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Department of Neurobiology and Behavior, University of California, Irvine, California 92697
Submitted 20 November 2003; accepted in final form 20 January 2004
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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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; Merzenich et al. 1975; Phillips et al. 1985b; Sally and Kelly 1988). Similar features are found throughout the lemniscal auditory system (Calford et al. 1983), including in the ventral division of the medial geniculate thalamus (MGv), which provides the main auditory input to primary ACx (Roger and Arnault 1989; Romanski and LeDoux 1993). Because MGv neurons project to cortical neurons with the same CF (Imig and Morel 1984; Miller et al. 2001; Winer et al. 1999), it is plausible that response characteristics exhibited by cortical neurons simply reflect response characteristics of the afferent thalamic neurons. Similarly, it might seem unlikely that response features in ACx that resemble those seen throughout the lemniscal auditory pathway would reflect a cortical specialization.
Breadth of tuning may be a notable exception. Frequency receptive fields typically are determined using extracellular recordings of spike discharge in response to pure tone stimuli. However, the narrow receptive fields thus derived may be misleading and underestimate the spectral breadth of inputs to cortical neurons as evidenced by a number of studies. Blockade of intracortical inhibition results in an expansion of frequency receptive fields derived from extracellular spike discharge, suggesting the presence of normally subthreshold excitatory postsynaptic potentials (EPSPs) that are inhibited by intracortical circuits (Foeller et al. 2001; Muller and Scheich 1988; Wang et al. 2000, 2002). Also, direct, intracellular recordings of synaptic inputs reveal that subthreshold receptive fields extend beyond the boundaries of suprathreshold (derived from spikes) receptive fields (Ojima and Murakami 2002; Ribaupierre et al. 1972; Volkov and Galazjuk 1991; Wehr and Zador 2003). Subthreshold receptive fields (sometimes referred to as subliminal, surround, or nonclassical receptive fields) could contribute to ACx function in a variety of ways. For example, EPSPs that are subthreshold when evoked by pure tones could integrate, spatially and temporally, with other EPSPs elicited by spectrotemporally complex stimuli to elicit spikes. Further, in aroused or attentive animals or animals undergoing behavioral training with acoustic stimuli, receptive fields could be larger, or differently shaped, than those observed under anesthesia (Edeline et al. 2001; Weinberger and Bakin 1998). Finally, changes in synaptic strength of previously subthreshold inputs by behavioral (or other) manipulations could underlie large scale reorganization of frequency representations in ACx (Kilgard and Merzenich 1998; Recanzone et al. 1993).
The present study was designed to answer two questions central to the issue of subthreshold receptive fields in ACx: how broad are they and to what extent do they involve integration of thalamocortical and intracortical inputs? We made intracellular and local field potential (LFP) recordings of toneevoked responses to measure synaptic activity, focusing on the initial, presumed excitatory, components. We determined onset latencies for responses to CF and non-CF stimuli to infer functional connectivity from the arrival time of acoustic inputs. We then determined the effect of intracortical muscimol microinjections on receptive field bandwidth because this manipulation should preferentially inhibit cortical (vs. thalamocortical) neurons. And finally, we reversed the effect of intracortical muscimol preferentially at the recording site (within a larger muscimol-inhibited cortical region) to distinguish between two hypotheses of the functional connectivity underlying receptive fields. The results indicate that at a given cortical site, thalamocortical and intracortical pathways preferentially mediate responses to CF and non-CF stimuli, respectively.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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All procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the University of California, Irvine IACUC. Male Sprague-Dawley rats (Charles River Laboratories, Hollister, CA), age >1 mo and weighing 110–240 g were used for combined intracellular and LFP studies. Adult rats weighing 250–500 g were used for LFP-only studies. Animals were anesthetized with 1.5 g/kg ip urethan (Sigma, St. Louis, MO) and 10 mg/kg ip xylazine (Phoenix Pharmaceuticals, St. Joseph, MO) and subsequently administered 0.6 mg/kg ip atropine (Phoenix). Animals remained in a state of deep anesthesia throughout the surgery and were given supplemental injections of urethan (40 mg) and xylazine (0.25 mg) at 
2-h intervals to maintain areflexia and a synchronized cortical electroencephalogram (EEG). Body temperature was maintained at 36–37° C using a feedback-controlled heating pad (Harvard Instruments, Holliston, MA). The animal was placed in a sound-attenuating chamber (model AC-3, IAC, Bronx, NY) mounted on an air table (Newport, Irvine, CA), and the head was secured in a stereotaxic frame (model 923, Kopf Instruments, Tujunga, CA) using blunt earbars (Kopf). A midline incision was made, and xylocaine ointment (AstraUSA, Westborough, MA) was applied to the incision. After the skull was cleared, the head was secured by a custom-made head holder screwed and cemented onto the skull. A craniotomy was performed over the right ACx, and the exposed cortex was kept moist with warmed saline. The earbars were removed. In early experiments, a drawing of the surface vasculature helped with reconstruction of recording sites. In most experiments, a Polaroid picture was taken of the exposed cortex through the surgical microscope (Carl Zeiss, Thornwood, NY) for the same purpose. To improve stability during experiments that included intracellular recordings, tracheal cannulation, lumbar suspension, and drainage of the cisterna magna were performed in addition to the surgery described in the preceding text. These procedures helped minimize brain pulsations caused by blood pressure fluctuations and respiration. After the experiments animals were killed with a lethal dose of anesthesia.
