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The Journal of Neuroscience, April 1, 1998, 18(7):2592-2601
Differential Effects of Amygdala Lesions on Early and Late
Plastic Components of Auditory Cortex Spike Trains during Fear
Conditioning
Jorge L.
Armony,
Gregory J.
Quirk, and
Joseph E.
LeDoux
Center for Neural Science, New York University, New York, New York
10003-6621
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ABSTRACT |
In auditory fear conditioning, pairing of a neutral acoustic
conditioned stimulus (CS) with an aversive unconditioned stimulus (US)
results in an enhancement of neural responses to the CS in the amygdala
and auditory cortex. It is not clear, however, whether cortical
plasticity governs neural changes in the amygdala or vice versa, or
whether learning in these two structures is determined by independent
processes. We examined this issue by recording single-cell activity in
the auditory cortex (areas Te1, Te1v, and Te3) of freely behaving,
amygdalectomized rats using a movable bundle of microwires. Amygdala
damage did not affect short-latency (0-50 msec) tone responses, nor
did it interfere with conditioning-induced increases of these onset
responses. In contrast, lesions of the amygdala interfered with the
development of late (500-1500 msec) conditioned tone responses that
were not present before conditioning. Furthermore, whereas onset
conditioned responses in the control group remained elevated after 30 extinction trials (presentation of CS alone), onset responses in
lesioned animals returned to their preconditioning firing level after
approximately 10 extinction trials. These results suggest that the
amygdala enables the development of long-latency (US anticipatory)
responses and prevents the extinction of short-latency onset responses
to threatening stimuli. The findings further suggest that auditory
cortex cells may participate differently in explicit and implicit
memory networks.
Key words:
emotion; cognition; declarative memory; implicit memory; amygdala; auditory cortex; fear
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INTRODUCTION |
The firing properties of cells are
modified in various brain areas during learning (Olds et al., 1972 ).
For example, after the association of an acoustic conditioned stimulus
(CS) with an electric shock unconditioned stimulus (US) in a standard
fear conditioning paradigm, spike discharges change in a number of brain regions, including areas of the auditory cortex, hippocampal formation, and amygdala (Diamond and Weinberger, 1984, 1986; Weinberger et al., 1984; Laroche et al., 1989; Quirk et al., 1995, 1997). Although
damage to the amygdala prevents the expression of behavioral fear
responses conditioned to the CS, damage to the auditory cortex or
hippocampus does not (Selden et al., 1991; Phillips and LeDoux, 1992;
Romanski and LeDoux, 1992; Armony et al., 1997a). These findings
might imply that redundant, behaviorally irrelevant traces are
established in areas such as the auditory cortex and hippocampus. It is
also possible, however, that experiences are encoded and stored in
parallel by complementary memory systems (Eichenbaum et al., 1994,
1996; Squire and Knowlton, 1995). Plasticity occurring in a particular
brain area thus might be uninvolved in one aspect of learning but
crucial to another.
The complementary nature of memory systems is nicely illustrated by the
effects of different brain lesions in humans on fear conditioning.
Patients with amygdala lesions fail to exhibit conditioned fear
responses to a CS [but remember that the CS and US were systematically related (Bechara et al., 1995; LaBar et al., 1995)], whereas patients with damage to the hippocampus and related cortical areas exhibit conditioned responses to the CS but have no memory of having
experienced the CS and US together (Bechara et al., 1995). The amygdala
is thus required for establishing a linkage between the CS and response control pathways, whereas explicit or declarative knowledge about stimulus relations is acquired through hippocampal-cortical circuits that function more or less independently of the amygdala.
Although the amygdala is not required for the establishment of
declarative memories about emotional situations, it may influence mnemonic processing in declarative memory circuits. For example, amygdala damage in humans eliminates the ability of emotional arousal
to enhance declarative memory performance (Babinsky et al., 1993;
Cahill et al., 1995). The amygdala can interact with hippocampal-cortical circuits by way of direct synaptic connections, as well as through various indirect pathways (Amaral et al., 1992; LeDoux, 1996). Nevertheless, little is known about the manner in which
the amygdala might influence plasticity in cortical areas.
Auditory cortex, like other areas of sensory cortex, is reciprocally
connected with the hippocampus (by way of parahippocampal circuits) and
is a putative component of the declarative memory circuit for explicit
auditory memory (Amaral, 1987; Squire and Zola, 1996). The auditory
cortex is also reciprocally connected with the amygdala (Amaral et al.,
1992; Romanski and LeDoux, 1993) and is thus a potential site of
interaction between declarative and emotional memory networks. In the
present study we have begun to explore these interactions by examining
the effects of amygdala lesions on the plasticity of cells in the
auditory cortex during fear conditioning.
