comparable with those of
conditioned control unoperated groups (Fig. 3). Context and CS freezing
responses were well developed against the very poor response of animals not subjected to footshocks (Fig. 3) and did not significantly decrease
18 d after the conditioning session (PC S-384 group) (Fig. 7). In
particular, CS freezing response was higher than context freezing
response (Fig. 3). Mixed ANOVAs (2 × 2) showed that there were
differences for different responses (CS and context) (F(1,28) = 4.84; p < 0.05) and for treatment (shocked and nonshocked) (F(1,28) = 26.34; p < 0.001). There were significant interactions between responses and
treatments (F(1,28) = 4.65;
p < 0.05). Post hoc Newman-Keuls test
showed that there were significant differences between CS and context
freezing (p < 0.05). During the first 3 min
subperiod of exposure to the new context (without CS, acoustic stimulation), the freezing response was very low in all groups of
animals and comparable with that of the control group that had not
received the footshocks (12.3% freezing of total exposure time). These
results show the absence of generalization phenomena and the
specificity of the freezing response to the CS in this new context.
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Figure 3.
CS and context freezing in unoperated control
(shocked and nonshocked) rat groups. Mean ± SEM freezing as
percentage of total time during retention testing in the conditioning
apparatus without acoustic stimulation (context) and in the other
apparatus with acoustic stimulation (CS). *p < 0.05, significant statistical differences between the conditioned
responses.
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Figure 4.
Effects of auditory thalamus bilateral TTX
inactivation at increasing post-acquisition delays (0.25, 1.5, and 6 hr). Black columns, TTX-injected groups. White
columns, Saline-injected groups. Mean ± SEM context and
CS total freezing duration during retention testing. For explanation,
see Figure 3.
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Figure 5.
Effects of dorsal hippocampus bilateral TTX
inactivation at increasing post-acquisition delays (0.25, 1.5, 6, and
24 hr). *p < 0.05, significant statistical
differences between treated and respective control groups. For
explanation, see Figure 4.
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Figure 6.
Effects of basolateral amygdala bilateral TTX
inactivation at increasing post-acquisition delays (0.25, 1.5, 6, 24, 48, and 96 hr). *p < 0.05, significant statistical
differences between treated and respective control groups. For
explanation, see Figure 4.
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Figure 7.
Effects of perirhinal cortex bilateral TTX
inactivation at increasing post-acquisition delays (0.25, 1.5,.6, 14, 48, 96, 192, and 348 hr). *p < 0.05, **p < 0.01, significant statistical differences
between treated and respective control groups. For explanation, see
Figure 4.
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Auditory thalamus
After AT reversible inactivation at all three post-acquisition
delays (0.25, 1.5, and 6 hr), neither CS freezing nor context freezing
responses were impaired (Fig. 4). Mixed ANOVAs (2 × 2 × 3)
showed that there were differences for different responses (F(1,98) = 11.9; p < 0.001) but not for treatment (F(1,98) = 2.01; NS) or for time lapsed from acquisition training
(F(2,98) = 0.25; NS). There were no
significant interactions. In all of the six groups, freezing duration
during the first 3 min in the new context without CS presentation
ranged between 11.7 and 15.6% of total time. One-way ANOVA showed that
there were no significant differences between groups
(F(5,49) = 0.62; NS), thus showing
that AT inactivation did not determine generalization phenomena.
Dorsal hippocampus
After DH inactivation, context freezing response was impaired up
to the 1.5 hr post-acquisition delay. On the other hand, CS freezing
response was never impaired (Fig. 5). Mixed ANOVAs (2 × 2 × 4) showed that there were differences for different responses (F(1,129) = 23.3; p < 0.001) and treatments (F(1,129) = 12.5; p < 0.001) but not for time lapsed from
acquisition training (F(3,129) = 0.74;
NS). There were significant interactions between responses and
treatments (F(1,129) = 7.48;
p < 0.01), responses and intervals (F(3,129) = 3.1; p < 0.05), and treatments and intervals
(F(3,129) = 3.3; p < 0.05). The post hoc Newman-Keuls test showed that there were significant differences between groups T-0.25 and T-1.5 and the
respective control groups (S-0.25 and S-1.5); p < 0.05 in both cases (Fig. 5). In the eight groups, freezing duration
during the first 3 min in the new context without CS presentation
ranged between 10.4 and 14.3% of total time. One-way ANOVA showed that there were no significant differences between groups
(F(7,64) = 0.75; NS), thus showing
that DH inactivation did not determine generalization phenomena.
