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Department of Biology, Washington University, St. Louis, Missouri
Submitted 31 January 2005; accepted in final form 5 May 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Ji and Suga 2003; Ji et al. 2001). This long-term cortical BF shift can be blocked by atropine, an antagonist of muscarinic acetylcholine (ACh) receptors, applied to the auditory cortex (AC) before the conditioning. It depends on cortical ACh increased by the conditioning (Ji and Suga 2003; Ji et al. 2001). These "tone-specific" BF shifts represent physiological auditory memory traces as found in other species of mammals (Weinberger 1998).
There has been a considerable amount of data indicating the importance of ACh and/or the cholinergic basal forebrain in evoking BF shifts (Bakin and Weinberger 1996; Bjordahl et al. 1998; Fadel et al. 2001; Ji and Suga 2003; Ji et al. 2001; Kilgard and Merzenich 1998; Ma and Suga 2003; Metherate and Ashe 1993, 1995; Metherate and Weinberger 1989,1990; Miasnikov et al. 2001; Rasmusson 2000; Weinberger 2003), and an enormous amount of data indicating that N-methyl-D-aspartate (NMDA) receptors (one of the glutamate receptors) plays an essential role in learning and memory (Kaczmarek et al. 1997; Riedel et al. 2003). The importance of ACh and muscarinic ACh receptors in augmenting BF shifts has been shown (Ji and Suga 2003; Ji et al. 2001; Ma and Suga 2003, 2005; Metherate and Weinberger 1990). However, the importance of NMDA receptors in evoking BF shifts has not yet been examined. The excitatory transmitters of collicular and cortical neurons, including corticofugal neurons, are not ACh but glutamate and/or aspartate (Dori et al. 1992; Faingold et al. 1989; Feliciano and Potashner 1995; Fonnum et al. 1981; Foote et al. 1975; Karlsen and Fonnum 1978; Kelly and Zhang 2002; Nieoullon and Dusticier 1983; Tsumoto 1990). The aim of our current studies is to examine whether NMDA applied to the AC or the inferior colliculus (IC) augments the conditioning-dependent cortical and collicular BF shifts, whether 2-amino-5-phosphovaleric acid (APV: an antagonist of NMDA receptors) applied to the AC or IC abolishes or decreases these cortical and collicular BF shifts, how the effect of NMDA on the BF shifts is influenced by blocking muscarinic ACh receptors with atropine, and how the effect of ACh on the BF shifts is influenced by blocking NMDA receptors with APV.
We have found that NMDA and APV have profound effects on collicular and cortical BF shifts elicited by auditory fear conditioning and that the effect of NMDA and ACh on the BF shifts are different from each other.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Materials, surgery, acoustic stimulation, electric leg stimulation, drug application, recording of action potentials, data acquisition, and data processing were the same as those described in Ji et al. (2001). The protocol for this research was approved by the animal studies committee of Washington University in St. Louis.
Experiments were performed with 27 adult big brown bats, E. fuscus, weighing 18–24 g. Under neuroleptanalgesia (Innovar, 4.08 mg/kg body weight), a 15-mm-long metal post was glued to the dorsal surface of the bat's skull. Two to 3 days after this surgery, the awake bat was placed in a polyethylene-foam body mold suspended by an elastic band at the center of a soundproof room maintained at 31°C. Its head was immobilized by fixing the metal post glued on the skull onto a metal rod with set screws and was adjusted to face directly at a loudspeaker located 74 cm away. However, conditioning and neurophysiological experiments were not performed for the initial 2–3 days to let the bat adapt to the experimental environment. The experiments were started for recording auditory responses from single neurons, exposing an animal to conditioning, and applying drugs. The bat was neither anesthetized nor tranquilized during the experiments.
Recording action potentials
For recording action potentials from the AC or the central nucleus of the IC, holes of about 50 µm diam were made in the skull with a sharpened needle under a dissection microscope. For drug application, however, a hole was 
1.0 mm diam. A sharpened, vinyl-coated tungsten wire microelectrode with a tip diameter of 7 µm was inserted orthogonally into the AC or dorso-ventro-laterally into the IC through the holes. An indifferent tungsten wire electrode was placed on the dura mater near the recording electrode. The awake bat showed no sign of distress with this procedure, yet responded vigorously to accidental touching of the exposed surgical wounds or the face. This indicated their awareness and ability to express pain, if so needed.
Acoustic stimuli and fear conditioning
Acoustic stimuli (20-ms tone bursts with a 0.5-ms rise-decay time) were delivered to the bat at a rate of 5/s. Their frequency and amplitude were first manually varied to measure the BF and minimum threshold of a given neuron. Then, the tone bursts were computer-controlled. The sharpness of the manually measured tuning curve was used to determine the step size (0.2–0.5 kHz) of computer-controlled frequency scans: the sharper the tuning curve, the smaller the step size. The frequency scan consisted of 34 150-ms time blocks. In each scan, a single tone burst was delivered at the beginning of each block, and the frequency of the tone burst was shifted in 33 steps across the BF of the neuron. In the last time block, no simulation was presented to count background discharges. The amplitudes of the tone bursts in the scan were always set at 10 dB above the minimum threshold of the neuron to easily detect a BF shift. An identical frequency scan was delivered 50 times to obtain an array of peristimulus time histograms (PSTHs) as a function of frequency.