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MATERIALS AND METHODS |
Animals and surgery
Male Sprague Dawley rats (300-350 gm) were pretreated with
atropine (0.24 mg/kg), anesthetized with nembutal (50 mg/kg, i.p.), and
placed in a Kopf stereotaxic frame with blunt ear bars. Supplemental doses of anesthetic were administered throughout surgery as needed, and
body temperature was regulated by a gel heating pad.
Bilateral amygdala ablation was achieved by placing two electrolytic
lesions on each side, with the following coordinates (in millimeters)
relative to bregma (LaBar and LeDoux, 1996): (1) anterioposterior (AP) =  2.3, mediolateral (ML) = ±4.8, dorsoventral (DV) = 8.4; (2)
AP = 2.8, ML = ±5.2, DV = 8.5. Lesions were made by
passing anodal constant current (1 mA, 15 sec) through a monopolar,
stainless steel electrode (200 µm diameter; Kopf NE-300) with an
exposed tip of 500 µm. The skull holes were then covered with sterile
bone wax. The intent was to destroy much of the lateral and basal
nuclei, but no effort was made to exclude damage to other regions of
amygdala.
Electrode implant procedures were identical to those described in Quirk
et al. (1997). A movable electrode bundle of 20 insulated nichrome
microwires (25 µm diameter each; adapted from Kubie, 1984) was
implanted in the auditory cortex (5.0 mm AP, 5.1 mm ML, 6.0 mm DV,
relative to bregma) (Paxinos and Watson, 1986). The wires were
insulated except for the cut tip (impedance ~2-3 M at 1 kHz) and
contained in a stainless steel tube (0.45 mm diameter). Each wire was
attached to one pin of two 10-pin connectors (Augat) embedded in a
triangular platform made of dental acrylic. The platform could be
advanced by turning three screws (1 turn = 460 µm). Placement
accuracy of the electrode bundle was improved by passing the tube and
wires through an additional, larger guide tube (0.81 mm diameter),
implanted just above the cortex. The tips of the electrode bundle were
aimed to rest just dorsal to auditory association cortex (areas
Te3/Te1v) (Zilles and Wree, 1985). The diameter of the bundle at the
recording sites was ~0.5 mm. At the end of surgery, the incision was
closed with suture around the acrylic block, a topical antibiotic was
applied, and the analgesic Buprenorphine (0.02 mg/kg, i.m.) was
administered. Rats were allowed 5 d to recover before
electrophysiological recordings began. Control animals were treated in
the same way, except that no lesions were made. All aspects of the
behavioral training and unit recording were identical for both groups.
Data for the control group were reported in Quirk et al. (1997). The
present study was run concurrently with the latter.
Unit recording
After recovery, the rat was placed in a test box (25 × 30 × 35 cm) with an electrifiable grid floor (Coulbourn
Instruments), enclosed in a sound attenuating chamber (Industrial
Acoustics, Bronx, NY). The electrode was connected to a headstage
containing field-effect transistors (FETs) (#U401; Marshall
Electronics, El Monte, CA) operating as source-followers with unitary
gain. Signals from the headstage were sent to multichannel amplifiers (AM Systems, Everett, WA) through a slip-ring commutator (Plastics One,
Roanoke, VA). The signal was amplified (10,000× gain), passively filtered (300-5000 Hz), digitized at 16 kHz (DataWave Technologies, Longmont, CO), and displayed on a computer monitor and a digital oscilloscope. Signals exceeding a selected voltage threshold were captured in 2 msec epochs and stored on disk for later analysis. Signal
waveforms corresponding to single cells were sorted off-line using the
DataWave software on the basis of waveform parameters (e.g., peak
voltage, spike height, time to peak, etc.). Only those spike clusters,
corresponding to a single cell, that could be separated from background
activity throughout all phases of the experiment were defined as coming
from single units (Quirk et al., 1995, 1997). This procedure ensures
that only individual cells are analyzed across an entire session (for
examples of typical waveforms, see Quirk et al., 1996). Typically,
neural activity could be recorded simultaneously from several wires,
and one to three individual cells could be isolated from each active
wire.
The electrode was advanced in 50-100 µm steps until discriminable
single units were found in several wires. Units were tested for tone
responsivity by delivering 50 msec tone pips (80 ± 5 dB, open
field) of various frequencies, as well as white noise, delivered
through a speaker mounted in the ceiling of the sound-attenuating chamber. Auditory signals were generated with a Digital Signal Processing board controlled by a DataWave Discovery clocked sequence (MOZART) running on the same computer as the data acquisition software.