Electrophysiology
Primary ACx in the rat lies on the dorsolateral aspect of temporal cortex, framed by a characteristic blood vessel pattern (Sally and Kelly 1988). Recording from the cortical surface within this area, we used short-latency, large-amplitude responses to click stimuli to localize ACx (Barth and Di 1990; Shaw 1988) and then made multiple penetrations into layer 4 of the cortex to confirm the tonotopic arrangement characteristic of primary ACx (Doron et al. 2002; Horikawa et al. 1988; Kilgard and Merzenich 1998; Sally and Kelly 1988).
INTRACELLULAR RECORDING. Methods for in vivo whole cell recordings are similar to those described previously (Metherate and Ashe 1993a). Patch pipettes were pulled from glass (1.5 mm OD glass, A-M Systems, Carlsborg, WA) on a horizontal puller (P-97, Sutter Instruments, Novato, CA) and had a tip diameter of 2.5 µm and resistances ranging from 8 to 14 M
when filled with (in mM) 140 K+-gluconate, 1 MgCl, 1 CaCl, 10 HEPES, and 1.6 EGTA, adjusted to pH 7.3 with KOH. The osmolality of the recording solution was adjusted to 260 mmol/kg. All drugs and chemicals were obtained from Fisher (Fair Lawn, NJ), with the exception of D-gluconic acid, which was obtained from Sigma Chemical.
Whole cell recordings were made from neurons in layers 2–4 as described previously (Blanton et al. 1989; Metherate and Ashe 1993a). Briefly, the electrode was inserted perpendicular to the pial surface, lowered to a depth of 200 µm using a microdrive (Inchworm, Burleigh Instruments, Fishers, NY) and weak positive pressure applied to avoid clogging the electrode tip [positive or negative pressure was applied through the side-port of the sealed electrode holder (Warner Instruments, Hamden, CT)]. The positive pressure was then removed and the electrode was advanced slowly with a current pulse (100 pA, 30 ms) delivered once per second. Proximity to a neuron's membrane produced an increased voltage response to the current pulse, at which time the application of a small amount of negative pressure resulted, ideally, in an increased voltage response that eventually indicated a tight seal (1G). When a stable gigaohm seal was achieved, steadily increasing negative pressure was applied to rupture the membrane. Occasionally, the membrane ruptured spontaneously. A successful rupture was indicated by the sudden appearance on the oscilloscope of a membrane potential (approximately –70 mV) with rhythmic voltage fluctuations (Metherate and Ashe 1993a).
Responses to acoustic stimuli were recorded using an intracellular amplifier (Axoclamp 2B, Axon Instruments, Foster City, CA), viewed on a digital oscilloscope (Tektronix, Irvine, CA), digitized at 5 kHz (IT-16, Instrutech, Port Washington, NY), averaged (20 or 40 trials), and stored on a computer (Macintosh G4, Apple Computer). Data acquisition was triggered 100 ms before acoustic stimulation. Computer software (AxoGraph, Axon Instruments) controlled data acquisition and analysis.
EXTRACELLULAR RECORDING. LFP recordings were obtained in nearly all experiments using glass microelectrodes (1.5 mm OD glass, A-M Systems; tip diameter: 2.5 µm, filled with 1 M NaCl, 1 M impedance at 1 kHz) pulled in multiple stages to obtain blunt tips, as for patch pipettes. In two experiments, dual tungsten electrodes were used for simultaneous recording from two sites (1–2 mm separation). Electrodes were inserted perpendicular to the pial surface, and movement was controlled using a microdrive (Burleigh Inchworm). Neural activity was filtered and amplified (1 Hz to 10 kHz, AI-401 Cyber-Amp, Axon Instruments) displayed on the oscilloscope, digitized at 5 kHz, and stored on computer. Data acquisition was triggered 100 ms before acoustic stimulation, and responses were averaged (25 or 50 trials; AxoGraph, Axon Instruments). The local EEG was monitored continuously on the oscilloscope.
