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Laboratory of Sensory Neuroscience, Carleton University, Ottawa, Ontario K1S 5B6, Canada
Submitted 3 December 2002; accepted in final form 15 February 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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) and
species-specific social communication calls
(Stebbins and Moody 1994), the
acoustic identification of objects and events
(Bregman 1990;
Yost 1992), and specialized
functions such as echolocation by bats
(Fenton 1995;
Moss and Schnitzler 1995;
Suga 1988). Many researchers
have used sinusoidal amplitude-modulated (AM) stimuli to determine how neurons
in the central auditory system respond to temporal variations in an acoustic
stimulus. By recording responses to modulated sounds at different rates of
modulation, it is possible to investigate systematically how central auditory
neurons are processing dynamic variations in the stimulus envelope.
Responses of neurons to AM tones have been recorded from various structures
in the auditory nervous system including auditory nerve, cochlear nucleus,
superior olive, dorsal nucleus of the lateral lemniscus, inferior colliculus,
and primary auditory cortex (see Frisina
2001 and Langner
1992 for reviews). At every level of the auditory pathway, the
discharge of sound-evoked action potentials is synchronized to the period of
AM at low modulation rates. However, there are marked differences among
structures in the upper limit of modulation frequencies that produce response
synchrony, the precision with which the neural discharges are phase-locked to
the modulation cycle, and the shape of the modulation transfer functions that
relate firing rate and response synchrony to a wide range of modulation
frequencies.
The upper limit of modulation frequencies that produce synchronous firing
to the envelope of a sinusoidal AM stimulus is generally higher for auditory
neurons near the periphery than it is more centrally. For example, in the
auditory nerve, responses are commonly phase-locked to modulation rates up to
800 Hz, whereas synchronous responses in the inferior colliculus are rarely
found at rates above 200 Hz (Møller
and Rees 1986; Palmer
1982; Rees and Møller
1983,
1987). Also, the modulation
transfer functions for response synchrony in the auditory nerve are typically
low-pass, whereas the transfer functions at higher levels including the
inferior colliculus usually exhibit band-pass characteristics (see
Frisina 2001). The maximum
vector strength is generally higher for neurons in the inferior colliculus
than it is for neurons in the auditory nerve
(Krishna and Semple 2000).
Also, the modulation transfer functions based on firing rate exhibit more
diversity as one ascends the auditory pathway and can include band-pass,
band-reject, and various other profiles
(Krishna and Semple 2000;
Langner and Schreiner 1988;
Rees and Møller 1983;
Walton et al. 2002). Many
band-pass neurons in the inferior colliculus are tuned to specific modulation
frequencies, suggesting the possibility of a spatial code for temporal
variations in the amplitude of the stimulus (see
Langner 1992).
Pharmacological studies have shown that local synaptic transmission is
important for determining response synchrony as well as firing rate of neurons
to AM sounds in several auditory lower brain stem nuclei. For example,
GABAA receptor agonists and antagonists delivered locally by
iontophoresis can substantially alter the synchrony of responses in the
cochlear nucleus (Backoff et al.
1999), the medial superior olive
(Grothe 1994), or the dorsal
nucleus of the lateral lemniscus (Yang and
Pollak 1997). On the other hand, Burger and Pollak
(1998) found that neither the
GABAA receptor antagonist, bicuculline, nor the
N-methyl-D-aspartate (NMDA) receptor antagonist,
2-amino-5-phosphonovaleric acid (APV), substantially affected the upper limit
of response synchrony of neurons in the inferior colliculus of the mustache
bat. However, in a recent study, Caspary et al.
(2002) reported that
iontophoretic release of bicuculline can alter the shape of modulation
transfer functions for some neurons in the chinchilla's inferior
colliculus.
Electrophysiological studies of excitatory and inhibitory neurotransmitters
in the rat's inferior colliculus show that both AMPA and NMDA receptors, as
well as GABAA receptors, shape responses to acoustic stimulation
(Faingold et al. 1989,
1991;
Zhang and Kelly 2001). In
vitro studies indicate that these receptors have substantially different time
courses for activation, suggesting that the interaction among receptor types
could play a significant role in determining the timing of responses to
dynamic acoustic stimuli (Li et al.
1999; Ma et al.
2002). In particular, the AMPA receptor has a rapid time course
and the NMDA receptor has a much slower time course for activation, resulting
in distinct early and late components of excitatory postsynaptic potentials
(EPSPs) elicited by current pulse stimulation of the lateral lemniscus
(Ma et al. 2002).
Zhang and Kelly (2001) have
shown that local iontophoretic application of the AMPA receptor antagonist,
1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide
disodium (NBQX), blocks tone-evoked activity in the rat's central nucleus of
the inferior colliculus (ICC) with a prominent effect on the early (fast)
component of the response, whereas the NMDA receptor antagonist,
(±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), has a
preferential blocking effect on the later (slow) component of the response.
Similar data have been reported for neurons in the barn owl's inferior
colliculus (Feldman and Knudsen
1994). The selective effect of AMPA and NMDA receptor antagonists
on the timing of evoked activity in the inferior colliculus suggests that
different receptor types might make selective contributions to the temporal
structure of responses elicited by amplitude-modulated sounds at different
rates of modulation. The main purpose of the present study was to determine
the effects of AMPA, NMDA and GABAA receptor antagonists on
responses of ICC neurons to AM tones over a wide range of modulation rates.
Modulation transfer functions for both firing rate and response synchrony were
determined before, during, and after local delivery of the receptor
antagonists by iontophoresis.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Experiments were conducted on 48 male adult Wistar albino rats (Rattus
norvegicus; 250–500 g) obtained from Charles River Canada, St.
Constant, Quebec, Canada. The external ears and tympanic membranes of all
animals were examined with an otoscope and determined to be free of infection
or other abnormalities. Animals were anesthetized with one of the following
two methods: an initial injection of pentobarbital sodium (60 mg/kg ip) and
supplemental injections of ketamine hydrochloride (30 mg/kg im) or
pentobarbital sodium (20 mg/kg ip) at intervals of 
1 h throughout the
course of an experiment or an initial injection of a combination of ketamine
hydrochloride (90 mg/kg im) and xylazine hydrochloride (10 mg/kg im) and
supplemental injections of ketamine hydrochloride (30 mg/kg im) and xylazine
hydrochloride (3.3 mg/kg im) at intervals of 1 h throughout the course of
an experiment. No differences were noticed in the results of experiments
conducted with these anesthetics.