Basolateral amygdala
After BLA reversible inactivation, context and CS freezing
responses were impaired up to the 48 hr post-acquisition delay (Fig.
6). Mixed ANOVAs (2 × 2 × 7) showed that there were
differences for different responses
(F(1,226) = 37.23; p < 0.001), treatments (F(1,226) = 71.34; p < 0.001), and time lapsed from acquisition training (F(6,226) = 3.08;
p < 0.01). There were significant interactions between
time lapsed and treatments (F(6,226) = 2.62; p < 0.05). The post hoc Newman-Keuls
test showed that there were significant differences between T-0.25,
T-1.5, T-6, T-24, and T-48 groups and the respective controls (S) for
both CS freezing response (p < 0.05 in all
instances) and context freezing response (p < 0.05 in all instances) (Fig. 6). In the 14 groups, freezing duration during the first 3 min in the new context without CS presentation ranged between 12.3 and 15.6% of total time. One-way ANOVA showed that
there were no significant differences between groups
(F(13,113) = 0.44; NS), thus showing
that BLA inactivation did not determine generalization phenomena.
Perirhinal cortex
After PC reversible inactivation, context and CS freezing
responses were impaired up to the 192 hr post-acquisition delay (Fig.
7). Mixed ANOVAs (2 × 2 × 8) showed that there were
differences for different responses
(F(1,248) = 31.14; p < 0.001), treatments (F(1,248) = 217.01; p < 0.001), and time lapsed from acquisition training (F(7,248) = 2.81;
p < 0.01). There were significant interactions between
responses and treatments (F(1,248) = 5.16; p < 0.05) and treatments and times lapsed
(F(1,248) = 3.19; p < 0.01). The post hoc Newman-Keuls test showed that there
were significant differences between groups T-0.25, T-1.5, T-6, T-24,
T-48, T-96, and T-192 and the respective control groups (S) both for
context freezing (p < 0.01 at 0.25;
p < 0.05 in all other instances) and CS freezing (p < 0.05 in all instances) (Fig. 7). In the 16 groups, freezing duration during the first 3 min in the new context
without CS presentation ranged between 13.4 and 16.7% of total time.
One-way ANOVA showed that there were no significant differences between groups (F(15,124) = 0.71; NS), thus
showing that PC inactivation did not determine generalization phenomena.
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DISCUSSION |
After the single session acquisition paradigm, all control groups
(operated and unoperated) exhibited very good conditioned freezing
responses to both CS and context, the former being stronger than the
latter (Fig. 3) (Phillips and LeDoux, 1992; Sacchetti et al., 1999).
The fact that unoperated groups (Fig. 3) and control groups subjected
to general anesthesia and injected saline (Figs. 4-7) exhibited quite
similar responses once more confirms that post-trial anesthesia does
not influence retention (Ambrogi Lorenzini et al., 1996, 1997). The
present results confirm the effectiveness of the single-trial paradigm
used, the 0.5 mA footshock intensity being sufficient to condition the
subjects (Sacchetti et al., 1999). The present results are well
comparable with previous ones obtained using conditioning paradigms
quite similar to those presently used. It has been reported, in fact,
that experimental subjects exhibit good and robust CS and context fear
conditioning lasting for months (Oler and Markus, 1998). Moreover, the
short total freezing duration during the first 3 min subperiod (new
context) exhibited by all control groups shows that this paradigm did
not induce generalization phenomena (Sacchetti et al., 1999). This result shows that the separately measured freezing responses are directly related to either one of the two specific mnemonic traces (CS
and context), other factors, if any, being negligible (Kim and
Fanselow, 1992; Sacchetti et al., 1999).
Indeed, a single acquisition session paradigm is the necessary
prerequisite for the investigation of the chronological evolution of
the involvement of a given neural structure in engram consolidation. In
fact, in multitrial acquisition paradigms, it is impossible to define
the subsequent mnemonic phases temporally, i.e., to determine exactly
when consolidation begins (Bures and Buresova, 1990; Ambrogi Lorenzini
et al., 1997). To ascertain consolidation chronology, reversible TTX
inactivations were performed at increasing post-acquisition delays.
Retention testing was always performed 48 hr after TTX administration.