Conditioning protocol
We used the same conditioning protocol as in previous studies of
the amygdala and auditory cortex (Quirk et al., 1995, 1997) to
facilitate comparisons between amygdala and auditory cortex recordings
as well as to allow comparisons of cortical recordings between
amygdala-lesioned and control animals. Briefly, the conditioned stimulus (CS) was a 2 sec pure tone (5 kHz, 80 dB) and the
unconditioned stimulus (US) was a mild electric footshock (0.5 mA, 0.5 sec) delivered through the grid floor of the test box.
The experiment consisted of three phases. During
sensitization, 10 CSs and 10 USs were explicitly unpaired.
This was immediately followed by 20 conditioning trials in
which the CS coterminated with the US (that is, the tone and shock were
always paired). After the conditioning phase, the rat was placed in its
home cage for 1 hr, after which it was returned to the test chamber for the extinction phase, during which 30 tone-alone trials were
delivered (i.e., no US was presented during the extinction phase). In
all phases, the intertrial interval was 1-3 min.
Before the sensitization and extinction phases, behavioral responses to
the CS were determined in a different context, using a 20 sec tone,
calibrated to the same intensity and frequency as the CS during
conditioning (Bruel and Kjaer). Cumulative seconds of freezing during
the CS were counted with a digital timer and used as a measure of
conditioned fear (Blanchard and Blanchard, 1969; Bolles and Fanselow,
1980). Freezing was defined as absence of all movement, except those
associated with breathing. The entire experiment took ~4 hr. To
compare cell responses before (i.e., in naive animals) and after
conditioning, each rat could be conditioned only once. This was a
limiting factor in the number of cells that could be obtained from each
animal.
Data analysis
Data were analyzed, after off-line spike discrimination, using
STRANGER (Biographics, Winston-Salem, NC). Statistical analysis was
performed using commercial software (Excel and Statistica).
Onset tone responses. Onset tone responses (i.e., unit
responses locked to the onset of the stimulus) were determined, before conditioning, by comparing the average firing rate in the first 50 msec
of the tone with the firing rate 500 msec before tone onset, during the
10 sensitization trials. Significant onset tone responses were
determined using a z test (p < 0.05). Onset
tone responses after conditioning were determined in a similar manner, using the firing rates from the first 10 extinction trials.
Long-term conditioned increases in the onset responses were
investigated in a similar manner by comparing onset tone responses (with the average pretone firing rate subtracted) before conditioning (10 sensitization trials) with those after conditioning (first 10 extinction trials), for the first 50 msec after tone onset. Because we
were interested in whether conditioning had an effect on the signaling
of the CS, we restricted the analysis of onset conditioning to those
cells that showed a positive tone response after the conditioning phase
(i.e., their firing rate in the first 50 msec of the tone was higher
than their rate before the tone).
Late tone responses. We investigated the effects of
conditioning on responses occurring after tone onset by analyzing
firing rates during the entire tone in 100 msec bins before (10 sensitization trials) and after (first 10 extinction trials)
conditioning. For each bin, the number of tone-responsive cells was
calculated using z scores (2 SD above pretone firing rate). Only cells
that were significantly tone responsive in at least two adjacent 100 msec bins were included. This analysis revealed a "region of
interest," between 500 and 1500 msec, in which the majority of late
tone responses occurred (Quirk et al., 1997). Thus, this region was further analyzed with Student's paired t tests
(p < 0.05, two-tailed) to determine tone
responsiveness, comparing the rate in the 500-1500 msec interval with
the pretone rate. (It should be pointed out that because this latter
analysis combines the rates of 10 consecutive bins, it will yield a
larger number of tone-responsive cells than that seen for any
individual bin.) Late tone responses could not be measured during
conditioning trials because inputs to the amplifiers were grounded
shortly before shock presentation to avoid shock artifact contamination
of the unit recordings.
Histology
At the end of the experiment, a small lesion was made by passing
current (8 µA, 10 sec) through one of the recording wires. Animals
were perfused transcardially with 10% buffered formalin. The brains
were removed and stored in a formalin-sucrose solution with 2%
nitroferrocyanide. The brains were frozen and cut on a sliding
microtome (40 µm sections), and mounted sections were stained for
nissl bodies and examined with a light microscope. The site of the
Prussian blue reaction (caused by the reaction of iron deposits from
the lesion with the nitroferrocyanide) was used to locate the region of
the recorded cells. Cases in which the amygdala lesions were incomplete
or thalamocortical fibers running through the striatum appeared to be
disrupted by the lesion electrode tracks were discarded.