A midline incision was made in the scalp, the skin and muscles were retracted laterally, and a small craniotomy was made to permit insertion of a pipette assembly for recording and drug release into the ICC. Several small screws were placed in the skull dorsally and fixed to a stainless steel rod with dental acrylic. The rod was then attached to a stereotaxic instrument holding the head firmly in place while leaving the external ear canals free for insertion of earphone drivers. Recordings were made with the rats inside a single-wall sound-attenuated booth (Eckel Industries).
All procedures used in these experiments were approved by the Carleton University Animal Care Committee and were in accordance with the guidelines of the Canadian Council on Animal Care.
Sound stimulation
Sounds were presented monaurally to the right ear through a sealed headphone assembly (Beyerdynamic DT 48) connected to a hollow speculum inserted into the rat's external meatus. To reduce acoustic cross talk, a second headphone assembly was inserted into the left external ear, although no sound was delivered through the headphone. The acoustic waveforms were generated digitally by MALab 881 software controlled by a Macintosh G-3 computer. The sound-generation and data-acquisition system (MALab 881) was designed and developed by Dr. Malcolm Semple (Center for Neural Science, New York University) and Steve Kaiser and produced by Kaiser Instruments.
The stimuli used in this study included noise bursts, tone bursts, and sinusoidal amplitude-modulated (AM) tones. Noise bursts (100-ms duration, 10-ms rise-fall time) served as a search stimulus. Tone-bursts (100-ms duration, 10-ms rise-fall time) were used to determine each single neuron's characteristic frequency (CF, the frequency at which the neuron showed the lowest response threshold) and rate-level function at CF. The AM stimuli (10-s duration, 10-ms rise-fall time) were used to study the effects of change in modulation rate on the strength of firing and the synchronization of discharges to the modulation envelope. Tone bursts were presented 20 times at a repetition rate of 1/s to generate a summed neural response. The AM stimulus was presented twice at a rate of 1/12 s to generate a summed response.
The sound pressure level for all stimuli was calibrated over a frequency range of 100–40,000 Hz using a condenser microphone (Bruel & Kjaer 4134) with the headphone assembly fitted into an enclosed chamber constructed from tygon tubing. The acoustic response of the headphone assembly was adjusted on-line to provide a constant sound pressure level over the range from 500 Hz to 30 kHz.
Recording and drug delivery
A piggy-back multibarrel glass electrode
(Havey and Caspary 1980) was
used for extracellular recording and iontophoretic delivery of drugs. The
electrode was fabricated by fixing a single-barrel recording micropipette to a
five-barrel glass pipette with a cyanoacrylate glue (Viachem, Montreal,
Quebec) at an angle of about 20°. The tip of the single-barrel pipette was
2–3 µm in diameter, and the tip of the five-barrel pipette was
8–10 µm. The recording electrode was filled with 3 M potassium
chloride. One barrel of the five-barrel pipette was filled with NBQX (5 mM, pH
9.0, Sigma), an AMPA receptor antagonist, another barrel was filled with CPP,
10 mM, pH 8.0, Sigma), an NMDA receptor antagonist, and a third barrel was
filled with (–)-bicuculline methiodide (BMI, 10 mM, pH 3.4, Sigma). The
remaining two barrels were filled with 165 mM sodium chloride for maintaining
an electrical balance across the injection pipette tip.
The electrode assembly was driven by a Kopf model 650 micropositioner. The multibarrel pipette was connected to iontophoresis pumps of a Neurophore-BH-2 micro-iontophoresis system. Neural activity registered by the single-barrel pipette was amplified by a Dagan EX 4–400 Quad differential amplifier and monitored audiovisually. Neural responses were digitized and discriminated on the basis of amplitude and waveform using an A/D converter and MALab 881 software. The occurrence time of spikes was recorded with 1-µs resolution, stored on computer and processed later with standard data base and graphics software.
Recording procedure
During a recording session, the left ICC was approached obliquely with the electrode tilted by 30° relative to the sagittal plane and stereotaxic coordinates were referenced to a point 3.8–5.0 mm lateral and 0.3–0.5 mm rostral to lambda. The electrode was then lowered into the brain to a depth between 2.3 and 6.0 mm while searching for responses to acoustic stimulation. As the electrode was lowered into the brain a retaining current of +10 nA was applied to the pipette barrels containing NBQX and CPP, and a current of –10 nA was applied to the barrel containing bicuculline to prevent leakage of the drugs during the search for single-unit activity and during predrug recording or postdrug recovery phases of the experiment.
Single-unit activity was recognized by spikes of constant amplitude and waveform. A window discriminator was used to isolate spikes from background activity. We typically used a noise burst presented to the right ear to search for responsive neurons. After an auditory neuron had been identified, tone bursts of variable frequency and amplitude were used to determine CF and the threshold at CF on the basis of sound-evoked spike counts and audiovisual monitoring of acoustically driven responses. Rate-level functions were then determined by systematically varying the sound pressure level of the tone at the cell's CF. The responses to AM tones were recorded with the carrier frequency at the cell's CF and the depth of modulation at 100%. The modulation rates were varied between 0.5 and 1,000 Hz. The sound pressure level of the AM stimulus was typically set at 15–20 dB above the tone-burst threshold at CF.
NBQX, and/or CPP, and/or bicuculline were delivered iontophoretically to the recording site. The currents used to release the drugs were –20 to –60 nA (typically about –30 nA) for NBQX, –5 to –15 nA (typically about –10 nA) for CPP, +5–25 nA (typically about +10 nA) for bicuculline. The effect of the drug on firing rate was monitored by repeatedly generating a rate-level function at the cell's CF. When a change in spike count reached a plateau, the responses to AM tones at various modulation rates were recorded. After the responses to modulated tones had been recorded, drug release was discontinued and the holding currents were re-applied. Recovery was observed by continuing to monitor the cell's rate-level function or responses to AM stimuli after the drug release was discontinued.