Acoustic stimulation
Pure tone stimuli were digitally synthesized and controlled using MALab (Kaiser Instruments, Irvine, CA) and a dedicated computer (Macintosh PowerPC, Apple Computer) and delivered through an electrostatic speaker (ES-1 with ED-1 driver, Tucker-Davis Technologies, Gainesville, FL) positioned 3 cm in front of the left ear. For calibration (SPL in decibels re: 20 µPa), a microphone (No. 4939 microphone and Nexus amplifier; Bruel and Kjaer, Norcross, GA) was positioned in place of the animal at the tip of the left earbar. Tones were 100 ms in duration with 10-ms linear rise and fall ramps.
Pharmacological manipulations
To inhibit intracortical activity, muscimol hydrobromide (5.1 mM in saline; Sigma) was administered through a glass micropipette with a broken tip (20–30 µm diam) attached via polyethylene tubing to a 1 or 5 µl Hamilton syringe (WPI, Sarasota, FL). The pipette was inserted into the cortex at the recording site after removal of the recording electrode. Muscimol (or saline, for controls) was injected in increments of 0.5–1.0 µl over 1–2 min, or, in one early experiment, muscimol was applied to the cortical surface. The muscimol pipette was left in place for 15 min after the injection and then removed and replaced with the recording electrode, after which tone-evoked responses were obtained. In some cases, this procedure was repeated one or more times to increase the muscimol dose. In later experiments, to investigate reversal of inhibition by picrotoxin (0.01–100 µM in saline; Sigma), we used a lower concentration of muscimol (200 µM, 0.5–2.0 µl). After recording responses in muscimol-inhibited cortex, the recording electrode was replaced with one containing picrotoxin.
Analysis of acoustic-evoked responses
CF and other acoustic response features were determined for a particular recording site by examining LFPs evoked by a standard stimulus set of six frequencies spanning five octaves (1 or 1.25 to 40 kHz in 1-octave steps) delivered at intensities from 70 dB SPL to below CF threshold, typically in 10 dB steps. Although the 1 octave resolution of the stimulus set is relatively crude, it was sufficient to determine changes in tonotopic organization over the cortical distances examined (1 mm steps), and we use the conventional term "CF" for convenience. CF was determined qualitatively by identifying the frequency of the stimulus with the lowest threshold response. When stimuli of more than one frequency elicited a response at threshold, intensity was varied by 5 dB and/or CF was determined by the response with the shortest onset latency (e.g., Fig. 3A, responses at 0 dB). Quantitative measures of evoked intracellular and LFP onset latencies (see details in the following text) and peak amplitudes were obtained for all responses. For measurements of response amplitude, baseline was defined as the average potential from tone onset to 5 ms after stimulus onset.
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A major part of the present study involved obtaining objective and accurate estimates of response onset latencies. The method is illustrated in Fig. 2B for an LFP. First, a "threshold" 1 SE below the mean baseline was established, and the point at which the response crossed the threshold determined. Then, two points 1 ms before and after the threshold-crossing were identified, and the slope of the line connecting these two points was determined. Finally, the intersection of this line with the average baseline potential was obtained and defined as response onset (Fig. 2B, small arrow). A similar procedure was used to obtain the onset latencies of intracellular responses.
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Statistical analyses were performed using Statview (v. 4.5 for Macintosh, Abacus Concepts). Tests on independent means were Student's t-test and factorial ANOVA, whereas the paired t-test and repeated-measures ANOVA were used for related means. In analyzing response features obtained at different frequencies and intensities (e.g., Fig. 3C), repeated-measures ANOVAs were performed separately at each intensity; for such ANOVAs, only a subset of the data was included so that the mean values being compared contained equal n (however, all data are plotted in figures). Detailed statistics results are in the figure legends; P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Intracellular recordings in primary ACx
We obtained intracellular recordings from eight neurons in primary ACx, using the in vivo whole cell recording method (Metherate and Ashe 1993a). Cell depths ranged from 275 to 612 µm below the pia, corresponding to layers 2–4. In cell-attached mode, the seal resistance was 1.0 ± 0.1 G; after rupture of the membrane with suction, the resting membrane potential (RMP) was –69 ± 3.2 mV, and the input resistance, estimated from responses to small hyperpolarizing current pulses, was 182 ± 64.2 M. The duration of recording ranged from 9 to 47 min.
Example intracellular responses to acoustic stimulation are shown in Fig. 1A (top), for a layer 3 neuron. For this neuron, rupture of the cell membrane was obtained using minimal suction after the seal resistance had reached a plateau at 1.5 G. After break-in, rhythmic membrane potential fluctuations characterized spontaneous activity as described previously (Metherate and Ashe 1993a; Metherate et al. 1992). The RMP was –81 mV immediately on break-in, but generally ranged from –52 to –63 mV for most of the recording (RMP defined as the potential during the peak hyperpolarizing phase of membrane potential fluctuations, in the absence of injected current). Spontaneous action potentials occurred during depolarizing phases of membrane potential fluctuations in about half the neurons. In most neurons, we made small adjustments in the level of injected DC current over time to maintain the membrane potential close to the RMP observed at the beginning of each data collection sequence. However, data obtained when the RMP was more depolarized than –50 mV were discarded.