This schedule ensures that the several investigated neuronal sites were
inactivated only during consolidation, without interfering with
acquisition (the inactivation was performed after acquisition)
or retrieval; retention testing was always performed when there were no
residual TTX effects (Zhuravin and Bures, 1991). Moreover, we must bear
in mind that DH, BLA, and PC support some spontaneous behaviors. In
fact DH, controls unconditioned freezing (Blanchard et al., 1970;
Blanchard and Blanchard, 1972b; McNish et al., 1997), BLA supports
unconditioned freezing (Blanchard and Blanchard, 1972a; Davis, 1992),
and PC controls spontaneous startle reactions (Rosen et al., 1992).
This means that the functional absence of these structures during
retrieval testing may have the same effect on unconditioned aversive
behaviors; therefore, there could be some unwanted interference with
the observable freezing response. On the other hand, AT being a crucial pathway for auditory input distribution (LeDoux et al., 1985, 1987) its
inactivation makes it impossible for the acoustic information to reach
the relevant sites. In the present experimental design, AT, DH, BLA,
and PC were selectively inactivated only during the post-acquisition
phase (to selectively study the consolidation of CS and/or context
memory traces), thus avoiding possible masking effects.
On the basis of administration site accuracy and TTX diffusion radius
estimation (see Materials and Methods), it can be stated that TTX
inactivated the chosen sites selectively, without significantly affecting adjacent brain structures (Figs. 1, 2). Indeed, the different
chronological involvement of the investigated neural sites in
memorization processing indicates that the observed effects of TTX
inactivation are not attributable to a nonspecific and diffuse
alteration of cerebral function but are directly related to the
inactivation of distinct neural structures. The absence of
generalization phenomena in all TTX-injected groups shows that the
intracerebral administration of this compound does not induce behavioral modifications and/or illness that may cause generalized aversion.
The present results show that, during consolidation, AT is not
necessary for the mnemonic processing of CS and context freezing responses. Because TTX inactivated the whole site, the lack of amnesic
effects cannot be imputed to its partial inactivation (Fig. 1). Good
context response retention confirms that AT is not necessary to
memorize nonauditory inputs (LeDoux et al., 1986). On the other hand,
it has been reported that AT irreversible lesions, performed in either
pre-acquisition (LeDoux et al., 1983, 1986; Romanski and LeDoux, 1992)
or post-acquisition (Jarrell et al., 1986), were followed by amnesia
specific to an acoustic CS. The present findings show that these
effects cannot be caused by the absence of AT activity during
consolidation. Rather, the reported amnesia could be caused by the
exclusion of AT during acquisition and/or retrieval. In fact, it has
been repeatedly stated that AT is involved in both the transmission of
sensory inputs to neocortical areas (e.g., auditory cortex, PC) (LeDoux
et al., 1983, 1985; Romanski and LeDoux, 1992), as well as to other
subcortical structures (amygdala) (LeDoux et al., 1983, 1985; Romanski
and LeDoux, 1992), and CS-US association (Cruikshank et al., 1992;
McEchron et al., 1995). If this is true, AT may be of importance as an
acoustic stimuli (CS) relay station toward subcortical and cortical
structures, possibly for CS-US coupling, but not for the subsequent
consolidation process. It may be underlined that this conclusion could
not be reached on the basis of irreversible lesions results.
The present findings not only confirm that DH is involved in contextual
and not in CS memorization (Black et al., 1977; Kim and Fanselow, 1992;
Phillips and LeDoux, 1992; Oler and Markus, 1998) but precisely define
DH temporal involvement in contextual consolidation, the site being
necessary only in the early period of this memorization phase. In
contrast, BLA is necessary for both CS and context freezing response
consolidation up to 2 d after acquisition. As far as we know, BLA
involvement in the consolidation of conditioned freezing responses has
never been reported before. Previously, BLA reversible inactivation was
performed only during acquisition (Helmstetter, 1992; Fanselow and Kim,
1994; Muller et al., 1997) or retrieval (Helmstetter, 1992; Muller et
al., 1997). In these mnemonic phases, BLA was found to be necessary for
both CS and context learning (Helmstetter, 1992; Fanselow and Kim,
1994; Muller et al., 1997). Partial PC reversible inactivation disrupts
fear conditioning consolidation. PC inactivation shows that this site
is necessary for both CS and context fear response learning, up to
8 d after acquisition. The present results provide the
chronological quantification of PC involvement besides confirming previous qualitative findings; when PC was irreversibly damaged some
days after the acquisition session, amnesia specific to acoustic CS
freezing (Corodimas and LeDoux, 1995), context freezing (Corodimas and
LeDoux, 1995), and CS startle response (Rosen et al., 1992; Campeau and
Davis, 1995) was observed.