To evoke the BF shifts of cortical and collicular neurons, the bat was exposed to conditioning with a 1.0-s train of acoustic stimuli (ASt), followed by a 1.0-s gap and by an electric leg-stimulus (ESl; hereafter, ASt + ESl). ASt and ESl were the conditioning and unconditioned stimuli, respectively. In ASt, tone bursts were 50 dB SPL and 10 ms and were delivered at a rate of 33/s. The rate of 33/s was chosen because it is the rate of sound emission at the middle portion of the approach phase of echolocation (Griffin 1962). The bat reaches a target 1.0 s after that, so that a 1.0-s gap was introduced between ASt and ESl. The frequency of ASt was set 5.0 kHz lower than the BF of a given cortical or collicular neuron to be studied, because in the big brown bat, ASt evokes the largest BF shift for cortical (Chowdhury and Suga 2000; Ma and Suga 2001) and collicular neurons (Gao and Suga 1998; Yan and Suga 1998) with a BF that is 5.0 kHz higher than ASt. ESl was a 50-ms monophasic electric pulse. The intensity of ESl was 0.10–0.40 mA, just above the threshold for eliciting a leg flexion. A paired stimulus (ASt + ESl) was delivered every 30 s for 15 min (30 times in total) or 30 min (60 times in total). To minimize a cumulative effect of conditioning, only one neuron was studied in a 1-day experiment, and the same animal was only used after at least a 3-day interval. In each 1-day experiment, a tone burst alone was delivered at different frequencies and at a rate of 5/s over 3 h to record single-unit activity and to obtain data in the control condition. This period presumably caused extinction of BF shifts, if any were remaining after a previous conditioning experiment.
Drug applications
In the AC of the big brown bat, auditory responses can be recorded within an area of 2.4 mm in diameter, which is mostly the primary AC (Dear et al. 1993). We first performed electrophysiological mapping to locate the 30-kHz iso-best frequency line, which dorsoventrally crosses an approximate center of the AC. The dorsal surface of the IC in the big brown bat was directly visible through the skull. A hole of 1.0 mm diam was made in the skull at the approximate center of the 30-kHz iso-best frequency line and also at the center of the visible portion of the IC for a drug application. The best frequencies of cortical neurons at the center of the hole, where a drug was applied, were 28.2 ± 4.7 (SD) kHz (n = 121). NMDA, APV, APV + ACh, or NMDA + atropine was applied to the AC or IC 5 min before the conditioning with a 1.0-µl Hamilton syringe or syringes to study their effect on the development of BF shifts elicited by the conditioning.
In general, the effect of a drug is dose-dependent. The amount and time-course of the effect increase relative to the dose applied. A large dose of one drug may mask the effect of another drug. In our experiments therefore the drug solutions applied were 0.05 µl of 20 mM NMDA (pH 7.0; dissolved in 0.9% saline), 0.05 µl of 10 mM APV (pH 7.0; dissolved in 0.9% saline), 0.05 µl of 1.0 M ACh (pH 4.5; dissolved in 0.9% saline), and 0.05 µl of 0.4 mM atropine sulfate (pH 5; dissolved in 0.9% saline). The supplier of these drugs was Sigma Chemical (St. Louis, MO). The above dose of NMDA augmented the auditory responses of cortical and collicular neurons over 1.01.5 h, as ACh did (Ji et al. 2001). The above dose of APV decreased the auditory responses of cortical and collicular neurons over 1.52.0 h. The above dose of atropine reduced the auditory responses of the neurons by only 10%. This effect disappeared within 50 min. However, atropine abolished cortical and collicular BF shifts over 1.52.0 h. Because the plateau of NMDA, APV, ACh, and atropine effects lasted 45 min, i.e., slightly longer than the duration of the 30-min conditioning, we fixed the doses as described above without obtaining the dose-effect curves.
In our previous experiments, 0.05 µl of a 0.9% saline solution was applied to the AC or IC for sham experiments. An application of saline solution had no effect on the auditory responses and BF shifts of 30 cortical and 27 collicular neurons that could be caused by a 15- or 30-min conditioning (Ji et al. 2001). Therefore these sham experiments were not repeated in our current studies.
Data acquisition and processing
The responses of a single cortical and collicular neuron to tone bursts were respectively recorded at 200-to 500-µm depths (layers III–V) in the AC and 300- to 1,500-µm depths in the central nucleus of the IC with tungsten wire microelectrodes. A BAK time-amplitude window discriminator was used to select action potentials from a single neuron. The waveform of an action potential of a single neuron was stored on a digital-storage oscilloscope at the beginning of the data acquisition and was used as a template. Action potentials discharged by the neuron were continuously monitored together with the template on the screen of the digital-storage oscilloscope during data acquisition. Data were acquired every 15 min over 225 min after the conditioning as long as action potentials visually matched the template. Data were stored on the hard drive of a computer and were used for off-line data processing.
Off-line data processing included plotting PSTHs displaying the responses of a single collicular or cortical neuron to 50 identical acoustic stimuli along with the frequency–response curves of the neuron based on the responses to the 50 frequency scans obtained before, during, and after the conditioning and/or drug applications. The magnitude of auditory responses was expressed by a number of impulses per 50 identical stimuli after subtracting background discharges counted in the last block of the frequency scan. The BF of the neuron was defined as the frequency at which the frequency–response curve was peaked. To study the time-course of a BF shift, BFs measured every 15 min were plotted as a function of time. The time-courses of BF shifts obtained from several neurons were averaged. Therefore each data point in an averaged time-course represents the mean and SE of BFs measured in a number of neurons used for averaging. A t-test was used to test the difference between the auditory responses obtained before and after the conditioning and/or drug applications and to test the difference in the BF shifts of collicular and cortical neurons.
The following criteria were used for a shift in the BF of a neuron evoked by the conditioning and/or drug applications. If a shifted BF of a neuron did not recover by >50%, the data were excluded from the analysis. In stable, long recording conditions, all BFs shifted by the conditioning and/or drug applications recovered by >50%. This recovery itself helped prove that the shift was significant and that the shift was not due to recording action potentials from different neurons. However, this criterion was not necessarily applied to cortical BF shift, because it lasted more than several hours after the conditioning and a drug application. Cortical BF shifts as well as collicular ones were highly specific to the frequency of a conditioning tone (Gao and Suga 1998, 2000). This indicates that BF shifts were not due to random change in recording action potentials from different neurons.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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), the effects of ACh or atropine on the cortical and collicular BF shifts are also shown in Figs. 3–6. As described in METHODS, the effects of NMDA, NMDA + atropine, or APV + ACh were examined on the BF shifts at "subthreshold" elicited by a 15-min conditioning session, whereas the effects of APV or atropine alone were examined on the suprathreshold BF shifts elicited by a 30-min conditioning session. The 15-min conditioning evoked statistically insignificant BF shifts. When ACh (Ji et al. 2001) or NMDA (current studies) was applied to the AC or IC before this conditioning, large BF shifts of cortical and collicular neurons were evoked. Neither ACh alone nor NMDA alone evoked the BF shifts. Therefore it was most likely that the BF shifts elicited by the 15-min conditioning were so small that we could not reliably detect them with the 0.2- to 0.5-kHz step-size of the frequency scan. We had thus interpreted that the 15-min conditioning elicited subthreshold BF shifts in the AC and IC and that these BF shifts were augmented by ACh (Ji et al. 2001) or NMDA (our current data).