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The receptive field bandwidth derived from tone-evoked EPSPs was broad, measuring 
5 octaves (the maximum we could test) at 70 dB for the example in Fig. 1A. Across neurons, bandwidth ranged from 3 to 5 octaves at moderate to high intensities (Fig. 1B). At 10 and 20 dB above threshold, where determination of bandwidth was not limited by the 5-octave stimulus range, EPSP bandwidth averaged 1.25 ± 0.75 and 2.75 ± 0.85 octaves, respectively (Fig. 1C). Although stimuli were delivered in relatively crude, 1 octave steps, these bandwidth estimates indicate remarkably broad synaptic receptive fields.
Tone-evoked EPSPs typically did not elicit spikes unless the neuron was depolarized with DC current; but in three neurons, higher-intensity stimuli did elicit spikes at RMP. Stimuli 
1 octave above CF (n = 2) or 2 octaves below CF (n = 1) produced suprathreshold responses, and spike-based bandwidth ranged from 1 to 2 octaves. In contrast, subthreshold bandwidth in these cells ranged from 3 to 5 octaves. In other words, subthreshold receptive fields were much broader than spike-based receptive fields.
Comparing intracellular and LFP responses to pure tones
After each intracellular recording, LFPs were recorded at the same location to allow for a direct comparison of intracellular and LFP features (n = 7). LFPs were recorded using electrodes similar to patch pipettes but with slightly larger tips and correspondingly lower impedances (1 M). Figure 1A (bottom) shows an LFP recording from the same layer 3 site as the intracellular responses (top). Tone-evoked LFPs were invariably of negative polarity, as expected for extracellular responses near the site of excitatory synaptic activity (Barth and Di 1990; Metherate and Ashe 1993b; Metherate et al. 1992; Muller-Preuss and Mitzdorf 1984). As can be seen in Fig. 1A, several LFP features resemble those of intracellular responses: both sets of responses indicate a CF of 10 kHz (sole, or shortest-latency, response at 20 dB), a bandwidth 5 octaves at 70 dB, and similar changes in onset latency with increasing intensity or spectal distance from CF (also see Fig. 2A).
Group data confirm the similarities between intracellular and LFP responses. CFs derived from intracellular and LFP responses were identical in 5/6 cases (in 1 cell, the intracellular CF could not be determined clearly). However, CF thresholds were higher in intracellular recordings (average: 40 ± 5.5 dB, range: 20–50 dB) compared with LFP recordings (average: 30 ± 5.5 dB, range: 10–40 dB; paired t-test, n = 5, P < 0.001). Bandwidths for paired intracellular and LFP recordings are shown in Fig. 1B and covered a similar range at each intensity up to the maximum detectable 5 octaves at high intensities. At 10 and 20 dB above threshold, where bandwidth determination was not limited by our stimulus range, intracellular and LFP bandwidth did not differ (Fig. 1C).
An important goal of this study was to infer functional connectivity, in part from differences in onset latency among LFP responses to stimuli of different frequencies. We therefore examined EPSP and LFP onset latencies and found that the response to CF stimuli had the shortest onset latency while the responses to non-CF stimuli— both higher and lower frequencies—were progressively longer with increasing spectral "distance" from CF. An example is shown in Fig. 2A, using intracellular and LFP recordings from the same site. For LFPs (Fig. 2A, top) and EPSPs (bottom), CF (10 kHz) stimuli elicited the shortest onset latency and responses to stimuli of other frequencies tended to have progressively longer latency onsets with increasing spectral distance from CF. Note that this trend holds for frequencies above and below CF; e.g., LFP and EPSP responses to stimulus frequencies 2 octaves above and below CF (40 and 2.5 kHz, respectively), all have longer latency onsets than do responses to stimuli at CF.
As can be seen for some traces in Fig. 2A, the exact timing of individual onsets was not always clear, especially when the onset was not abrupt. The difficulty in identifying onset precisely led us to devise an objective method for estimating onset latency. The method is illustrated in Fig. 2B for an LFP response and is detailed in METHODS. Briefly, onset latency was determined by extrapolating a line based on the slope of the LFP around a threshold point established from statistical variations (–1 SE) in the baseline potential. A threshold relatively near to the baseline was chosen because response onset often seemed to begin well before the strongest portion of the response, producing an initially gradual, two-component onset (Fig. 2B). A near-baseline threshold ensured that the early component of the response influenced our estimate of onset latency and resulted in more accurate estimates than if the strongest portion of the response was extrapolated to the baseline instead. Average LFP latencies are described in greater detail in the following text (Fig. 3C) and clearly show increasing onset latencies with spectral distance from CF.