Thus, an early period (up to 1.5 hr) of freezing response consolidation
may be defined. In it, DH, BLA, and PC all appear to be necessary for
contextual learning processing, and BLA and PC both appear to be
necessary to learn the response to an acoustic CS. During the following
2 d, BLA and PC are equally necessary for the memorization of both
responses. In the last and longer lasting period of consolidation (up
to 8 d), only PC appears to be necessary for the memorization of
both responses. This may suggest that, during early consolidation, each
site critically processes a particular component (facet) of the
engrams. In other words, during early consolidation, CS and context
engram elaboration may not be a sequential process, migrating from one
site to another (e.g., CS from BLA to PC; context from DH to BLA and
finally to PC), but rather a complex process requiring the simultaneous
participation of DH, BLA, and PC. We may recall that, by means of
irreversible lesion techniques, DH and BLA were shown to be involved in
fear conditioning memory processing for days and weeks after
acquisition (Kim and Fanselow, 1992; Maren et al., 1996; Frankland et
al., 1998; Maren, 1998). Moreover, it was reported that irreversible hippocampal damage is followed by place memory impairment. The impairment became progressively less severe with the increase of the
delay between the acquisition trial and the irreversible damage (from 1 to 12 weeks). From these results, a progressive involvement of cortical
areas in place memory was inferred (Sutherland et al., 1987). Possibly,
all these results were attributable to some interference with storage
and/or retrieval processes rather than with elaborative and
consolidative ones. This contention is based on the present results; if
TTX was administered at post-acquisition delays longer than a few hours
(DH) or a few days (BLA), memory disruption was not observed.
It has been stated that no less than 6 hr are necessary to build an
adequate contextual representation (Rudy and Morledge, 1994). DH
appears to be actively involved in the period during which the diverse
sensorial inputs must be integrated to compose the coherent
representation of the training environment. For subsequent long-term
consolidation and memorization, DH would no longer be necessary.
Indeed, the short DH context involvement duration throws doubt on the
hypothesis that DH is necessary for context representation storage, in
accord with previous statements (Otto et al., 1997). On this point, we
may also recall that, in rats, a modification of electrical hippocampal
activity (EPSP, population spike) was observed after exposure to new
surroundings; the modification began during training and disappeared
after 1 or 2 hr (Green et al., 1990). On the other hand,
electrophysiological results obtained both in vitro
(McKernan and Shinnick-Gallagher, 1997) and in vivo (Rogan
et al., 1997) have shown that, after acquisition, there are in the BLA
long-lasting modifications of electrical activity believed to be
related to CS-US coupling. The longer BLA and PC involvement (days and
not hours) may also indicate that these structures are involved in the
storage of both contextual representation and CS-US association, as
suggested previously (Davis, 1992; Corodimas and LeDoux, 1995; Maren
and Fanselow, 1996; Maren et al., 1996; Rogan et al., 1997; Maren,
1998). In particular, the longer PC involvement may mean that, during
the late period of consolidation, the information processed by DH and
BLA may go to PC, this last being the site involved for the longest
time in the elaboration of both engrams. This hypothesis is in
concordance with previous statements, i.e., that PC is "involved in
cortical storage of information acquired through various systems,
including the explicit or declarative memory system of the hippocampal
formation and the emotional memory system involving the amygdala"
(Corodimas and LeDoux, 1995). In fact, CS and context fear conditioning
need a consolidation phase lasting several days. If a long duration could have been surmised for context conditioning, it appears less
easily understandable for CS learning. Context conditioning is based on
several sensory inputs, which have to be associated and integrated to
build a complex, interrelated representation, requiring an elaboration
that may indeed last hours and even days (Rudy and Morledge, 1994).
Conversely, the association process involving a single sensorial input,
the CS, and the US, could be assumed to be simpler and shorter lasting.
On the contrary, the present findings show that this association
process is still going on several days later. Concerning the
chronological evolution of the two engrams, the finding that DH
integrity is necessary only for the context engram suggests that CS and
context engrams may be separately processed. On the other hand, at all
the longest post-acquisition delays, the two engrams appear to be still
actively processed together, following a similar chronological pattern in BLA and PC. Maybe the two engrams are processed in parallel and are
eventually coupled in a complete and integrated representation of the
aversive event.