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NMDA applied to the AC without conditioning augmented the auditory responses of all 10 cortical and 11 collicular neurons studied. Figure 1 A shows the auditory responses and frequency–response curves of a cortical neuron tuned to 28.0 kHz (histogram 1 and 
). The response of the neuron at its BF increased by 41% 30 min after an NMDA application to the AC (histogram 2 and 
). Then, it decreased back to the response in the control condition 120 min after (histogram 4 and dashed curve). (The recovery of an auditory response was defined as the changed response at the BF recovered within ±15% of the control response at the BF. See the data shown in Figs. 1 and 2.) The overall shapes of the frequency–response curve and the BF did not change regardless of the prominent increase in response magnitude. Figure 1B shows the responses and frequency–response curves of a collicular neuron tuned to 23.0 kHz (histogram 1 and ). The response of the neuron at 23.0 kHz increased by 48% 30 min after the NMDA application to the AC (Fig. 1B, histogram 2 and ). Then, it had decreased back to the response in the control condition 60 min after (Fig. 1B, histogram 4 and dashed curve). Again, the overall shapes of the frequency–response curve and the BF did not change. The maximum amount of increase in the response at BF was 52.3 ± 7.3% (SE) for the 10 cortical neurons and 40.5 ± 6.2% for the 11 collicular neurons (Fig. 2Aa, open symbols). This difference in the amount of increase between the cortical and collicular neurons was insignificant (P > 0.05). Although the recovery of the increased response tended to be slightly slower for the 10 cortical neurons (105 ± 4.7 min) than that for the 11 collicular neurons (90 ± 4.5 min), this difference in recovery was also statistically insignificant (P > 0.05). The BFs of these cortical and collicular neurons were measured over 150 min after a NMDA application. Both the cortical and collicular neurons showed no sign of BF shifts for NMDA application (Fig. 2Ab, open symbols).
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). The response of this neuron at 24.5 kHz reduced by 45% 30 min after an APV application to the AC (histogram 2 and ). It recovered to the response in the control condition 120 min after the application (histogram 4 and dashed curve). Figure 1D shows the responses and frequency–response curves of a collicular neuron tuned to 22.5 kHz (histogram 1 and ). The response at 22.5 kHz decreased by 43% 30 min after the APV application to the AC (histogram 2 and ). It recovered to the response in the control condition 120 min after (histogram 4 and dashed curve). The maximum amount of reduction was 48.3 ± 5.6% for the 10 cortical neurons and 44.3 ± 5.1% for the 9 collicular neurons (Fig. 2Aa, filled symbols). The difference in decrease between the cortical and collicular neurons was insignificant (P > 0.05). The time-course of the decrease in response was the same for the cortical and collicular neurons (P > 0.05). Both the collicular and cortical neurons showed no BF shifts for APV (Fig. 2Ab, filled symbols). As shown above, the effects of APV and those of NMDA were the same between the cortical and collicular neurons. The collicular response changes apparently depended on the cortical response changes and were produced by the corticofugal feedback.
Effects of NMDA or APV applied to the IC on cortical and collicular auditory responses (without conditioning)
To complement the above experiments, NMDA or APV was applied to the IC. NMDA applied to the IC augmented the auditory responses of all 13 cortical and 9 collicular neurons studied, whereas APV applied to the IC reduced the auditory responses of all 12 cortical and 11 collicular neurons studied. The maximum increase in the response at the BF evoked by NMDA was 50.0 ± 5.6% for the cortical neurons and 43.0 ± 4.7% for the collicular neurons (Fig. 2Ba, open symbols). The maximum decrease in response at the BF evoked by APV was 68.0 ± 5.8% for the cortical neurons and 65.2 ± 6.3% for the collicular neurons (Fig. 2Ba, filled symbols). The amount and time-course of the changes evoked by NMDA or APV did not differ between the cortical and collicular neurons (P > 0.05). However, the effect of APV lasted 30 min longer than that of NMDA (P < 0.05). NMDA and APV applied to the IC did not evoke BF shifts (Fig. 2Bb). NMDA or APV applied to the IC showed an identical effect on the cortical and collicular neurons. As described above, NMDA or APV applied to the AC or IC changed to the same extent the auditory responses of all the cortical and collicular neurons studied. These observations perhaps indicate that NMDA or APV applied to the AC or IC uniformly affected neurons in the AC or IC where a drug was applied.
Because both the cortical and collicular changes became large within a few minutes after a drug application and stayed that way over 30 min, these drugs were applied 5 min before the conditioning to examine the drug effects on the development of BF shifts elicited by 15- or 30-min conditioning.
Cortical and collicular plasticity evoked by 15-min conditioning accompanied with NMDA applied to the AC
A 15-min conditioning consisting of a short train of ASt followed by an ESl did not evoke reliable BF shifts of all 10 cortical and 13 collicular neurons studied. A saline solution applied to the AC or IC before the conditioning also did not evoke BF shifts (Fig. 3, B and D, curve a), as previously reported by Ji et al. (2001). However, the conditioning accompanied with NMDA applied to the AC evoked large cortical and collicular BF shifts. In Fig. 3A, a cortical neuron was tuned to 30.0 kHz (). When NMDA was applied to the AC before the conditioning, its responses were augmented to tone bursts between 27.0 and 38.0 kHz, but not to the tone burst at 25.0 kHz, the frequency of the conditioning tone. Its background discharges did not increase. The amount of augmentation was 28% at 30.0 kHz and 152% at 28.0 kHz. Because of this frequency-dependent augmentation, the frequency–response curve changed its shape and the BF shifted from 30.0 to 28.0 kHz, i.e., toward the frequency of the conditioning tone at 25.0 kHz (). At 150 min after the onset of the conditioning, the amount of augmentation reduced to 76% at 28.0 kHz, whereas the response at 30.0 kHz reduced to 27% less than the control response. The shifted BF did not recover (Fig. 3A, dashed curve), even 210 min after the conditioning (Fig. 3B, curve b). All 12 cortical neurons studied with the 15-min conditioning accompanied with NMDA showed basically the same changes as described above. Curve b in Fig. 3B shows the mean time course of BF shifts of the 12 cortical neurons. The cortical BF shift reached a plateau at 2.0 ± 0.06 kHz 15 min after the onset of the conditioning, and showed no sign of recovery even 210 min after.