Intracellular onset latencies were determined similarly. Onset latency data at 70 dB (20–30 dB above threshold) showed that CF stimuli tended to have the shortest onset latency (average: 18.5 ± 1.53 ms, range: 12.9–26.8 ms) with responses to non-CF stimuli having progressively longer onset latencies with distance from CF. However, a wide range of response latencies resulted in limited statistical significance (Fig. 2C).
Taken together, the comparison of intracellular and LFP data in terms of polarity, bandwidth, and changes in onset latency with intensity and spectal distance from CF, demonstrate that LFPs reflect important features of local synaptic activity. Because LFPs are suitable for the long-duration recordings needed for this study, at a predetermined depth (layer 4) in each animal and before and after pharmacological manipulations, we subsequently focused on LFPs to infer synaptic connectivity in ACx.
Layer 4 LFP response to pure tones
In 25 animals, we recorded tone-evoked LFP activity in multiple penetrations across ACx. These multiple penetrations were performed to confirm the topographic arrangement of frequency representations expected for primary ACx and to determine which, if any, features of LFP responses varied across frequency representations (changes in response features observed in multiple penetrations across ACx also would support further the notion that LFPs reflect local activity). At each site, the recording depth was kept constant at 600 µm to sample activity in layer 4 (in 5 experiments, current source density analysis revealed the major short-latency, tone-evoked current sink to be at 600 µm; data not shown). To determine CF and other response features, we used the same standard, 5 octave stimulus set as before. In each animal, we first determined the area responsive to sound stimuli by recording surface responses to clicks. We made a first penetration near the anterior end of the shortest-latency, largest-amplitude surface responses (click map), and recorded layer 4 responses to the stimulus set. We then made one to four additional penetrations in 1 mm steps directly posterior to the first penetration and recorded layer 4 responses to the same stimulus set. In most animals (n = 19), we observed a shift in effective stimuli from high frequencies at the anterior penetration to lower frequencies at more posterior locations (arrows in Fig. 3 and subsequent figures indicate CF threshold). This sequence is consistent with previous reports of the tonotopic organization of primary ACx in the rat (Doron et al. 2002; Horikawa et al. 1988; Sally and Kelly 1988).
In the 19 animals with a confirmed tonotopic arrangement, the region of the first penetration was invariably a high-frequency area with CF = 40 kHz (Fig. 3B). Because 40 kHz was the highest frequency delivered, these anterior sites might actually have higher CFs. However, the threshold intensity at these sites was relatively low, averaging 9.5 ± 1.6 dB SPL (range: 0–20 dB SPL), similar to thresholds seen in more posterior penetrations with lower frequency CFs (in the following text). Thus the anterior sites likely have CFs near 40 kHz. In each animal with a tonotopic arrangement, responses revealed a lower-frequency region at a second site more posterior to the "high-frequency site" (Fig. 3, A and B). This "mid-frequency site" was 1.5–2 mm posterior (mean: 1.7 ± 0.1 mm). CF at the mid-frequency site was usually 10 kHz (n = 15) but sometimes 5 kHz (n = 3) or 20 kHz (n = 1). Thresholds at the mid-frequency sites averaged 16.3 ± 3.3 dB SPL (range: 0–40 dB SPL) not different from those at the high-frequency site (paired t-test, n = 19, P > 0.05).
In 6/25 animals examined for frequency organization, no clear evidence for tonotopy emerged. In these animals, two to four penetrations were made spanning a distance of 0.8–2.8 mm (mean: 1.7 ± 0.3 mm) from the anterior portion of the click map, i.e., the same procedure that revealed tonotopy in most animals. Unlike in the animals with clear tonotopy, however, several sites 2.8 mm apart appeared to have the same CF (n = 5), and/or some sites responded weakly at threshold to a range of frequencies spanning three octaves or more (n = 2). For the latter animals, small and variable responses near threshold prevented a clear determination of CF and therefore may have prevented determination of a progression of CFs with distance. However, CFs were clear in other cases that did not show a change of CF with distance. Further, responses at higher intensities were robust in all 6 animals, yet 5/6 did not show the expected shift of frequency ranges with distance (cf. responses at 30 dB SPL in Fig. 3, A and B, for expected shift). The surface blood vessel patterns and distribution of click responses in these animals appeared similar to tonotopic animals, suggesting that recordings were made in analogous cortical regions. However, absent a fine-grain mapping procedure, it remains possible that we were recording in a nonprimary field (Doron et al. 2002; Horikawa et al. 1988; Sally and Kelly 1988). In any case, data from animals lacking tonotopic organization were not analyzed further.