Data analysis
Peristimulus time histograms for both tone bursts and sinusoidally modulated tones were collected from all neurons involved in this study. The responses to tone bursts were categorized on the basis of the temporal pattern of spike discharge into two broad groups: onset and sustained. Onset responses were defined as those with a transient burst of action potentials at the beginning followed by inactivity for the remainder of the tone (100 ms). Sustained responses were defined as those with sound-evoked activity for the duration of the tone. These included responses in which a pause separated an initial burst of action potentials from continued firing as well as responses in which spike discharges were maintained for the entire period of the tone without interruption.
For responses to AM tones, spikes recorded during the first 100 ms of each stimulus presentation were excluded from the analysis to avoid contamination by transient onset activity. Period histograms were constructed to show the summed distribution of spikes over each modulation cycle and to show the extent to which spike discharges were synchronized to the modulation envelope.
A measure of vector strength, as described by Goldberg and Brown
(1969), was used to
characterize the synchrony of neural firing with each modulation cycle of the
AM stimulus. Vector strength was defined as follows
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Where 
i is the phase of spike i relative to the
sinusoidal modulation cycle [i.e., 2
(frequency of modulation) (occurrence
time of spike i)]. A VS of 1 indicates perfect phase-locking, whereas a VS of
0 reflects a lack of correlation between the neural firing and the modulation
waveform.
Vector strength was plotted versus modulation frequency to create a temporal modulation transfer function (MTFVS). We also calculated a modulation transfer function based on the neuron's firing rate (MTFFR) to determine how the drugs affected the total amount of neural activity at each modulation rate.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Normal response properties
Our sample of 89 neurons included 25 that responded to a 100-ms tone with only a transient, short-latency burst of action potentials (an onset response) and 64 that generated action potentials for the duration of the tone burst (a sustained response). Because these two groups of neurons exhibited different patterns of response to AM stimuli they were treated separately in our data analysis.
Figure 1 shows the effect of
sinusoidal AM on a neuron with a sustained response to tone bursts. The
response to a 50-dB SPL tone burst presented at CF (3.0 kHz) is illustrated in
Fig. 1A. This neuron
had a monotonic rate level function with an excitatory threshold 30 dB
SPL and a saturation point near 50 dB SPL
(Fig. 1C). The
response to an AM tone with the carrier frequency at CF (50-Hz modulation
rate, 50 dB SPL) was continuous for the duration of the modulated stimulus
(Fig. 1B). The number
of action potentials was dependent on the rate of modulation as indicated in
Fig. 1E. The
MTFFR had a band-pass shape and peaked at a modulation rate of 20
Hz. The action potentials were synchronized to the period of the AM, as shown
by the histograms for different rates of modulation in
Fig. 1D. The degree of
synchrony as measured by vector strength at different rates of modulation (the
MTFVS) is illustrated in Fig.
1F.
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Figure 2 shows the effect of sinusoidal AM on a neuron with an onset pattern of firing to tone bursts. Slightly more than half of the onset neurons that we encountered responded continuously to modulated sounds (13 of 25 cells) as shown in this example. The other neurons (12 of 25 cells) responded to AM tones only at the beginning of each stimulus presentation and, therefore could not be analyzed further with regard to continuous firing rate or synchrony of discharge to the modulation envelope. For the neuron illustrated in Fig. 2, the response to a CF tone (27.0 kHz at 50 dB SPL) and the rate level function are shown in A and C, respectively. The continuous response to a 50-Hz modulated tone with the carrier frequency at CF is shown in Fig. 2B. The distribution of spikes over the period of the AM stimulus at different modulation rates is represented by histograms in Fig. 2D. The cell responded well to the AM stimulus at modulation frequencies between 20 and 200 Hz but showed no response at higher or lower frequencies. Thus the MTFFR was narrowly band-pass with a best rate of 50 Hz (Fig. 2E). The spikes were highly synchronized to the modulation envelope as indicated by the MTFVS (Fig. 2F).
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The predrug data have been summarized in Fig. 3 by plotting the mean MTFVS and the mean normalized MTFFR for all neurons with sustained or onset responses to tone bursts. Neurons with sustained firing had various shapes of MTFFR including band-pass, low-pass, high-pass, all-pass, band-suppressed, and others that did not fit our simple classification scheme. Of the 64 ICC neurons with sustained responses to tone bursts, 44% (28 neurons) were band-pass, 5% (3 neurons) were low-pass, 6% (4 neurons) were high-pass, 3% (2 neurons) were all-pass, 30% (19 neurons) were band-suppressed, and 13% (8 neurons) were other. Band-pass neurons included those that responded to midrange (10–200 Hz) modulation rates only (42% of the cells) as well as those that responded more broadly to AM stimuli but with a preferred rate in their MTFFR (58% of the neurons). Because of differences among neurons in the shapes of their MTFFR and their preferred rates of modulation, the mean MTFFR was nearly flat as shown in Fig. 3A.
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When the modulation rate was between 50 and 100 Hz, the responses of neurons with sustained firing to tone bursts were highly synchronized to the modulation cycle of the stimulus as indicated by the mean MTFVS in Fig. 3A. The maximum vector strength derived from the mean MTFVS was 0.85 at rate of 50 Hz. Vector strength dropped to 0.50 and 0.13 at 1 and 500 Hz, respectively. The upper limit of synchronized firing as defined by a mean vector strength of 0.3 was 250 Hz.
The averaged data for onset neurons are shown in
Fig. 3B. These neurons
typically had a band-pass MTFFR narrowly tuned to modulation rates
50 Hz. Thus the mean MTFFR showed a clear maximum at 50 Hz
dropping to near zero at frequencies <10 and >200 Hz. The responses were
highly synchronized to the modulation envelope and the mean vector strengths
were 0.93 and 0.91 at 50 and 100 Hz, respectively, as indicated by the mean
MTFVS shown in Fig.
3B. The vector strengths for higher or lower modulation
rates were not calculated because the firing rates were too low. Thus the
upper limit of response synchrony to AM stimulation could not be defined with
precision for onset neurons.