Photomicrographs of the lesions were obtained with a CatsEye digital
camera (Sony) and acquired on a Macintosh PowerPC 8100 with commercial
software (Adobe Photoshop).
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RESULTS |
Histology
Figure 1 illustrates a typical
amygdala lesion. Lesions were centered primarily on the lateral and
basal nuclei and in some cases extended medially into the central
nucleus. Some animals also had some damage to the amygdalostriatal
zone. Those cases exhibiting severe damage of the caudate-putamen, near
the electrode track, were discarded. Although caudate-putamen lesions
do not interfere with the conditioning of fear behavior (LeDoux et al., 1985; Iwata et al., 1986), auditory thalamocortical fibers pass through
the caudate, and normal auditory transmission to the cortex could be
affected by damage to this region.
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Figure 1.
Photomicrographs of coronal sections showing a
typical bilateral amygdala lesion. Lesions were centered at the lateral
and basolateral nuclei, and in some cases damage extended into the central nucleus. Damage to the caudate nucleus above the amygdala was
variable from case to case. Ce, Central nucleus;
LA, lateral nucleus; BL, basolateral
nucleus.
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Recording electrode placements were located in auditory cortex (mainly
in association areas Te1v and Te3). Figure
2 illustrates the sites of the individual
electrode bundles for all the lesion and control animals used in this
study, showing a clear overlap of recording locations between the two
groups.
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Figure 2.
Drawing of a coronal section, at ~5 mm posterior
to bregma, showing the electrode placements for control (open
circles) and lesioned (filled circles)
animals. Each circle corresponds to one electrode
placement (each rat was implanted only once). Most placements were
located in areas Te1v/Te3, which are part of the auditory association
cortex in the rat. Te1, Te1v, Te3, Temporal cortex,
areas 1-3. Adapted from Swanson (1992).
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Behavior
The effects of CS presentation on fear behavior in the animals
from which successful recordings were made was assessed by measuring
the amount of time accounted for by freezing behavior during a 20 sec
exposure to the CS outside of the conditioning context before and after
conditioning. Before the sensitization phase, no rats in either of the
groups (control and amygdala lesion) showed any substantial freezing to
the CS (0.07 ± 0.07 sec and 0.13 ± 0.13 sec, respectively).
After conditioning, control animals exhibited a significant increase in
freezing to the CS [8.7 ± 2.0 sec; t(12) = 4.45; p < 0.001), whereas rats with amygdala lesion
showed no increase in their freezing to the CS, even after 20 pairings
(mean freezing time after conditioning = 0.50 ± 0.40 sec;
t < 1). These results, shown in Figure
3, are consistent with a large body of
literature demonstrating a crucial role for the amygdala in the
acquisition and expression of conditioned fear responses (for review,
see Davis, 1992; Kapp et al., 1992; LeDoux, 1995, 1996; Gallagher and
Chiba, 1996; Maren and Fanselow, 1996).
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Figure 3.
Freezing responses to the 20 sec tone conditioned
stimulus (CS) before and after conditioning for control
(n = 14) and lesion (n = 11)
groups. After conditioning, control rats exhibited a significant
increase in freezing to the CS (p < 0.001),
whereas amygdala-lesioned animals showed no change.
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Unit activity
A total of 19 lesioned animals completed the full conditioning
protocol. Eight of those were later discarded because of incomplete amygdala lesions or significant damage in the caudate-putamen (see
Materials and Methods), or because no individual cells could be
isolated satisfactorily throughout the entire experiment. Thirty-two cells were isolated, held, and analyzed from the remaining 11 rats. The
average number of cells recorded per animal was similar to the control
cases (40 cells in 14 rats). Furthermore, the average spontaneous
firing rate of cells before conditioning collected for 500 msec before
each tone trialin control and lesioned animals was similar: 3.9 ± 0.7 and 5.5 ± 1.1 Hz, respectively. Overall, conditioning did
not have a significant effect on the spontaneous firing of cells in
either group: the average spontaneous rates after conditioning were
3.1 ± 0.6 and 5.6 ± 1.1 Hz for the control and lesioned
animals, respectively. That is, amygdala lesions did not have an effect
on the number cells that could be discriminated, the quality of the
recordings, or the basic properties of the cells. The number of cells
studied was comparable to other conditioning studies of the auditory
cortex (Cruikshank and Weinberger, 1996).
Onset tone responses before and after conditioning
Before conditioning, cells in auditory cortex in both control and
lesioned animals responded to the tone at short latencies, within the
first 50 msec after tone onset. A typical example of an auditory cortex
neuron showing onset tone responses in a rat with amygdala damage is
shown in Figure 4. Overall, 8/32 (25%) of cells exhibited significant excitatory onset responses in the lesioned animals compared with 14/40 (35%) cells in the control group.