Some considerations on the functional relationships between DH, BLA,
and PC may be presented. Regarding PC and DH, both sites were found to
be involved in context response consolidation, PC being involved much
longer than DH. Moreover, it was shown that PC, but not DH, is also
involved in CS freezing response consolidation. These data may mean
that PC is not simply a connecting route between DH and neocortex but
plays an autonomous role. In this connection, it may be underlined that
DH and PC were found to be differentially involved in the learning
process of other experimental paradigms. For instance, DH and PC were
found to be involved in spatial paradigm learning (Black et al., 1977;
Morris et al., 1986; Wiig and Bilkey, 1995; Suzuki, 1996; Ennaceur and
Aggleton, 1997; Otto et al., 1997; Liu and Bilkey, 1998), but in the
same paradigms, it was shown that PC is involved also in nonspatial
information learning (Ennaceur and Aggleton, 1997; Wiig and Bilkey,
1995), whereas DH is not (Black et al., 1977; Morris et al., 1986; Wiig
and Bilkey, 1995). If we bear in mind that contextual learning is often
considered as an elementary type of spatial learning (Black et al.,
1977; Nadel and Willner, 1980), the present findings on DH and PC
involvement in conditioned fear learning are coherent with previous
results obtained when spatial and nonspatial tasks were to be learned. Regarding BLA and PC, it cannot be excluded that PC acts as a connecting relay between amygdala and neocortex, as proposed previously (Rosen et al., 1992; Campeau and Davis, 1995), but it appears likely
that the PC role in late consolidation may be distinct from, and
independent from, that of BLA. It may be underlined that, although it
is generally accepted that in fear conditioning paradigms BLA plays a
key role (Davis, 1992; Maren and Fanselow, 1996; Maren et al., 1996;
Maren, 1998), the present findings show that, within consolidation, PC
is at least equally important. The present PC characterization is of
interest because only very few experimental reports on the respective
and related functions of BLA and PC are available and because so far
the functional importance of PC had been assessed using experimental
paradigms in which BLA did not appear to play a significant role
(delayed nonmatching to sample, object retention, and concurrent
discrimination) (Zola-Morgan et al., 1989; Meunier et al., 1993;
Gaffan, 1994; Wiig and Bilkey, 1994; Suzuki, 1996).
The roles of DH, BLA, and PC have been investigated in the learning of
another aversive conditioned response, the passive avoidance response
(PAR). It has been shown that DH and BLA are involved in PAR
consolidation up to 1.5 hr after acquisition (Bucherelli et al., 1992;
Parent and McGaugh, 1994; Ambrogi Lorenzini et al., 1996) and PC up to
8 d after acquisition (Ambrogi Lorenzini et al., 1998b). There is
an evident similarity between the temporal involvement of DH and PC
during the consolidation phase of conditioned freezing and PAR. This
similarity may suggest that, in aversive learning, these two structures
play a role that is not so much qualitatively related to the response
to be learned as functionally constant. On the other hand, BLA is
differently involved in PAR and freezing consolidation. It has been
surmised repeatedly that the function of BLA is quite strictly related
to the emotive characteristics of the used paradigms (Davis, 1992;
McGaugh et al., 1995; Maren and Fanselow, 1996). It could very well be
that this functional specificity explains the diverse findings (Davis,
1992; McGaugh et al., 1995; Maren and Fanselow, 1996; Maren, 1998). In
fact, although fear conditioning and PAR may seem to be superficially similar, on the contrary they appear to activate or require quite different neural mechanisms. In particular, in the PAR paradigm, the
avoidability of US may influence the emotive involvement of the animal
and consequently cause an unequal BLA involvement. In fact, it has been
proposed that BLA is necessary for the storage of fear conditioning
(Davis, 1992; Maren and Fanselow, 1996; Maren et al., 1996; Maren,
1998) but not for PAR storage (McGaugh et al., 1995, 1996). On this
point, the shorter temporal involvement of BLA in consolidation for PAR
(Bucherelli et al., 1992) than for fear conditioning could reflect its
different role in the storage process.
| |
FOOTNOTES |
Received April 30, 1999; revised July 21, 1999; accepted Aug. 11, 1999.
We thank A. Aiazzi, S. Cammarata, M. Dolfi, and A. Vannucchi for their
technical assistance.