Features of tone-evoked responses that imply connectivity
For the 19 animals with confirmed recordings in tonotopic primary ACx, we undertook a detailed analysis of the layer 4 responses to the standard stimulus set. For each animal, data were analyzed both at the high-frequency site (CF = 40 kHz) and at the mid-frequency site (CF generally 10 kHz). We first analyzed the onset latency of tone-evoked LFP responses because minimum onset latencies at a particular site are determined, in part, by anatomical connections. As is clear from the LFP examples already described (Figs. 2A and 3, A and B), and from the mean LFP onset latencies in Fig. 3C, onset latency increased for stimulus frequencies away from CF at both high- and mid-frequency sites. Changes in onset latency were smaller, yet still significant, at higher intensities; e.g., for the mid-frequency site in Fig. 3C, changes in onset averaged 4.3 ms/octave at 10 dB and 0.7 ms/octave at 60 dB above threshold (data averaged in 1 octave intervals from –3 to +1 octaves from CF). Onset latencies for CF stimuli decreased with increasing intensity at each site (Fig. 3C, ANOVAs, P values <0.01) and appeared to asymptote at higher intensities (50–60 dB, Fig. 3D). Finally, for a given intensity, CF stimulus-evoked onset latencies at the high-frequency site were consistently less than those at the mid-frequency site (Fig. 3D).
Note, as previously mentioned (Fig. 1), that LFP responses at moderate to high intensities could span 5 octaves. Even more remarkably, such data at a high-frequency site indicate a receptive field extending at least five octaves below CF (for an individual example, see Fig. 4C). These broad receptive fields are similar to the subthreshold receptive fields seen in intracellular recordings (Fig. 1) but substantially broader than those derived from suprathreshold (single unit) activity in primary ACx (see DISCUSSION).
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3 octaves below CF at both midand high-frequency sites. Note, also, that despite the boosting of responses to non-CF stimuli, the response to CF stimuli still had the shortest onset latency (Fig. 4B; peak amplitudes normalized to facilitate comparison of onsets). Intracellular recordings confirmed shorter onset latencies for CF stimulus-evoked EPSPs despite boosting of responses to non-CF stimuli (Fig. 4D). The effects of boosting dominated the average data at higher intensities for stimulus frequencies below CF (Fig. 4E). Response amplitudes to CF stimuli increased monotonically, on average, with increasing stimulus intensity, even when analyzing data only from sites displaying boosted responses. Two hypotheses on the connectivity underlying frequency receptive fields
LFP features have important implications for how frequency receptive fields are constructed in ACx. For example, at a given recording site, CF stimuli elicit the shortest latency responses, implying a direct anatomical connection from the thalamus. Non-CF stimuli—5 octaves from CF— elicit longer-latency responses. Two hypotheses posit extreme scenarios to account for how CF and non-CF information arrive at a given recording site (Fig. 5; for this exercise, we loosely define "non-CF" as several octaves from CF). In the first (Fig. 5A), extensive thalamocortical terminal arbors project over a wide cortical area and thus relay non-CF as well as CF information to the recording site. According to this scheme, increased latencies for non-CF input could result from longer thalamocortical path lengths. In the second scenario (Fig. 5B), non-CF information arrives at the recording site via an intracortical mono- or polysynaptic pathway. The increased latency for non-CF input therefore results from intracortical processing that includes one or more synaptic delays. (An additional factor, that non-CF stimuli elicit longer latency spikes than CF stimuli throughout the auditory system, applies to both hypotheses but does not account for the small timing differences among synaptic onsets observed here; see DISCUSSION). The remainder of this study is aimed at distinguishing between these two hypotheses.
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To examine the involvement of intracortical processing in relaying CF versus non-CF inputs, we inhibited intracortical activity with microinjections of muscimol, a GABAA receptor agonist that inhibits postsynaptic activity but not fiber activity (for review, see Martin and Ghez 1999).