These percentages are statistically indistinguishable ( 2 = 0.84; p = 0.36).
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Figure 4.
Poststimulus time histograms showing the tone
response of a cell in an amygdala-lesioned rat. This cell exhibited a
short-latency (<50 msec) onset response before conditioning. As a
result of conditioning, the magnitude of the onset response increased
relative to the sensitization phase (Pre-Conditioning).
Each histogram represents 10 trials; bin width is 50 msec.
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After conditioning, 12 cells (30%) in the control group exhibited an
increase in their firing rate in the first 50 msec after tone onset
(see Materials and Methods). A similar proportion of neurons (12 cells;
37%) showed conditioning-induced onset increases in the
amygdalectomized rats (2 = 0.45; p = 0.50). Two (5%) and three (9%) of these cells in the control and
lesion groups, respectively, did not respond to the tone during the
sensitization phase but developed onset tone responses as a result of
conditioning. An example of conditioned increases in a cell from a
lesioned animal is shown in Figure 4. Thus, amygdala lesions affected
neither short-latency (0-50 msec) tone responses nor the likelihood
that conditioning would induce onset plasticity in those responses.
Conditioning-induced late tone responses
In addition to the short-latency onset plasticity described above,
conditioning also produced increases in tone responses that started
around 500 msec after tone onset and lasted for ~1 sec (Quirk et al.,
1997). We refer to these as late conditioned tone responses. An example
of such late conditioned increase in an intact animal is shown in
Figure 5. Before conditioning, this cell
did not respond to the tone. Conditioning did not have an effect on the
onset response of the cell to the tone. After CS-US pairing, however,
a significant late response to the tone developed, starting at ~700
msec after tone onset.
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Figure 5.
Example of a cell in a control rat showing
long-latency conditioned tone responses. Before conditioning, the cell
did not respond to the tone. After conditioning, however, the cell
developed a significant tone response, starting at ~500 msec after
tone onset and achieving its peak at 1500 msec after tone onset, which was the time of footshock onset during conditioning (indicated by the
arrow). Shock was not delivered during these tests,
because they occurred during extinction trials. Each histogram
represents 10 trials; bin size is 100 msec. No cells showing these late
conditioned responses were found in lesioned animals (see
Results).
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The development of late tone responses as a result of conditioning was
a general phenomenon in cells of control animals. Figure 6 (top) shows the percentage
of tone-responsive neurons in intact rats throughout the tone, with a
100 msec bin resolution, before and after conditioning. Before
conditioning, most tone responses were concentrated at the onset and
offset of the tone, with little signaling during the rest of the
stimulus. After conditioning, however, we observed a substantial
increase in the number of cells exhibiting late tone responses in two
or more bins (see Materials and Methods). As in the example shown in
Figure 5, these late responses started at ~500 msec after tone onset
and peaked at 1500 msec, which was the latency of the shock onset
during the conditioning phase of the experiment. In contrast, as shown
in Figure 6 (bottom), no evidence for late conditioned
tone-responsive cells was seen in lesioned animals.
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Figure 6.
Ribbon plots showing the percentage of cells that
were significantly tone responsive (see Materials and Methods) before
(white) and after (gray)
conditioning for the control and lesion groups. Although there were
prominent onset and offset responses before and after conditioning in
both groups, conditioning resulted in an increase in the number of
cells in the control group showing late responses to the tone CS,
starting at ~900 msec after tone onset and reaching a peak at 1500 msec (time of shock onset during conditioning). This
conditioning-induced late response was absent in lesioned animals. The
duration of the tone was 2 sec; bin width is 100 msec.
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To make a statistical comparison of the number of neurons showing
conditioning-induced late tone responses in control and lesion groups,
we defined a region of interest between 500 msec (end of all onset
responses) and 1500 msec (onset of footshock). The number of
tone-responsive cells in each group in this region was calculated using
two-tailed, paired t tests (p < 0.05) (see Materials and Methods). After conditioning, 11 of 40 cells
(28%) in control animals showed late tone responses. (A color-coded raster plot of the response of these cells throughout training is shown
in Fig. 7A.) In contrast, only
2 of 32 cells (6%) in lesioned animals exhibited tone responses in the
500-1500 msec interval. A 2 test revealed that the
difference in these late conditioning-induced tone-responsive cells
between control and lesion groups was significant (2 = 5.43; p < 0.02).
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Figure 7.