Considering the idea that band-pass neurons might play a special role in establishing a place code for modulation rate in the ICC, we examined how the values for best rate were distributed in our sample. The best modulation rates for all neurons with a band-pass MTFFR covered a range of values from 10 to 300 Hz with the largest percentage of cells responding maximally to 50 Hz (see Table 1). The prevalence of neurons with a best rate of 50 Hz can be attributed largely to the inclusion in our sample of neurons with either onset or sustained patterns of response to tone bursts. The cells with an onset pattern showed a distinct preference for 50 Hz, whereas those with sustained response patterns showed much more diversity in their preferred rate of modulation.
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There was no significant correlation between the best modulation frequency and the cell's CF as determined from their tone burst responses. The absence of a significant correlation was apparent for our entire sample of neurons (r = 0.07), for the subset of neurons with sustained responses to tones (r = 0.07), for those sustained neurons with band-pass MTFFR's (r = 0.28), or for the subset of neurons with onset responses to tones (r = 0.17).
Effects of CPP
The NMDA antagonist, CPP, reduced the firing rate to both tone bursts and AM stimuli as shown in Fig. 4, A and B, for a neuron with sustained firing and a nonmonotonic rate level function in response to tone bursts. The firing rate to AM tones was highly dependent on the modulation frequency prior to application of the drug. The normal MTFFR for this neuron was band-pass with a best modulation frequency at 40 Hz. CPP reduced the level of firing to tone bursts at all stimulus levels above threshold and greatly reduced the rate of firing to AM stimuli at all modulation frequencies. The MTFFR, however, retained its band-pass shape and its preferred modulation rate. The effect of CPP on firing rate was reversible, and response strength was restored after cessation of drug application.
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For the neuron shown in Fig. 4, the timing of action potentials in response to AM tones was highly synchronized to the modulation waveform across a wide range of modulation rates. Before application of CPP the vector strength was near 0.8 for all modulation frequencies between 0.5 and 150 Hz with a maximum vector strength of 0.89 at 40 Hz (Fig. 4B). After drug application, the synchrony of responses remained high at all modulation rates that still elicited a response. Action potentials were tightly phase locked to the modulation cycle as shown by the period histograms and the MTFVS (Fig. 4, B and C).
A reduction in firing rate by CPP was observed in 15 of the 16 neurons tested. The mean reduction in the response to tone bursts at the peak of the rate level function was 57% (drug/predrug ratio = 0.43). The mean reduction in response to AM tones at best modulation frequency was 53% (drug/predrug ratio = 0.47). For most neurons, the reduction in firing rate was proportional to predrug levels, and the MTFFR retained its shape and preferred modulation frequency. Of the 16 neurons tested, only two showed a change in best modulation rate: an increase in one case and a decrease in the other.
Eight neurons had a band-pass MTFFR before drug application. Five of these showed a proportional decrease in firing at all modulation frequencies that produced a response before the drug was applied. In one neuron. the firing rate was reduced by a constant amount at all modulation frequencies that normally produced a response. This resulted in the elimination of responses at low rates and a disproportionate skewing of the MTFFR distribution. One band-pass neuron showed complex changes in its MTFFR distribution that were difficult to classify and another neuron showed no change in firing rate.
There was little change in response synchrony as determined from the MTFVS in spite of the substantial reductions in firing rate. For each of the neurons tested with CPP, the maximum vector strength and the best modulation rate for vector strength were very similar to those recorded before drug application. Eleven of the cells that received CPP had a distinct best modulation frequency apparent in their MTFVS. During application of the drug none of these showed a change in vector strength >0.05 at the best modulation frequency.
Effects of NBQX
The effects of the AMPA antagonist, NBQX, are illustrated in Fig. 5A,Fig. 5D for a neuron that had sustained firing and a nonmonotonic rate level function in response to tone bursts. Responses to amplitude modulated stimuli were recorded at two sound pressure levels, 50 and 80 dB, as indicated by the two arrows on the rate level curve shown in Fig. 5A. NBQX reduced the firing rate at most sound pressure levels above threshold but did not completely eliminate the responses to tones at the cell's CF (7.5 kHz). The rate level function for this neuron retained its nonmonotonic shape (Fig. 5A).
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The responses to AM tones at 50 dB SPL with the carrier frequency at CF are illustrated in Fig. 5 B and C. The MTFFR at 50 dB SPL was band-pass with peak firing at modulation rates in the range of 20–50 Hz. NBQX reduced firing at all modulation rates that normally produced a response, but the shape of the MTFFR during drug application was still bandpass with a peak firing rate at 20 Hz. The synchrony of responses to AM stimuli at 50 dB SPL was largely unchanged by application of NBQX. The MTFVS at this sound pressure was essentially low-pass before drug application. During NBQX, the vector strength was not changed at those modulation frequencies for which the firing rate remained high enough to permit a meaningful calculation.
The responses to AM tones at 80 dB SPL are illustrated in Fig. 5, D and E. At this sound pressure, the MTFFR was low-pass rather than band-pass. Nevertheless the effect of NBQX was the same: a reduction in firing at all modulation rates that normally produced a response. The MTFVS at 80 dB was different from that obtained at 50 dB, but the effect of NBQX was the same, viz., no substantial change in response synchrony during drug application. The temporal pattern of discharges during the modulation cycle was largely unaffected despite the reduction in firing rate (Fig. 5E).
Of the 44 neurons tested with NBQX, 41 showed a reduction in firing to both tone bursts and modulated sounds. The mean reduction in response to tone bursts at the sound pressure that produced maximum firing before drug application was 66% (drug/predrug ratio = 0.34) and the mean reduction in firing to AM stimuli at the best modulation frequency was 70% (drug/predrug ratio = 0.30). Typically, the reduction in firing was found at all modulation frequencies that normally produced a response. The number of spikes was reduced in some cases by a constant and in other cases by a proportion of the predrug activity levels at different modulation rates. The shape of the MTFFR was not substantially altered by NBQX. Excluding 9 neurons that showed little or no activity during drug application, there was no change in the best modulation frequency in 29 of the remaining 35 neurons tested. Two neurons showed a slight decrease and four neurons showed an increase in their preferred modulation rate. Additional examples of the effects of NBQX are shown in Fig. 6.