In nine experiments, after recording baseline responses we applied muscimol (5.1 mM; 1–2.5 µl) to the mid-frequency recording site. In four of these nine experiments, muscimol was microinjected (1.0 µl) into layer 4. In one experiment, muscimol was applied to the cortical surface. In another four experiments, we made two to five injections into layer 4, typically 0.5 µl per injection, 30–60 min apart with intervening recordings that revealed progressively stronger suppression, and we assumed cumulative doses because the effects of muscimol at this concentration are long-lasting (Edeline et al. 2002; Martin and Ghez 1999; present study). Muscimol at such doses would be expected to diffuse several millimeters from the injection site (Edeline et al. 2002; Martin and Ghez 1999) and inhibit much of primary ACx. We began data collection 15–20 min after the muscimol injection(s). Muscimol strongly reduced CF stimulus-evoked LFP magnitude for hours (Fig. 6A; recovery was attempted in 1 case, with 50% recovery seen after 6 h). On average, muscimol significantly reduced response peak amplitude for intensities at and above threshold (Fig. 6B) and reduced completely the later components of evoked responses (Fig. 6A). In 6/9 animals, threshold either did not change (Fig. 6A, arrowhead indicates predrug CF threshold) or increased 10 dB. In 3/9 animals, threshold after muscimol increased 20–40 dB. Nonetheless, muscimol did not significantly change average CF threshold (2.2 ± 2.22 dB before muscimol vs. 13.3 ± 4.71 dB after; paired t-test, n = 9 pairs, P = 0.062). As a control for nonspecific effects, injection of 0.5 µl (n = 1 animal) or 1 µl (n = 4) saline at the recording site did not affect responses to CF stimuli (93.1 ± 6.2% of predrug amplitude, all intensities pooled; Fig. 6B), whereas 1 µl muscimol reduced amplitudes to 25.7 ± 2.1% of baseline (paired t-test with all intensities pooled, P < 0.05). Saline also did not affect response threshold (predrug threshold: 4.0 ± 2.45 vs. 4.0 ± 2.45 dB after saline; paired t-test, n = 5 pairs, P > 0.05). Similarly, as can be seen in Fig. 6B, saline did not affect the mean response amplitude at threshold (predrug: 89.9 ± 17.22 µV vs. 84.7 ± 10.15 µV after saline, paired t-test, n = 5 pairs, P > 0.05).
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The reduction of response magnitude to CF stimuli with no consistent change in onset latency or threshold suggested that muscimol was acting as desired—inhibiting intracortical activity without affecting thalamocortical input. We therefore examined the effect of muscimol on responses to non-CF stimuli because preferential reduction of such responses would support the hypothesis that intracortical pathways mediate non-CF inputs (Fig. 5B), whereas equivalent reduction of responses to CF and non-CF stimuli would suggest that intracortical pathways contribute similarly to both (Fig. 5A). An example of muscimol's effect is shown in Fig. 7A. As in the previous example, muscimol reduced responses to CF stimuli but did not change CF threshold (
). However, response amplitudes to non-CF stimuli were also reduced and, in many cases, reduced fully. When averaged data were compared for inhibition of responses to CF versus non-CF stimuli (non-CF data from 1 to 3 octaves below CF combined), only small differences emerged (Fig. 7B). However, the reduction of responses to non-CF stimuli appeared more prominent at the frequencies most spectrally-distant from CF. Because the complete reduction of these responses necessarily would reduce bandwidth, we quantified bandwidth for individual sites and then determined average bandwidth at each intensity. An analysis of bandwidth 20–70 dB above the threshold for CF stimulus-evoked responses showed that muscimol reduced breadth of tuning 20–50 dB above threshold (Fig. 7C; muscimol had no significant effect 60–70 dB above threshold, but note that our detection limit of 5 octaves probably precluded measurement of full predrug bandwidths).
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Local reversal of inhibition at the recording site after inhibition of ACx by muscimol
In this final experiment, we added picrotoxin (a GABAA receptor channel blocker) to the recording electrode after recording responses in muscimol-inhibited ACx (Fig. 8A). Our rationale was the following: if thalamocortical pathways preferentially mediate responses to CF stimuli and intracortical pathways preferentially mediate responses to non-CF stimuli (Fig. 5B), then reversing muscimol's inhibition only at the recording site should preferentially restore responses to CF stimuli. If, on the other hand, thalamocortical inputs contribute equally to CF and non-CF stimulus-evoked responses (Fig. 5A), then reversing muscimol's effect at the recording site should restore responses to CF and non-CF stimuli equally. We therefore determined the effects of local picrotoxin application on intensity functions (LFP amplitude vs. stimulus level) for CF (10 kHz) and non-CF (1.25 kHz) stimuli, using a non-CF stimulus 3 octaves below CF to minimize the possibility that picrotoxin could diffuse to the main cortical representation of the non-CF stimulus.
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The averaged data in Fig. 9Ai show that muscimol markedly reduced response amplitude to CF stimuli and picrotoxin produced partial recovery that approached control amplitudes at high intensities. The average data in Fig. 9Aii show that muscimol also reduced response amplitudes to non-CF stimuli but that reversal by picrotoxin was weaker. In Fig. 9B, plotting the muscimol and picrotoxin data relative to predrug amplitudes reveals more clearly the greater reversal of suppression for response amplitudes to CF versus non-CF stimuli. Note that the picrotoxin effect varied with intensity (CF data in Fig. 9B). These data support the idea that CF information is relayed directly to the recording site by thalamocortical projections, whereas non-CF input arrives preferentially via intracortical pathways (Fig. 5B).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Intracellular and LFP responses to tones: do LFPs reflect local EPSPs?