A, Color-coded raster plot showing
the average firing rate of cells in the control group that exhibited
significant late tone responses (500-1500 msec after tone onset; see
Results) after conditioning (n = 11). The
top of the figure shows the sensitization trials
(preconditioning) and the bottom shows extinction trials (the conditioning phase is not shown). Each row is one trial, and the
bin size is 100 msec. Firing rates were averaged across cells and
smoothed with a nearest-neighbor average. Note that there was no
indication of late responses before conditioning, and that the
long-latency conditioned response is maximal (red) just
before the time of the shock onset during conditioning (indicated by
the arrow), similar to the example shown in Figure 5.
B, Color-coded raster plot showing the average firing
rate of cells that develop short-latency (<50 msec) onset conditioned
increases, for the control (n = 12) and lesion
(n = 12) groups. Each row is one
trial, showing the first 500 msec after tone onset; bin size is 10 msec. The top half shows the 10 sensitization and 20 conditioning trials, and the bottom half shows the 30 extinction trials. Animals were returned to their home cages for 1 hr
after the end of conditioning and before the beginning of extinction.
Note that in the control group the magnitude of onset responses after
30 extinction trials remained elevated relative to the response before
conditioning (sensitization). In contrast, cells in lesioned animals
returned to their preconditioning levels after 10 extinction
trials.
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In summary, conditioning resulted in a significant increase in the
number of cells displaying a late (500-1500 msec) tone response in
intact animals, but no such changes were observed in cells recorded in
animals with amygdala lesions. Unlike onset conditioned increases (see
below), late conditioning-induced tone diminished with extinction
trials in the control animals.
Extinction of onset conditioned responses
One hour after the end of the conditioning phase, the animals were
brought back to the test chamber and exposed to 30 extinction trials
(tone alone). As reported previously (Quirk et al., 1997), auditory
cortex cells in intact animals retained the conditioning-induced increases of their tone responses after 30 extinction trials (in contrast, extinction occurred in lateral amygdala cells under the same
conditions) (Quirk et al., 1997). An example of an auditory cell from a
control animal exhibiting extinction-resistant onset conditioning in
the present study is shown in Figure
8A. In contrast, cells
recorded in the auditory cortex of amygdalectomized rats returned to
their preconditioning level during extinction, as shown in Figure
8B. Figure 7B shows a color-coded average
raster plot of all the cells that exhibited an increase in their onset response (0-50 msec) during conditioning (see above) as a function of
the trials in the different training phases (sensitization, conditioning, and extinction). Before conditioning, a slightly smaller
number (but not statistically significant; see above) of cells in the
lesion group responded to the tone onset (hence the lower firing rate
in this group seen in Fig. 7B, when compared with controls),
but immediately after conditioning, both groups showed a similar number
and strength of onset tone responses. Cells in lesioned and control
animals, however, exhibited very different response patterns during
extinction. Whereas in the control group animals the conditioned onset
response in auditory cortex was still higher than the preconditioning
(sensitization) response after 30 extinction trials, responses of
auditory cortex cells in amygdala-lesioned rats extinguished their
conditioned onset increases after approximately 10 extinction trials.
This effect was confirmed statistically by comparing the responses at
the beginning (average of trials 1-10) and end (average of trials
20-30) of extinction. Cells in control animals showed no extinction in
their onset responses (paired t test; p > 0.1), whereas cells in the lesioned rats significantly decreased their onset response to the tone as a function of extinction trials (p < 0.005), as shown in Figure
9.
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Figure 8.
Poststimulus time histograms showing the effects
of extinction on short-latency (<50 msec) onset conditioning in cells
from control (left) and lesioned (right)
animals. The cell from the control animal developed onset conditioned
increases after conditioning (extinction trials 1-10) that lasted
through the entire extinction phase (30 trials). In contrast, the cell
from the lesioned rat developed a short-lasting onset conditioned
increase and returned to its preconditioning response level at the end
of the extinction phase.
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Figure 9.
Average onset tone responses (0-50 msec) of cells
that conditioned, from the control and lesion groups, plotted for the
10 sensitization trials (Pre Conditioning), the first 10 trials of extinction (Post Conditioning), and the last
10 trials of extinction (trials 20-30; Post
Extinction), relative to the postconditioning tone response. In
both groups, tone responses before conditioning were significantly
smaller than after conditioning (p < 0.01). In the control group, the responses at the end of extinction did not
differ from the postconditioning values (p > 0.1), whereas in the lesion group extinction trials resulted in a
significant reduction of the tone responses
(p < 0.005).
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DISCUSSION |
We recorded from individual neurons in auditory cortex in rats
with bilateral amygdala lesions during fear conditioning and compared
the results with those obtained in intact animals (Quirk et al.,
1997).