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Twenty-four of the 44 neurons tested with NBQX had bandpass MTFFR at moderate sound pressure levels (15–20 dB above threshold) before drug application. Half of the 24 neurons showed a reduction in activity that was either a constant (7 cases) or a proportion (5 cases) of the predrug level at different modulation rates. Typically, these neurons retained their band-pass MTFFR with a best modulation frequency similar to that found before drug application. Five neurons had complex changes in activity that modified the shape of the MTFFR to some extent, although band-pass characteristics were still evident during drug application. Seven neurons had activity levels that were too low to permit classification of their MTFFR during NBQX.
There was little change in response synchrony to AM stimuli in spite of
substantial reductions in firing rate. At peak modulation rates (determined
from the predrug MTFVS) the vector strength remained unchanged
(
VS <0.05) in 24 of the 27 cells tested. On the other hand, some
cells showed minor to moderate changes in vector strength at off-peak
modulation rates (see Fig. 6, A
and B). Seven neurons showed a decrease in vector
strength at modulation frequencies >50 Hz. Five neurons showed an increase,
and two neurons showed a decrease in vector strength at modulation frequencies
<50 Hz.
Effects of bicuculline
Figure 7 shows an example of the effects of the GABAA antagonist, bicuculline, on a neuron with sustained firing to tonal stimulation and a monotonic rate-level function. With bicuculline, there was a proportional increase in firing rate at all sound levels above threshold (Fig. 7A). The MTFFR for AM stimulation at 30 dB SPL was band-pass with a best modulation rate of 80 Hz. Bicuculline resulted in an increase in firing at all modulation frequencies but did not affect the shape of the MTFFR or change the best modulation frequency (Fig. 7B). For the same neuron, the MTFVS and the corresponding period histograms revealed a high level of response synchrony in the range between 40 and 100 Hz. Application of bicuculline had little effect on vector strength at any modulation frequency in spite of the increase in the over-all level of firing (Fig. 7, B and C).
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A second example of the effects of bicuculline on a neuron with a sustained response to tone bursts is shown in Fig. 8. Bicuculline resulted in an increase in firing rate to tone bursts at all sound pressure levels above threshold and greatly increased the response to modulated sounds (Fig. 8, A and B). The discharge of action potentials was well synchronized to the modulation envelope with a maximum vector strength at 10 Hz (see the period histograms and MTFVS in Fig. 8, B and C). Examination of the distribution of spikes before and during drug application showed a similarity in the temporal pattern of the responses. In spite of the increase in firing rate (93 times at 10 Hz), the degree of response synchrony determined from the maximum vector strength in the MTFVS was not substantially affected by bicuculline.
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An example of the effects of bicuculline on a neuron that had an onset response to tone bursts prior to drug application is shown in Fig. 9. For this neuron, the firing rate to both tone bursts and sinusoidal AM stimuli was greatly increased by drug application. At high sound pressure levels (60–80 dB SPL), a sustained response component emerged in the firing pattern that was not evident in the predrug response to tone bursts (Fig. 9C). The onset and sustained response components are plotted separately in the rate-level functions shown in Fig. 9A.
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The response to AM tones was increased across a wide range of modulation
frequencies, but the band-pass characteristic of the MTFFR remained
the same with a best modulation frequency 60 Hz
(Fig. 9B). Despite
the change in firing pattern in response to tone bursts and the increase in
firing rate in response to AM stimuli, the synchrony of discharges to the
modulation period was not greatly affected by bicuculline. Both the period
histograms and the MTFVS indicate that vector strength and best
modulation frequency were unchanged (Fig.
9, B and D).
Figure 10 illustrates the effects of bicuculline on another neuron with an onset response to tone bursts. For this neuron, bicuculline increased firing to tonal stimulation over a wide range of sound pressure levels (Fig. 10A) without altering the onset pattern of the response (Fig. 10C). The response to sinusoidal AM tones was greatly enhanced during drug injection, and the MTFFR retained its band-pass shape with a best modulation rate of 100 Hz as indicated in Fig. 10B. The synchrony of the response to modulated tones was not greatly affected by bicuculline as indicated by the period histograms and the MTFVS in Fig. 10, B and D. The maximum vector strength was high under both control and drug conditions.
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In summary, bicuculline increased firing in response to tone bursts in 33 of 36 neurons and in response to AM stimuli in 26 of 36 neurons tested. The mean firing rate increased by a factor of 8.49 for tones and 10.67 for AM stimuli (i.e., the ratio of drug to predrug firing was 8.49 for tones and 10.67 for modulated sounds). The basic shape of the MTFFR was not altered, and the best modulation frequency remained the same for most neurons tested with bicuculline. Excluding 9 cells for which no best rate could be determined before drug application, 23 of 27 neurons showed no change, 4 neurons showed a slight downward shift, and none showed an upward shift in the peak of the MTFFR. Further analysis of the effects of bicuculline on 15 neurons with band-pass MTFFR's revealed 3 with an increase in firing that favored below-peak modulation rates, 10 with an increase that strongly favored modulation rates around peak, 1 with an increase that favored high modulation rates, and 1 with equal increase in firing at all modulation rates.
The firing rate was high enough to calculate a vector strength at
equivalent sound pressure levels before and during application of bicuculline
in 27 neurons. The maximum vector strength was unchanged in 25 of these cases
(VS < 0.05). Two neurons of 16 with sustained responses to tones
bursts showed a reduction in peak vector strength in response to AM stimuli.
None of the 11 neurons with an onset response to tones showed a change in
vector strength >0.05 at their peak modulation rate although 4 of these
neurons did show some reduction at off-peak rates. There was no change in the
preferred modulation frequency as determined from the MTFVS in any
of the 27 neurons.