In Fig. 3C, a collicular neuron was tuned to 23.0 kHz (). The conditioning accompanied with NMDA applied to the AC evoked the frequency-dependent augmentation of the responses of the collicular neuron: 22% increase at 23.0 kHz and 150% increase at 22.5 kHz. Therefore the BF of the neuron shifted toward the conditioning tone that was 18 kHz (). The neuron showed no response change at 18 kHz. Unlike the cortical BF shift, the collicular BF shift recovered 150 min after the onset of the conditioning (dashed curve). On average, the BF shift of the 13 collicular neurons evoked by the conditioning accompanied with NMDA was largest (1.08 ± 0.09 kHz) at 45 min after the onset of the conditioning and completely recovered 165 min after (Fig. 3D, curve b). The collicular BF shift was significantly smaller than the cortical BF shift (Fig. 3, B, curve b vs. D, curve b; P < 0.05).
NMDA applied to the AC or IC without conditioning augmented the cortical and collicular auditory responses to nearly the same amount. However, its augmenting effect on the BF shifts evoked by the conditioning was quite different between cortical and collicular neurons.
Cortical and collicular plasticity evoked by 15-min conditioning accompanied with NMDA applied to the IC
To complement the above experiments, NMDA was applied to the IC before the 15-min conditioning, and its effects were studied on the auditory responses and the BF shifts of 10 cortical and 17 collicular neurons. The conditioning accompanied with NMDA augmented the auditory responses and shifted the BFs of all the cortical and collicular neurons studied. The increase in background discharges of these neurons, 8 ± 0.7%, was insignificant (P > 0.05). The cortical BF shift was 2.0 ± 0.16 kHz (n = 10) and recovered to the control BF at 150 ± 4.7 min after the onset of the conditioning (Fig. 3B, curve c). Therefore the BF shift in the AC elicited by the conditioning accompanied with NMDA applied to the IC was as big as that evoked by the conditioning accompanied with NMDA applied to the AC, but it was short-term. The BF shift was 1.00 ± 0.09 kHz for 15 collicular neurons. It recovered to the control BF 150 ± 3.6 min after (Fig. 3D, curve c). Thus there was a clear difference in BF shifts between the cortical and collicular neurons.
Effects of APV applied to the AC on the development of cortical and collicular plasticity elicited by 30-min conditioning
Unlike the 15-min conditioning, a 30-min conditioning evoked long-term cortical and short-term collicular BF shifts. A saline solution applied to the AC and IC before the conditioning had no effect on these BF shifts evoked by the conditioning (Fig. 4, B and D, curve a), as previously reported by Ji et al. (2001). APV applied to the AC before the conditioning reduced the development of the BF shifts caused by the conditioning of all nine cortical and eight collicular neurons studied and changed the cortical BF shift from long-term to short-term.
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). APV applied to the AC before the conditioning reduced the auditory responses at the frequencies between 34.0 and 41.5 kHz. The reduction was the largest at 38.0 kHz, the neuron's BF. The BF shifted by 0.5 kHz toward the conditioning tone at 33.0 kHz 30 min after the onset of conditioning (). The BF recovered to that in the control condition within 90 min, but the recovery of the auditory response took 150 min (dashed curve). For the nine cortical neurons studied, the BF shift was 0.70 ± 0.10 kHz, and the recovery time was 90 ± 5 min. It was significantly smaller (53% less) and shorter-lasting compared with that caused by the 30-min conditioning without APV (Fig. 4B, curve b vs. curve a; P < 0.01). APV applied to the AC before the conditioning had the same effects on eight collicular neurons studied as on the cortical ones. That is, it reduced the auditory responses and the development of the BF shift elicited by the conditioning. For the eight collicular neurons studied, the mean BF shift was 0.5 ± 0.07 kHz. It was significantly smaller (76% less) than that evoked by the 30-min conditioning without APV (Fig. 4D, curve b vs. curve a; P < 0.01).
Effects of APV applied to the IC on the development of cortical and collicular plasticity elicited by 30-min conditioning
APV applied to the IC significantly reduced the development of the cortical BF shift elicited by the 30-min conditioning. In Fig. 4C, a cortical neuron was tuned to 33.0 kHz (). After the conditioning, following an APV application to the IC, the neuron's response decreased in the range from 31.0 to 35.0 kHz. The maximum reduction was 77% that occurred at 33.0 kHz. The BF shifted from 33.0 to 32.5 kHz 30 min after the onset of the conditioning (). It was further shifted to 32.0 kHz 90 min after (
), i.e., toward the frequency of the conditioned tone at 28.0 kHz. This shift was small and short-term (dashed curve). The mean BF shift of the eight cortical neurons studied was 1.00 ± 0.07 kHz (Fig. 4B, curve c), instead of 1.75 ± 0.05 kHz (n = 10) that was elicited by the conditioning without APV (Fig. 4B, curve a). This difference was significant (P < 0.05).
On the other hand, APV applied to the IC before the conditioning drastically reduced the auditory responses of all eight collicular neurons studied by 83 ± 5.3% and abolished the development of the collicular BF shift which otherwise was elicited by the conditioning (Fig. 4D, curve c).