Short-latency (onset) responses
Amygdala lesions did not affect short-latency (0-50 msec) tone
responses in auditory cortex that exist before conditioning. Moreover,
there was no effect of the lesions on the conditioning-induced modification of these short-latency responses. These results are consistent with the idea that short-latency conditioned tone responses in auditory cortex are driven by direct inputs from the thalamus (Quirk
et al., 1996) and thus do not need to rely on an intact amygdala.
Although onset conditioning develops in the auditory thalamus
(Disterhoft and Stewart, 1976; Gabriel et al., 1976; Ryugo and
Weinberger, 1978; Edeline et al., 1990), it has not been established
whether thalamic cells that project to the amygdala are plastic, nor is
it known whether such plasticity requires an intact amygdala. [A
recent study by Poremba and Gabriel (1997) showed that amygdala lesions
interfere with thalamic plasticityalthough not in the auditory
thalamusin an avoidance conditioning task in rabbits.]
Late conditioned responses
The majority of analyses of plasticity in auditory cortex during
conditioning have focused on short-latency (<50msec) responses (for
review, see Weinberger, 1995). However, we have observed recently that
several cells (11 of 40; 28%) in auditory cortex in control animals
showed a late conditioned response to the CS, which lasted from ~500
to 1500 msec (Quirk et al., 1997). As illustrated in Figure
7A, most cells exhibiting this late conditioned response did
not show any response to the CS before conditioning. Thus, conditioning
resulted in a recruitment of cells that started to respond to the late
part of the CS. Interestingly, this conditioned neural response peaked
at 1500 msec, which was the latency of the US during the conditioning
phase. We have hypothesized that this response may reflect some
attentional or anticipatory mechanism (Armony et al., 1997b; Quirk et
al., 1997). No evidence of this late response was observed in cells
recorded in animals with amygdala lesions, suggesting that this
"anticipatory" response may be amygdala-dependent (see below). This
amygdala dependency could reflect direct projections to the cortex from
the amygdala, feedback to the cortex from various amygdala-triggered
responses, including nonspecific arousal responses within the brain
(described in more detail below), or somatic, autonomic, or endocrine
responses expressed peripherally and returning to the brain (LeDoux,
1996).
Extinction of onset conditioned increases
Extinction trials (presentation of the CS alone) result in a
reduction of behavioral conditioned responses. In previous studies involving a conditioning protocol identical to the one used in the
present experiment, we observed that cells in the lateral nucleus of
the amygdala, the sensory gateway to the amygdala, lost their onset
conditioned increases (i.e., they returned to their preconditioning
levels of tone-elicited spike trains) after 30 extinction trials (Quirk
et al., 1995). In contrast, cells in the auditory cortex in intact
animals did not show any significant extinction in their short-latency
responses to the CS (Quirk et al., 1997), consistent with the idea that
the cortex, specifically sensory areas, may be involved in the storage
of some aspect of fear memories.
Interestingly, although amygdala lesions did not interfere with the
development of onset conditioning in auditory cortex, they did have an
effect on the rate of extinction of such increases. Conditioned cells
returned to their preconditioning level of responses after ~10
extinction trials, as shown in Figure 7B. That is, although the lateral nucleus of the amygdala itself does not seem to be a site
of extinction-resistant storage of the CS-US pairing information, the
amygdala nonetheless appears to be necessary for the consolidation or
maintenance of extinction-resistant responses in auditory cortex. Whether other amygdala subnuclei downstream from the lateral nucleus, such as basal or central nuclei, maintain or extinguish their conditioned responses after presentations of the unreinforced CS is
unknown and is an important question for future research, especially
because these downstream areas are the source of fibers that project
back to the cortex (Amaral et al., 1992) and to other areas that allow
the amygdala to influence the cortex indirectly (for a summary, see
LeDoux, 1996).
Role of the amygdala in fear processing
A large body of evidence lends support for a critical role of the
amygdala in controlling conditioned fear responses, through its
projections to brainstem structures (Davis, 1992; Kapp et al., 1992;
LeDoux, 1995, 1996). Little is known, however, about the role of the
amygdala in modulating cortical areas during fear conditioning. Nuclei
of the amygdala have extensive projections back to cortical areas, and
these could play a role in modulating cortical processing of emotional
stimuli (Amaral et al., 1992; LeDoux, 1996). A number of hypotheses
have been proposed suggesting that the amygdala may modulate mnemonic
and attentional processing in cortical areas (Kapp et al., 1992; Rolls,
1992; Gallagher and Holland, 1994; McGaugh et al., 1995; Packard et
al., 1995; Weinberger, 1995; Cahill and McGaugh, 1996; Armony et al.,
1997b). For example, stimulation of the central nucleus produces
neocortical arousal, which is mediated by cholinergic projections from
the basal forebrain in rabbit (Kapp et al., 1994), and stimulation of
the nucleus basalis produces facilitation of neuronal responses to
tones in auditory cortex in awake rats (Edeline et al., 1994).