Special attention was paid to six neurons with band-reject MTFFR
because it has been suggested that this response profile might be shaped by
local synaptic inhibition (Krishna and
Semple 2000). Three examples of the effects of bicuculline on
neurons with a band-reject MTFFR are shown in
Fig. 11. For the neuron shown
in Fig. 11A, the
firing rate was increased at all modulation frequencies, but the band-reject
profile of the MTFFR remained the same. For the neuron shown in
Fig. 11B, the firing
rate was greatly increased at both high and low modulation rates with
relatively little increase in the midfrequency range. For the neuron shown in
Fig. 11C, only one
peak was evident in the MTFFR before bicuculline, but during drug
application, a prominent band-reject profile became apparent. In both of these
latter cases, the band-reject characteristic of the MTFFR was
enhanced rather than diminished by the drug. There was no evidence of a
reduction in response suppression in any of the six band-reject neurons tested
with bicuculline. The vector strength of the synchronized response was not
greatly affected by bicuculline under any condition in which the firing rate
was high enough to permit a meaningful calculation. The MTFVS's for
these three representative neurons are shown in
Fig. 11.
|
Combined effects of bicuculline and NBQX
Eighteen neurons were tested with combined injections of NBQX and bicuculline. In 16 of these cases, an increase in firing rate produced by bicuculline was offset by a decrease in firing produced by NBQX. An example of this result is shown in Fig. 12 for a neuron with an onset response to tone bursts. Before drug application, this neuron had a band-pass MTFFR with a best modulation frequency of 60 Hz and a highly synchronized discharge pattern as reflected in the period histograms and MTFVS shown in Fig. 12, A and B. Bicuculline increased firing at all modulation rates between 20 and 100 Hz, and NBQX decreased firing over the same range. During combined application of bicuculline and NBQX, the firing rate reached a steady level between that found with either drug alone. Response synchrony was not substantially affected by the combination of drugs or by either drug alone as indicated by the period histogram and the MTFVS shown in Fig. 12, A and B.
|
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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For the vast majority of neurons in the rat's ICC, the firing rate to AM stimuli was highly dependent on the frequency of the modulation. The specificity of the response to modulation rate was reflected in the shape of the MTFFR, which plots discharge rate over a wide range of modulation frequencies. The most commonly encountered shape of MTFFR in our experiment was band-pass (53% of all neurons that showed continuous firing to AM stimuli). Other types of MTFFR included band-suppressed, all-pass, high-pass, low-pass, and other (25, 3, 5, 4, and 10% of the neurons, respectively).
The diversity of MTFFR types is similar to that reported by
other investigators for ICC neurons in the rat, gerbil, cat, guinea pig, and
other species (Brugge et al.
1993; Krishna and Semple
2000; Langner and Schreiner
1988; Møller and Rees
1986; Rees and Palmer
1989; Schreiner and Langner
1988). Precise comparisons of the proportion of different types of
MTFFR observed in different studies and across species are
complicated by the level dependence of the response pattern. For example, for
cochlear nucleus and inferior colliculus neurons the shape of the
MTFFR changes from low-pass to bandpass as the level of the
stimulus is increased (Frisina et al.
1985,
1990a,b;
Rees and Møller 1987;
Rees and Palmer 1989). Other
more complex changes can occur as illustrated by the responses recorded from
the neuron shown in Fig.
5A,Fig. 5D of the
present study. The classification scheme used in our study is based on a sound
pressure level fixed at 15–20 dB above the neuron's excitatory response
threshold.
Our results indicate that neurons with onset and sustained responses to
tone bursts respond differently to modulated sounds. Those with sustained
responses exhibit a variety of MTFFR profiles and have different
best modulation frequencies. Among the band-pass neurons in this group, the
best modulation frequencies are widely distributed across the range between 10
and 300 Hz. In contrast, neurons with onset responses to tones and a
continuous discharge of action potentials to AM stimuli (50% of our
sample) have MTFFR profiles that are similar to one another, i.e.,
they are narrowly band-pass with a best modulation frequency 50 Hz. Thus
the neurons with sustained responses to tone bursts show sufficient diversity
in the population to support a possible place code for modulation rate,
whereas neurons with onset responses to tone bursts do not.
The responses of most ICC neurons are highly synchronized to the period of
AM with a preferred frequency of modulation that is closely related, but not
always identical, to the frequency that produces peak firing rates. In our
study, the maximum vector strengths determined from the mean MTFVS
were 0.85 and 0.95 for neurons with sustained and onset responses to tone
bursts, respectively. These values are similar to those reported by other
authors for neurons in the ICC of rats and other mammalian species
(Caspary et al. 2002;
Krishna and Semple 2000;
Langner and Schreiner 1988;
Møller and Rees 1986;
Rees and Palmer 1989;
Schreiner and Langner 1988).
The mean upper limit of synchronized firing among the neurons examined in our
study was 250 Hz (based on neurons with sustained responses to tone bursts
using a criterion vector strength of 0.3). This value is similar to that
reported for ICC neurons by other investigators
(Burger and Pollak 1998;
Casseday et al. 1997;
Krishna and Semple 2000;
Langner and Schreiner 1988;
Rees and Møller 1983;
Schuller 1979) and is
generally lower than that found in the auditory nerve
(Cooper et al. 1993;
Frisina et al. 1996; Javal
1980; Joris and Yin 1992;
Møller 1976;
Palmer 1982) and some lower
auditory brain stem structures including the ventral cochlear nucleus (Frisina
et al.
1990a,b;
Møller 1973;
Rhode and Greenberg 1994) and
medial superior olive (Grothe
1994; Grothe et al.
1997,
2001) although limited
frequency following has been reported for other lower auditory brain stem
nuclei including the dorsal cochlear nucleus
(Joris and Smith 1998),
lateral superior olive (Joris and Yin
1995; Kuwada and Batra
1999), and dorsal nucleus of the lateral lemniscus
(Huffman et al. 1998). In
general, a high level of synchrony of responses and a limited ability to
follow high frequencies of modulation are characteristic features of ICC
neurons (e.g., Krishna and Semple
2000; Langner and Schreiner
1988; Rees and Møller
1983; Schreiner and Langner
1988; Walton et al.
2002).
Synaptic influence on firing rate to modulated tones
The excitatory effect of an amplitude modulated sound is greatly reduced by
local application of either AMPA or NMDA receptor antagonists. This conclusion
supports our previous observations showing that both AMPA and NMDA receptors
contribute to excitatory responses in the inferior colliculus and that both
play a role in auditory sensory processing
(Kelly and Zhang 2002;
Ma et al. 2002;
Zhang and Kelly 2001). The
reduction in firing to modulated tones typically occurs across the full range
of modulation frequencies that produce excitation under normal conditions.