Effects of NMDA + atropine applied to the AC before the 15-min conditioning on cortical and collicular plasticity
As shown in Fig. 3, the 15-min conditioning alone caused no cortical and collicular BF shifts (Ji et al. 2001), but caused the large, long-term cortical BF shift and the large, short-term collicular BF shift when it was accompanied with NMDA applied to the AC. To examine the contribution of NMDA receptors to these changes while blocking muscarinic ACh receptors, NMDA and atropine were simultaneously applied to the AC before the 15-min conditioning. Then, we found that the auditory responses and the BF shifts of cortical and collicular neurons became smaller and more short-term than those elicited by NMDA plus the conditioning without blocking ACh receptors. In Fig. 5A, a cortical neuron was tuned to 21.0 kHz (). NMDA + atropine applied to the AC before the conditioning augmented the responses of the neuron to tone bursts (118% increase at 19.5 kHz), and shifted its BF from 21.0 to 19.5 kHz (), i.e., toward the conditioning tone at 16.0 kHz. About 150 min after the onset of the conditioning, the auditory responses and the BF recovered to those in the control condition (dashed curve). On average, the cortical BF shift was 1.35 ± 0.08 kHz (n = 9) and the recovery time of the BF was 150 min after the onset of the conditioning (Fig. 5B, curve a). Atropine apparently reduced the development of the long-term cortical BF shift elicited by the conditioning accompanied with NMDA and made it short-term.
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). Its response at 24.5 kHz was augmented by 96% and its BF shifted from 25.5 to 24.5 kHz (), i.e., toward the frequency of the 20.5 kHz conditioning tone when the conditioning was preceded by NMDA + atropine applied to the AC. These changes recovered to the control condition 105 min after the onset of the conditioning (dashed curve). The eight collicular neurons studied in the same way showed basically the same changes as described above. The collicular BF shift was 0.7 ± 0.11 kHz (n = 8; Fig. 5D, curve a), which was the same as that evoked by the conditioning accompanied with NMDA applied to the AC (Fig. 5D, curve c). However, it lasted for 120 min, 45 min shorter than that evoked by the conditioning accompanied with NMDA without atropine (P < 0.05). Effects of NMDA + atropine applied to the IC before 15-min conditioning on cortical and collicular plasticity
As shown in Fig. 3, NMDA applied to the IC before the 15-min conditioning augmented the responses to tone bursts and the subthreshold cortical and collicular BF shifts elicited by the conditioning. When atropine was applied together with NMDA to the IC before the conditioning, however, both cortical and collicular neurons showed almost no augmentation of the auditory responses of the cortical (11 ± 0.9%, n = 9) and collicular (7 ± 1.0%, n = 10) neurons studied. The BF shift was small and short-term for both the cortical and collicular neurons. The BF shift at the peak was 0.72 ± 0.10 kHz for the 9 cortical neurons studied (Fig. 5B, curve b) and 0.5 ± 0.10 kHz for the 10 collicular neurons studied (Fig. 5D, curve b). These BF shifts evoked by the 15-min conditioning accompanied with NMDA were, respectively, reduced 53 and 55% by atropine (P < 0.01 for curves b vs. d in Fig. 5B; P < 0.05 for curves b vs. d in Fig. 5D).
Effects of APV + ACh applied to the AC before 15-min conditioning on cortical and collicular plasticity
Because atropine applied to the AC or IC reduced the changes in the auditory responses and BF shifts of both cortical and collicular neurons evoked by the conditioning accompanied with NMDA, we examined how the changes evoked by the 15-min conditioning accompanied with ACh were affected by blocking NMDA receptors with APV. We applied APV and ACh together to the AC before the 15-min conditioning. In Fig. 6 A, a cortical neuron was tuned to 36.0 kHz (). When both APV and ACh were applied to the AC before the conditioning, the cortical neuron's response increased by 36% at 35.0 kHz and its BF shifted from 36.0 to 35.0 kHz, i.e., toward the conditioning tone at 31.0 kHz, 30 min after the onset of the conditioning (). Ninety minutes after, however, the BF partially recovered () and stayed at 35.5 kHz thereafter (dashed curve). That is, this small cortical BF shift was long-term. Curve a in Fig. 6B shows the mean of the BF shifts of the 11 cortical neurons studied in the same way. The BF shift developed to 1.2 kHz and plateaued there for 45 min. Then, it decreased and plateaued at 0.75 ± 0.1 kHz (n = 11). It showed no sign of recovery even 210 min after the onset of the conditioning. The BF shift at the plateau caused by 15-min conditioning accompanied with ACh was reduced 57% by APV (Fig. 6B, curves c vs. a).
Collicular neurons showed almost no changes in response and BF for the conditioning accompanied with APV + ACh applied to the AC. The mean BF shift of nine collicular neurons studied was 0.3 ± 0.04 kHz (Fig. 6D, curve a), which was a statistically insignificant shift (P > 0.05).
Effects of APV + ACh applied to the IC before 15-min conditioning on cortical and collicular plasticity
ACh applied to the IC before the 15-min conditioning augments the responses to tone bursts and the subthreshold BF shifts elicited by the conditioning, so that the 0.2-kHz cortical and 1.0-kHz collicular BF shifts are evoked (curve d in Fig. 6, B and D; Ji et al. 2001). However, ACh applied together with APV to the IC reduced the collicular and cortical auditory responses and completely abolished the development of the cortical BF shift elicited by the conditioning accompanied with ACh (Fig. 6B, curve b). It evoked the very small collicular BF shift, which was statistically insignificant (Fig. 6D, curve b; P > 0.05). In Fig. 6C, a collicular neuron was tuned to 25.0 kHz (). After an APV + ACh application to the IC before the conditioning, the response of the neuron at 25.0 kHz decreased by 60%. Its BF did not change (Fig. 6C, ).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). A comparison between these two sets of data gives us an insight into the contributions of NMDA and ACh receptors to BF shifts. Effects of an agonist and an antagonist of NMDA or ACh receptors on the auditory responses and the BFs of cortical and collicular neurons
Like ACh, NMDA applied to the AC or IC evoked the augmentation of the auditory responses of cortical and collicular neurons but not a change in their BFs. Like atropine, APV evoked the reduction of the auditory responses of cortical and collicular neurons, but not a change in their BFs. The cortical and collicular changes evoked by NMDA (or APV) were very similar to each other regardless of whether NMDA (or APV) was applied to the AC or IC. The cortical and collicular changes evoked by NMDA were also very similar to those evoked by ACh, whereas those evoked by APV were much larger than the changes evoked by atropine (Fig. 2). The difference of the effect between APV and atropine, however, may be reduced if the dose of atropine is increased.