Correspondence should be addressed to Prof. Corrado Bucherelli,
Dipartimento di Scienze Fisiologiche, Viale G. B. Morgani 63, I-50134 Florence, Italy. E-mail: ambuc{at}cesit1.unifi.it.
| |
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E. L. Malin and J. L. McGaugh
Differential involvement of the hippocampus, anterior cingulate cortex, and basolateral amygdala in memory for context and footshock
PNAS,
February 7, 2006;
103(6):
1959 - 1963.
[Abstract]
[Full Text]
[PDF]
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B. Sacchetti, B. Scelfo, and P. Strata
The Cerebellum: Synaptic Changes and Fear Conditioning
Neuroscientist,
June 1, 2005;
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217 - 227.
[Abstract]
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J. G. Pelletier, E. Likhtik, M. Filali, and D. Pare
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March 1, 2005;
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[Abstract]
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R. D. Burwell, D. J. Bucci, M. R. Sanborn, and M. J. Jutras
Perirhinal and Postrhinal Contributions to Remote Memory for Context
J. Neurosci.,
December 8, 2004;
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[Abstract]
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D. Pare, G. J. Quirk, and J. E. Ledoux
New Vistas on Amygdala Networks in Conditioned Fear
J Neurophysiol,
July 1, 2004;
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[Abstract]
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R. D. Burwell, M. P. Saddoris, D. J. Bucci, and K. A. Wiig
Corticohippocampal Contributions to Spatial and Contextual Learning
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April 14, 2004;
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[Abstract]
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P. Blandina, M. Efoudebe, G. Cenni, P. Mannaioni, and M. B. Passani
Acetylcholine, Histamine, and Cognition: Two Sides of the Same Coin
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M. G. Giovannini, M. Efoudebe, M. B. Passani, E. Baldi, C. Bucherelli, F. Giachi, R. Corradetti, and P. Blandina
Improvement in Fear Memory by Histamine-Elicited ERK2 Activation in Hippocampal CA3 Cells
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October 8, 2003;
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[Abstract]
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R. T. LaLumiere, T.-V. Buen, and J. L. McGaugh
Post-Training Intra-Basolateral Amygdala Infusions of Norepinephrine Enhance Consolidation of Memory for Contextual Fear Conditioning
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July 30, 2003;
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P. SAH, E. S. L. FABER, M. LOPEZ DE ARMENTIA, and J. POWER
The Amygdaloid Complex: Anatomy and Physiology
Physiol Rev,
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[Abstract]
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H. Lehmann, D. Treit, and M. B. Parent
Spared Anterograde Memory for Shock-Probe Fear Conditioning After Inactivation of the Amygdala
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D. J. Howse, A. S. Squires, G. M. Martin, and D. M. Skinner
Perirhinal Cortex Lesions Impair Context Aversion Learning
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L. H. Corbit, S. B. Ostlund, and B. W. Balleine
Sensitivity to Instrumental Contingency Degradation Is Mediated by the Entorhinal Cortex and Its Efferents via the Dorsal Hippocampus
J. Neurosci.,
December 15, 2002;
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A. Vazdarjanova
Chasing "fear memories" to the cerebellum
PNAS,
June 11, 2002;
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B. Sacchetti, E. Baldi, C. A. Lorenzini, and C. Bucherelli
From the Cover: Cerebellar role in fear-conditioning consolidation
PNAS,
June 11, 2002;
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[Abstract]
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G. M. Muir and D. K. Bilkey
Instability in the Place Field Location of Hippocampal Place Cells after Lesions Centered on the Perirhinal Cortex
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June 1, 2001;
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E. H. Baeg, Y. B. Kim, J. Jang, H. T. Kim, I. Mook-Jung, and M. W. Jung
Fast Spiking and Regular Spiking Neural Correlates of Fear Conditioning in the Medial Prefrontal Cortex of the Rat
Cereb Cortex,
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[Abstract]
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A. E. Wilensky, G. E. Schafe, and J. E. LeDoux
The Amygdala Modulates Memory Consolidation of Fear-Motivated Inhibitory Avoidance Learning But Not Classical Fear Conditioning
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September 15, 2000;
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D. Pare and D. R. Collins
Neuronal Correlates of Fear in the Lateral Amygdala: Multiple Extracellular Recordings in Conscious Cats
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April 1, 2000;
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TOP
ABSTRACT
INTRODUCTION