Although AMPA and NMDA receptors in the ICC have different temporal
properties, including the time course for activation and decay and the
duration of their effects, there is no indication from our data that the
selective receptor antagonists target specific modulation rates. In some
cases, the reduction in firing was constant across all modulation frequencies,
and in other cases, it was proportional to the excitatory response evoked
prior to drug application. But, in most cases the shape of the
MTFFR was not substantially altered by either AMPA or NMDA receptor
antagonists, and there was no indication of a differential effect associated
with a particular class of receptor antagonist. Both AMPA and NMDA receptors
contributed to the strength of excitation, but neither appeared to be crucial
for shaping selective responses to specific rates of AM.
The GABAA antagonist, bicuculline, greatly increased the firing
rate of neurons in ICC to modulated tones. This result is consistent with many
previous reports that show the importance of GABA in regulating monaural and
binaural responses in ICC to various acoustic stimuli including tones and
modulated sounds (Burger and Pollak
1998; Caspary et al.
2002; Fujita and Konishi
1991; Koch and Grothe
1998; Park and Pollak
1993,
1994;
Le Beau et al. 1996;
Pollak and Park 1993;
Zhang et al. 1999).
The increase in firing rate occurred over a wide range of modulation
frequencies, and the shape the MTFFR was not greatly affected by
bicuculline, although in many cases sound-evoked activity emerged at
modulation rates that did not evoke a response before application of the drug.
In the vast majority of neurons examined by us, the best modulation frequency
for producing maximum firing was the same before and during application of
bicuculline. In general, this result confirms the reports by Burger and Pollak
(1998) and Caspary et al.
(2002) regarding the effects of
bicuculline on responses to AM stimulation by neurons in the ICC of mustache
bat and chinchilla, respectively.
After careful analysis of their data, Caspary et al.
(2002) showed that bicuculline
produced a selective increase in discharge rates at low modulation frequencies
in 36% of the band-pass and 53% of the low-pass neurons in the chinchilla's
ICC. We also found a selective elevation in firing rate at low modulation
rates for band-pass neurons in the rat's ICC, but in our sample, only 20% of
the cells (3 of 15) showed this effect. In our study, the percentage of
low-pass neurons was much less than reported for chinchilla, and none of these
cells was tested with bicuculline. It is not clear whether species differences
or procedural factors account for this discrepancy between the two
studies.
In our experiment, 67% of the ICC neurons with a band-pass MTFFR
showed an increase in firing with bicuculline that favored modulation rates
around their peak response (10 of 15 cells). Caspary et al.
(2002) reported a similar
effect in 32% of the neurons examined in the chinchilla's ICC. This increase
in activity, although associated with a particular rate of modulation, does
not necessarily reflect a selective release from inhibition but could be due
to a nonselective release from inhibition with an increase in firing that is
proportional to the amount of underlying excitation. For most of the cells in
our sample, we found that bicuculline produced an increase in firing rate that
was proportional to the amount of predrug activity regardless of the shape of
their MTFFR. This proportional increase in firing rate with
bicuculline might be related to the fact that excitation of neurons in the
rat's inferior colliculus is mediated in part by NMDA receptors, which are
known to be voltage dependent and therefore capable of determining the gain of
acoustically driven responses (Kelly and
Zhang 2002; Zhang and Kelly
2001).
Of particular interest were neurons in ICC that had band-reject
MTFFR's, i.e., neurons with reduced firing over a range of
modulation frequencies relative to the activity at higher and lower
frequencies. The reduced activity associated with this type of
MTFFR has been attributed to synaptic inhibition by Krishna and
Semple (2000). Considering the
importance of GABA as an inhibitory transmitter in ICC, we anticipated that
local application of the GABAA receptor antagonist, bicuculline,
would diminish or eliminate the band of suppression in the MTFFR.
This effect, however, was not found in any of the neurons examined in spite of
the increase in the overall rate of firing produced by the drug. In some
cases, there was a general increase in firing at all modulation frequencies
including those that produced the rejection band before application of the
drug. For these neurons, the band-reject shape of the MTFFR was
retained, although the firing rate was increased. In other cases, there was an
increase in firing that was more pronounced at modulation frequencies that
produced strong excitatory responses prior to drug application. For these
cells, the band-reject shape of the MTFFR was enhanced during drug
application. Other neurons, which showed no obvious band of suppression before
release of the drug, developed a band-reject profile during application of
bicuculline. In these cases, a previously unrecognized area of excitation
emerged that revealed a band of reduced activity in the MTFFR that
was not apparent before the drug. These results suggest that the band-reject
profiles of the MTFFR's are shaped by factors other than local
GABAergic synapses in ICC, perhaps by synaptic inhibition within neural
circuits at lower levels of the central auditory system.
Synaptic contribution to the synchrony of responses to AM tones
The synchrony of responses of ICC neurons to the period of AM was not
greatly affected by the NMDA receptor antagonist, CPP. In general, vector
strength remained at predrug levels at all modulation frequencies for which
firing was sufficient to permit a reliable estimate of synchrony. The shape of
the MTFVS was unchanged in most cases with no shift in the best
modulation frequency or the upper limit of synchronous responding. These
results are consistent with the findings of Burger and Pollak
(1998) showing that the NMDA
antagonist, APV, had no effect on the upper limit of response synchrony to AM
stimuli in the mustache bat's ICC.
The AMPA receptor antagonist, NBQX, also had little effect on response
synchrony, although it was somewhat more disruptive than CPP. No change was
found in vector strength at peak modulation rates. In about half the neurons
tested, there was an increase or decrease in vector strength at off-peak
modulation rates, but the changes were not large nor were they consistent from
cell to cell. Brain slice studies have shown that AMPA and NMDA receptors in
the rat's ICC have different time courses for activation
(Ma et al. 2002), and in vivo
recordings indicate that the AMPA and NMDA receptor antagonists, NBQX and CPP,
have selective effects on the fast and slow components of neural responses
evoked by contralaterally presented tone bursts
(Zhang and Kelly 2001).