The effects of NMDA, APV, ACh, or atropine on cortical and collicular auditory responses indicate that as the responses of cortical (or collicular) neurons change, those of collicular (or cortical) neurons also change by the same amount and in the same time course (Fig. 2, A and B). The auditory responses of cortical and collicular neurons strongly depend on the corticofugal feedback loop. The BFs of cortical and collicular neurons are not changed by any of NMDA, APV, ACh, and atropine applied to the AC or IC without conditioning. However, a highly focal pressure injection of a drug to the AC with a micropipette may evoke focal changes in neural activity in the AC and may cause BF shifts. This possibility remains to be tested. As shown in our current results and as discussed later, the developments of the cortical and collicular changes elicited by conditioning are influenced differently by NMDA, APV, ACh, or atropine applied to the AC or IC.
Differences in effect on conditioning-dependent BF shifts between NMDA and ACh
NMDA applied to the AC before the 15-min conditioning augmented the subthreshold BF shifts evoked by the conditioning and produced the large long-term cortical (Fig. 3Bb) and the short-term collicular BF shift (Fig. 3Db). The cortical BF shift was two times larger than the collicular one, although NMDA applied to the AC increased the auditory responses of cortical and collicular neurons by an equal amount. NMDA applied to the IC before the conditioning augmented the subthreshold BF shifts evoked by the conditioning and produced a short-term cortical BF shift that was the same in amount as the long-term cortical BF shift evoked by the conditioning accompanied with NMDA applied to the AC, but was quite different in recovery time (Fig. 3B, curves b vs. c). It also evoked a short-term collicular BF shift that was very similar to that evoked by the conditioning accompanied with NMDA applied to the AC (Fig. 3D, curves b vs. c). These data are different from the data obtained from focal electric stimulation of the AC.
Focal electric stimulation of the AC evokes short-term cortical and collicular BF shifts that are the same in magnitude, but the cortical BF shift tends to last slightly longer than the collicular one (Ma and Suga 2001). The duration of this cortical BF shift becomes slightly shorter and the same as that of the collicular BF shift when the cholinergic basal forebrain is lesioned (Ma and Suga 2003). This observation indicates that activation of the AC by focal electric stimulation activates the cholinergic basal forebrain.
ACh applied to the AC makes the cortical BF shift evoked by focal electric stimulation of the AC larger and changes it from short-term to long-term (Ma and Suga 2005). The long-term cortical BF shift produced by the 15-min conditioning accompanied with NMDA applied to the AC is probably due to both an increase in the cortical auditory responses by NMDA (Fig. 2Aa) and the activation of cortical ACh receptors by ACh released by the cholinergic basal forebrain that was activated by the AC through the amygdala. On the other hand, NMDA applied to the IC before the conditioning increased collicular auditory responses (Fig. 2Ba) and transiently increased the cortical BF shift (Fig. 3Bc). This cortical BF shift did not change into long-term, presumably because of the weak activation of the cholinergic basal forebrain by NMDA applied to the IC though the MGB, AC, and amygdala, which was unlike NMDA directly applied to the AC.
Similar with NMDA applied to the AC, the 15-min conditioning with ACh applied to the AC evoked the long-term cortical and the short-term collicular BF shift. The cortical BF shift was two times larger than the collicular one (Fig. 3, Bd vs. Dd). The conditioning accompanied with ACh applied to the IC evoked the short-term collicular BF shift as did that accompanied with NMDA applied to the IC. However, it evoked only a very small cortical BF shift unlike that accompanied with NMDA applied to the IC (Fig. 3, Bc vs. Be), despite the fact that ACh or NMDA applied to the IC both evoked the same amount of augmentation of cortical auditory responses (Fig. 2). We have no explanation of this difference.
Differences in effect on conditioning-dependent BF shifts between APV and atropine
APV applied to the AC before the 30-min conditioning reduced in more than one-half the long-term cortical (Fig. 4Bb) and short-term collicular BF shifts (Fig. 4Db) developed by the conditioning, and changed the cortical BF shift to short-term. This observation indicates that the cortical and collicular BF shifts cannot be fully developed without the activation of cortical NMDA receptors. APV applied to the IC before the conditioning abolished the collicular BF shift (Fig. 4Dc), reduced in half the amount of cortical BF shift, and made it short-term (Fig. 4Bc). This observation indicates that the development of the cortical BF shift is assisted by the collicular BF shift and that the neural net in the AC and/or corticothalamic feedback loop can produce the cortical BF shift, as described by Suga and Ma (2003).
The effects of atropine applied to the AC show noticeable differences from those of APV applied to the AC. Namely, atropine applied to the AC before the conditioning blocks the development of the cortical BF shift (Fig. 4Bd) and reduces the collicular BF shift by 19% (Fig. 4Dd; Ji et al. 2001). Atropine is much less effective in reducing the cortical auditory responses than APV (Fig. 2), but it is much more effective in reducing the cortical BF shift than APV. The excitatory synaptic transmitter in the central auditory system is glutamate, so that the collicular BF shift evoked by the corticofugal feedback is presumably affected only slightly by atropine applied to the AC. Atropine applied to the IC before the conditioning abolishes the collicular BF shift (Fig. 4De) and reduces the cortical BF shift by 39% (Fig. 4Be; Ji et al. 2001); it had similar effects to those of APV applied to the IC. These observations indicate that BF shifts are blocked where muscarinic ACh receptors are blocked by atropine, but are still evoked in other places because auditory signal processing in the central auditory system is not blocked by atropine.