Furthermore, pairing of a tone with iontophoretic application of ACh
induces frequency-specific changes in auditory cortex neurons, similar to those observed during fear conditioning (Metherate and Weinberger, 1990). Findings such as these have led Weinberger and colleagues to
propose a conceptual model in which cortical plasticity in fear
conditioning requires concurrent auditory input from the thalamus and
amygdala-elicited diffuse cholinergic input from the basal forebrain
(for review, see Weinberger, 1995). According to this hypothesis, a
lesion of the amygdala would completely abolish the development of
cortical plasticity. The present results do not lend support to that
model, because we found that amygdala lesions failed to affect the
induction of short-latency (0-50 msec) fear-conditioned cortical
plasticity in auditory cortex. Nonetheless, amygdala lesions did block
the development of late (500-1500 msec) tone responses after
conditioning. Thus, the model of Weinberger and coworkers might be more
apt for this component of the conditioned response.
We have recently developed a computational model of emotion-cognition
interactions grounded on the anatomy and physiology of the fear
conditioning circuit (Armony et al., 1997b). The model is consistent
with the results reported here. According to the model, auditory cortex
cortical plasticity induced by direct thalamocortical projections,
through Hebbian learning, should be independent of the amygdala.
Auditory thalamic projections to the amygdala are also thought to be
responsible for the plasticity in the amygdala, both in the model
(Armony et al., 1995) and in experimental recordings (Quirk et al.,
1995). In turn, the amygdala may influence later cortical responses, by
way of either direct or indirect projections. Indirect sources include
the various nonspecific arousal or modulatory systems in the brain, as
well as feedback from peripherally expressed responses (for a summary,
see LeDoux, 1996). These late, amygdala-dependent responses may
redirect attentional resources to the CS, possibly in anticipation of,
and in preparation for, the expected arrival of the US. This hypothesis
is still fairly speculative, but it does integrate much of the data
described above.
Conclusion
The results presented in this study are consistent with the notion
of complementary memory systems that form neural traces in parallel
during emotional arousal. Through amygdala-based plasticity, an
association is formed between the CS and the aversive US such that the
CS gains access to evolutionarily programmed defense responses mediated
by amygdala outputs. Plasticity also occurs in cortical areas and makes
possible the establishment of explicit or declarative memories about
the situation through interactions with the medial temporal lobe memory
system (McClelland et al., 1995; Squire and Knowlton, 1995; Eichenbaum
et al., 1996). At the same time, activation of the amygdala during the
emotional event modulates the strength of explicit, declarative
memories represented in various cortical memory circuits (McGaugh et
al., 1995, 1996; Cahill and McGaugh, 1996).
Our findings begin to make explicit the manner in which the amygdala
might influence cortically based memories. Specifically, the relatively
early (within 50 msec) representation is processed in the auditory
cortex independent of the amygdala. This plasticity involves, for the
most part, the enhancement of preexisting responses to the CS.
Late responses to the CS (500-1500 msec), responses that did not exist
before training, anticipate the arrival of the US and are dependent on
the amygdala. We hypothesize that the early and late auditory cortex
conditioned responses are part of the explicit or declarative
representation of the experience processed in conjunction with the
medial temporal lobe memory system and that the amygdala modulates the
late but not the early component of this representation of the
experience. This hypothesis is guiding additional studies in our
attempt to understand how complementary memory systems interact during
emotional learning.
| |
FOOTNOTES |
Received Nov. 11, 1997; revised Jan. 16, 1998; accepted Jan. 16, 1998.
This work was supported by Public Health Service Grants MH38774,
MH46516, and MH00956 to J.E.L. We are grateful to Mian Hou for help
with histology.
Correspondence should be addressed to Joseph E. LeDoux, Center for
Neural Science, New York University, 4 Washington Place, Room 809, New
York, NY 10003-6621.
Dr. Armony's present address: Department of Experimental Psychology,
University of Oxford, South Parks Road, Oxford OX1 3UD, UK.
Dr. Quirk's present address: Department of Physiology, Ponce School of
Medicine, P.O. Box 7004, Ponce, Puerto Rico
00732-7004.
| |
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Top
Abstract
Introduction