Therefore we anticipated that the AMPA receptors in ICC might play a selective
role in generating synchronized responses to AM stimuli at high modulation
rates. However, the AMPA receptor antagonist, NBQX, was less effective than
expected, and there was no strong indication that specific glutamate receptor
types make selective contributions to response synchrony at different
modulation rates.
The GABAA antagonist, bicuculline, also had little effect on
response synchrony. The maximum vector strength remained high and the
MTFVS was unchanged, at least at modulation rates that generated
levels of firing high enough to permit a meaningful calculation of vector
strength before and during release of the drug. Even though the number of
action potentials was greatly increased, the timing of the responses was still
synchronized to the same phase of the modulation waveform over a wide range of
modulation rates. These data are consistent with the observations of Burger
and Pollak (1998) in the
mustache bat and Caspary et al.
(2002) in the chinchilla.
Several factors might be involved in the maintenance of response synchrony
in the inferior colliculus despite disruption of the balance of excitation and
inhibition by local application of receptor antagonists that increase or
decrease firing rate. First, the synchrony of responses in ICC to AM tones is
probably determined to a large extent by the pattern of responses in lower
auditory brain stem nuclei or other structures that project to the inferior
colliculus. The neurons in ICC receive direct afferent connections from
neurons in cochlear nucleus, superior olive, and lateral lemniscus
(Kelly et al. 1998; Malmierca
and Merchán 2003; Oliver and Huerta
1992), which themselves have synchronized responses to modulated
sounds (Frisina 2001). These
nuclei provide the excitatory and inhibitory input for neurons located in the
inferior colliculus. Thus the responses in ICC are likely shaped by the
convergence of synchronized activity arising from these other structures. The
limited ability of ICC neurons to synchronize responses to high rates of
modulation relative to neurons in the eighth nerve and other neurons in lower
auditory brain stem nuclei could be attributed to a loss of precise timing
through multiple synaptic delays or the imposition of synaptic jitter at
various stages of processing (Langner
1992; Rees and Palmer
1989). The high maximum vector strengths at specific modulation
rates typical of ICC neurons might be due to the summation of correlated
inputs from various sources (e.g., Joris et al.
1994
a,b).
Second, our results do not exclude the possibility that local reverberating
circuits in ICC contribute to the synchrony of activity as suggested by Reetz
and Ehret (1999) on the basis
of their in vitro brain slice recordings. The timing of responses to modulated
sounds might be maintained by local circuits despite changes in the level of
excitation or inhibition produced by the release of receptor antagonists. The
extent to which reverberating circuits in ICC might influence the synchrony of
responses to AM stimuli, however, remains unclear. There are no published data
on the role of reverberating circuits in shaping the temporal properties of
responses in ICC to acoustic stimulation nor is it known whether the timing of
these circuits would be affected by local changes in the balance of excitation
and inhibition.
Third, the synchrony of responses to AM stimuli might be maintained by the
intrinsic properties of the ICC neurons themselves. Combinations of specific
potassium or other ion channels can determine the timing of responses or set
the frequency of intrinsic oscillations of neurons in the CNS
(Hutcheon and Yarom 2000;
Llinas 1988). Intrinsic
membrane properties can also affect the timing of neural responses in the
central auditory system (Oertel
1997; Peruzzi and Oliver
2000; Sivaramakrishnan and
Oliver 2001; Trussel 1997, 2002). Neurons in brain slice
preparations of the cochlear nucleus have intrinsic oscillations at
frequencies of 50–100 Hz, and these oscillations are dependent on
voltage-gated sodium channels (Manis
2001). In vivo patch-clamp recordings from neurons in the bat's
ICC have revealed oscillating currents that persist after tone burst
stimulation (Covey et al.
1996). Also, Sarbaz and Rees
(1996) noticed an oscillation
in the responses of ICC neurons to tonal stimulation that was related to the
preferred frequency of AM in the same cells. Further data are needed to
determine the significance of the oscillating potentials in ICC, their
dependence on specific ion channels, and their relation to synchronized firing
of neurons to AM stimuli.
Conclusions
We have shown that both NMDA and AMPA receptors in the rat's ICC contribute to the excitation of neurons by amplitude-modulated sounds and that GABAA receptors contribute to their inhibition. Local application of specific NMDA, AMPA, or GABAA receptor antagonists results in a corresponding decrease or increase in the activity evoked by modulated tones. In most cases, the change in firing rate produced by these receptor antagonists was not selective for specific modulation frequencies. The best modulation frequency of the MTFFR was not substantially changed. Furthermore, in most cases, there were no changes in response synchrony, i.e., the maximum vector strengths and peak modulation frequencies in the MTFVS were not altered by either excitatory or inhibitory antagonists. In some neurons, minor changes in vector strength were observed at off-peak modulation frequencies, but these effects were not common. In general, response synchrony was maintained in spite of changes in the relative balance of local excitation and inhibition.
|
ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
|---|
The authors gratefully acknowledge financial support for this research through grants to Dr. Kelly from the Natural Science and Engineering Research Council (NSERC) of Canada and the Hearing Foundation of Canada. Dr. Zhang was supported through an NSERC postdoctoral fellowship.
|
FOOTNOTES |
|---|
Address for reprint requests: J. B. Kelly, 329 Life Science Bldg., Psychology Dept., Institute of Neuroscience, Carleton University, Ottawa, Ontario K1S 5B6, Canada (E-mail: jkelly{at}ccs.carleton.ca).
|
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, the level used (50 dB SPL) with
amplitude modulated sounds. D: period histograms showing the
distribution of spikes over each modulation cycle of the AM stimulus at
different modulation rates from 0.5 to 300 Hz. The responses are summed over 2
stimulus presentations of 10 s each (excluding the 1st 100 ms to avoid onset
responses). The total number of spikes at each modulation rate is shown on the
right of each histogram. E: the modulation transfer function
(MTFFR) determined from the firing rate produced by modulated tones
at various modulation rates. F: the modulation transfer function
(MTFVS) determined from vector strength measures of response
synchrony to the modulation envelope of the AM stimulus at various modulation
rates.
, mean normalized MTFFR's.
A: the mean MTFFR and MTFVS for neurons with a
sustained firing to tone bursts. B: the mean MTFFR and
MTFVS for neurons with an onset response pattern to tone
bursts.