Roles of NMDA and ACh receptors in producing BF shifts
The 15-min conditioning accompanied with NMDA + atropine applied to the AC evoked the short-term cortical BF shift that was 33% smaller than that evoked without atropine (Fig. 5Ba) and the short-term collicular BF shift that was similar to that evoked without atropine (Fig. 5Da). The conditioning accompanied with NMDA + atropine applied to the IC evoked the significantly smaller short-term cortical and collicular BF shifts than those evoked without atropine (Fig. 5, Bb and Db). These observations indicate that endogenous ACh in the AC and the IC is necessary to produce the large, long-term cortical BF shift and the large, short-term collicular BF shift.
The 15-min conditioning accompanied with APV + ACh applied to the AC evoked a long-lasting cortical BF shift, but it was 64% smaller at the plateau than that without the APV application (Fig. 6Ba). The collicular BF shift was so small that it was statistically insignificant (Fig. 6Da). The conditioning accompanied with APV + ACh applied to the IC evoked neither a collicular nor a cortical BF shift (Fig. 6, Bb and Db). These observations suggest the following. 1) The long-term cortical BF shift can be evoked by the conditioning accompanied with ACh even when cortical NMDA receptors are blocked significantly by APV. ACh is necessary to produce the long-term cortical BF shift, but NMDA is not. This conclusion is also supported by the observation that the conditioning accompanied with NMDA + atropine applied to the AC did not evoke the long-term cortical BF shift (Fig. 5Ba). 2) The cortical BF shift is augmented by the activation of cortical NMDA receptors. 3) The blockade of cortical NMDA receptors causes no information of the cortical BF shift to be carried down to the IC. 4) The blockade of collicular NMDA receptors reduces the collicular auditory responses and the ascending auditory information of BF shifts.
The cortical BF shift is not the linear summation of the BF shifts that are independently evoked by the NMDA and ACh receptors, but it is due to the interaction between them. In Fig. 7, A and B show the parts of the data presented in Figs. 5B and 6B, respectively. The cortical BF shift evoked by the conditioning accompanied with NMDA + atropine applied to the AC (Fig. 7A, curve b) was smaller and shorter lasting than that evoked by the conditioning accompanied with NMDA applied to the AC (Fig. 7A, curve a). This finding indicates that the cortical BF shift becomes smaller and shorter without the activation of cortical ACh receptors by endogenous ACh. However, the difference between curves a and b (Fig. 7A, curve a–b) does not indicate that the BF shift is totally due to the activation of cortical ACh receptors by endogenous ACh, because curve a–b is quite different from curve d in Fig. 7B that shows the BF shift evoked by the conditioning accompanied with APV + ACh applied to the AC. It rather shows that the BF shift is due to both the activation of cortical ACh receptors by endogenous ACh and the interaction between activated ACh and NMDA receptors.
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Activation of ACh receptors enhances NMDA-induced membrane depolarization by increasing calcium current (Markram and Segal 1990a,Markram and Segal 1990b; Segal 1992) and produces a long-lasting enhancement of NMDA receptor–mediated synaptic transmission (Aigner 1995; Aramakis et al. 1997, 1999). On the other hand, activation of NMDA receptors in the cholinergic basal forebrain evokes an increase in the cortical ACh level (Rasmusson 2000 for review; Fadel et al. 2001). Both NMDA and ACh are involved in producing long-term potentiation (LTP) (Auerbach and Segal 1994, 1996; Hasselmo and Bower 1993; Kaczmarek et al. 1997; Malenka and Nicoll 1993; Markram and Segal 1990b). Activation of NMDA receptors is necessary but not sufficient for the induction of LTP (Aigner 1995; Gu 2002). APV blocks the induction of LTP in the AC (Cox et al. 1992; Kudoh and Shibuki 1996, 1997; Seki et al. 1999, 2001). Atropine blocks the induction of LTP in the hippocampus (Hirotsu et al. 1989). The interaction between ACh and NMDA receptors and their roles in producing LTP are presumably involved in the mechanisms for BF shifts.
LTP and long-term depression (LTD) respectively strengthen and weaken synaptic connectivity (Sheng and Kim 2002), through the depolarization-dependent change in the density of AMPA receptors at the membrane postsynaptic to the modulatory neurons. Strengthening and weakening may also be explained by the Hebbian rule and inhibitory neurons, respectively. Protein synthesis may occur in the auditory cortex within 50 min after the onset of the conditioning, so BF shifts may be stabilized not only by increasing connectivity of preexisting synapses, but also by forming new synapses (Engert and Bonhoeffer 1999; Maletic-Savatic et al. 1999). The data obtained by Ji and Suga (2003) indicate that the cortical BF shift changes from short-term to long-term and that the maximum BF shift for the 30-min conditioning is determined 70 min after the onset of the conditioning. Both the cellular and subcellular phenomena are presumably involved in the development of the cortical BF shift.
Reservations regarding the results and conclusions
There are multiple factors related to BF shifts and drug effects. The cortical BF shift is so small for 15-min conditioning that it was insignificant, but large for 30-min conditioning. It becomes larger when the 30-min conditioning is repeatedly delivered to the bat (Gao and Suga 2000). The effect of atropine applied to the AC on the cortical BF shift varies with the time relationship between the 30-min conditioning and an atropine application (Ji and Suga 2003). The amount and recovery time of the cortical BF shift evoked by focal electric stimulation of the AC depends on the duration of the electric stimulation (Ma and Suga 2001) and on the duration of an ACh application to the AC (Ma and Suga 2005). Therefore the results of these studies may vary if the paradigms of conditioning as well as those of a drug application are varied. For example, the short-term cortical BF shift evoked by the 15-min conditioning with NMDA applied to the IC may become long-term if the duration and/or the dose of a NMDA application are increased. Our current findings and conclusions stand as they are under this experimental paradigm.
In the big brown bat, NMDA (current data) or ACh (Ji et al. 2001) applied to the IC did not change the collicular BF shift from short-term to long-term, and strong electric stimulation (a train of electric pulses, 0.1 ms, 1.25–83 µA) of the AC did not evoke long-term collicular BF shifts (Jen et al. 1998; Ma and Suga 2001, 2003). Unlike the AC therefore the IC itself seems to have no subcellular mechanisms to produce a long-term collicular BF shift. However, in the house mouse, the electric stimulation of the AC with 0.5-µA, 1.0-ms electric pulses evoked a long-term collicular BF shift (Yan and Ehret 2001). In the guinea pig, auditory fear conditioning evokes long-term cortical BF shifts (Galvan and Weinberger 2002) but short-term thalamic BF shifts (Edeline and Weinberger 1991). Therefore the difference in the collicular BF shifts between the bat and the mouse may not be simply due to their species difference. This remains to be further explored.
Our present data and two models for cortical BF shifts
There have been the models of Gao-Suga (1998) and Weinberger (1998) that proposed the neural pathways for the development of the long-term cortical BF shift elicited by auditory fear conditioning (CS-US). An important component in both of these models is the cholinergic basal forebrain. Our current data indicate that ACh, rather than NMDA, plays an essential role in producing the long-term cortical BF shift (Fig. 7Bd) and support both of the models. However, it should be noticed that the Gao-Suga model is different from the Weinberger model in other aspects as described below.
The Gao-Suga model (Gao and Suga 1998; Suga and Ma 2003; Suga et al. 2000) states that small, short-term cortical and collicular BF shifts specific to tone bursts are evoked by the AC and corticofugal feedback activated by the tone bursts. When the tone bursts followed by electric leg-stimulation (i.e., CS-US) are delivered to the animal, both the auditory and somatosensory cortices send signals to the amgydala through the association cortex. When associative learning takes place in the amygdala, it sends the "associated" signals to the cholinergic basal forebrain. The cortical ACh level increases, and the cortical BF shift is augmented, becoming longer lasting. The collicular BF shift is also augmented by the augmented cortical BF shift through the corticofugal system and contributes to the production of the large, long-term cortical BF shift. On the other hand, the Weinberger model (Weinberger 1998, 2004) states that CS-US association occurs in the multi-sensory thalamic nuclei (MGBm/PIN), and the MGBm-to-AC projection evokes a small, short-term cortical BF shift. This BF shift is augmented and changed into long-term by an increased cortical ACh level elicited by the cholinergic basal forebrain that is activated by the MGBm/PIN through the amygdala.
The Gao-Suga model is clearly different from the Weinberger model in the following three aspects. 1) Instead of the MGBm-to-AC projection, the AC and corticofugal feedback (i.e., the neural net intrinsic to the auditory system) evoke tone-specific BF shifts. 2) Instead of the MGBm-to-amygdala projection, the cortex-to-amygdala projection transmits the information of CS and US to the amygdala for the augmentation of the BF shifts. 3) Instead of the simultaneous development of the CS-US dependent plasticity in the AC and the amygdala, the development of the CS-US dependent plasticity in the AC is delayed from that in the amygdala.
The key findings explained below support the Gao-Suga model. 1) Tone-specific cortical and collicular BF shifts can be evoked by either focal electric stimulation of the AC alone (Ma and Suga 2001 2003; Suga and Ma 2003; Zhang and Suga 1997) or by a 30-min train of tone bursts alone (Chowdhury and Suga 2000; Ma and Suga 2001; Yan and Suga 1998). That is, the BF shifts can be evoked by mechanisms that are intrinsic to the auditory system, without any CS-US association in the multi-sensory thalamic nuclei such as MGBm. These findings do not contradict any existing neurophysiological data, because neither electric stimulation nor lesion experiments have been performed to show that the projection from the MGBm to the AC is essential to evoke the tone-specific cortical BF shifts. 2) The corticofugal feedback evokes the conditioning-dependent short-term collicular BF shift, and this collicular BF shift contributes to the large, long-term cortical BF shift (Gao and Suga 1998, 2000; Ji et al. 2001). 3) Inactivation of the somatosensory cortex by muscimol does not affect cortical auditory responses, but selectively abolishes the development of the conditioning-dependent cortical and collicular BF shifts (Gao and Suga 2000). Electric stimulation of the somatosensory cortex after, but not before, acoustic stimulation or electric stimulation of the AC augments the cortical and collicular BF shifts. This augmentation does not occur if the basal forebrain is lesioned (Ma and Suga 2003; Suga and Ma 2003). Therefore the somatosensory cortex, through the cholinergic basal forebrain, plays an essential role in the development of the conditioning-dependent BF shifts. 4) Experiments with tone bursts accompanied with electric stimulation of the cholinergic basal forebrain (Bakins and Weinberger 1996; Ma and Suga 2003) or ACh applications to the AC (Ma and Suga 2005) indicate that ACh released in the AC by the cholinergic basal forebrain augments the development of cortical and collicular BF shifts without the activation of the MGBm by CS-US. 5) Conditioning-dependent auditory responses occur in the amygdala before the AC (Armony et al. 1997, 1998; Li et al. 1996a,Li et al. 1996b; Maho et al. 1995; Maren 2000; Quirk et al. 1995, 1997) and, perhaps, before the MGBm (Maren and Quick 2004). 6) Inactivation of the amygdala prevents the development of conditioning-dependent plastic changes in the MGBm (Maren et al. 2001; Poremba and Babriel 2001). 7) The collicular BF shifts occur downstream to the MGBm. Therefore the MGBm is not the first site where CS-US association occurs.
The Gao-Suga model was proposed to explain the neural pathway for BF shifts without discussing those for conditioned behavioral responses. Neither inactivation of the AC (Jarell et al. 1987) nor decortication (Dicara et al. 1970; Mauk and Thompson 1987; Norman et al. 1974) interferes with the acquisition of conditioned behavioral responses. In other words, conditioned behavioral responses can be evoked without cortical BF shifts. Therefore the BF shifts elicited by auditory fear conditioning can be analyzed and modeled separately from the pathways for the conditioned behavioral responses. The importance of the MGBm/PIN-to-amygdala projection in eliciting conditioned behavioral responses has been well established (Ledoux et al. 1986). The difference in the functional role between the MGBm-to-amygdala and cortex-to-amygdala projections remains to be further examined (Doyere et al. 2003; Romanski and Ledoux 1993).
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Address for reprint requests and other correspondence: N. Suga, Dept. of Biology, Washington Univ., One Brookings Dr., St. Louis, MO 63130 (E-mail: suga{at}biology.wustl.edu)
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