In the present study, the principal response features common to whole cell and LFP recordings from the same site included: similar CFs, similar breadth of frequency receptive fields at each intensity tested, receptive field breadth 5 octaves at moderate to high intensities, and minimum response latencies to CF stimuli and progressively longer onset latencies to stimuli with increasing spectral distance from CF. The main differences between intracellular and LFP responses were that intracellular recordings tended to have higher thresholds at CF and longer latencies than corresponding LFPs. These data indicate that LFPs reflect synaptic potentials in a local group of neurons with similarly broad spectral integration centered on the same CF but with varied thresholds and onset latencies (LFP latencies and thresholds likely reflect those of neurons with the shortest latencies and lowest thresholds).
LFPs are considered an extracellular reflection of synchronous synaptic potentials and are especially clear in laminated structures such as hippocampus and neocortex (Eggermont and Smith 1995; Johnston and Wu 1995). Data from simultaneous extracellular and intracellular recordings in ACx in vitro and in vivo have demonstrated that electrical stimulation of afferents at intensities that consistently produce subthreshold EPSPs invariably elicits LFPs and synaptic potentials of opposite polarity but with similar latencies (Cruikshank et al. 2002; Hsieh et al. 2000; Metherate and Ashe 1993b, 1994; Metherate and Cruikshank 1999). In particular, in the auditory thalamocortical slice preparation, MG stimulation evokes layer 4 EPSPs and LFPs with virtually identical onset latencies (Cruikshank et al. 2002). Thus LFPs can be useful for exploring synaptic connectivity as in the present study. While the exact volume over which LFP activity can be detected is unknown, note that CFs differed between recording sites separated by 1 mm. Such differences might not exist if neural activity from distant frequency representations could be detected by the recording electrode and suggest that high-impedance LFP electrodes sample activity over a distance 1 mm. Although measures of single-unit activity are more precise in terms of localizing neural activity and bear a clearer neural basis, advantages of LFPs include the measurement of presumed subthreshold activity (e.g., can be used to determine breadth of total synaptic input) at predetermined recording sites (e.g., layer 4), and recordings that are reproducible and stable (Barth and Di 1990; Eggermont 1996; Galvan et al. 2001; Norena and Eggermont 2002; Ohl et al. 2000; Steinschneider et al. 1999). Conversely, despite the advantages of LFPs the uncertainty about the volume over which summed neural activity is recorded requires intracellular confirmation of critical features.
Functional connectivity inferred from response to CF stimuli
At a given recording site, CF stimuli evoked the shortest onset latency, which was expected given previous observations of minimum spike latency at CF (Brugge et al. 1969; Eggermont 1996; Phillips and Hall 1992). However, CF stimuli at the high-frequency site evoked shorter latency onsets than did CF stimuli at the mid-frequency site (average: 1.5 ms difference). Shorter minimum spike latencies for higher-frequency CF stimuli have been observed throughout the auditory system, including cochlear nerve (Evans 1972; Kiang 1965), cochlear nucleus (Kitzes et al. 1978), inferior colliculus (Langner et al. 1987; Sanes and Constantine-Paton 1985), and auditory cortex (Mendelson et al. 1997; but see Phillips 1998a) and likely result from timing differences in the transduction of acoustic stimuli in the cochlea; i.e., high-frequency stimuli are transduced near the base of the basilar membrane, whereas low-frequency stimuli are transduced further along the basilar membrane closer to its apex. Rough estimates of travel time along the basilar membrane based on published accounts of cochlea, cochlear nerve, and cochlear nucleus recordings (Evans 1972; Kiang 1965; Kitzes et al. 1978; Robles and Ruggero 2001) range from 0.3 to 0.7 ms/octave, similar to the 0.75 ms/octave obtained in the present study. These findings suggest that precise response timing is maintained throughout the auditory system (Heil and Irvine 1997). Such precision must reflect specialized synaptic mechanisms at each level of the auditory "labeled line" (Oertel 1999; Trussell 1999), and similar specializations may exist in ACx as well (Metherate and Aramakis 1999).
The notion of a labeled line implies that CF input to neurons in primary ACx comes from MGv neurons with the same CF. Supporting evidence is provided by the effects of muscimol in the present study, which imply long-lasting inhibition of cortical neurons with little effect on afferent (thalamocortical) axons (Edeline et al. 2002; Talwar et al. 2001). Whereas muscimol significantly reduced LFP amplitude and receptive field bandwidth, CF stimulus-evoked response threshold and onset latency did not change significantly, suggesting that these features rely on monosynaptic thalamocortical afferents (see next section for detailed rationale). Similarly, the lack of a consistent effect on CF stimulus-evoked response threshold and onset latency suggests that muscimol microinjections into the cortex did not diffuse to the thalamus. These findings are consistent with the results of studies using physiological recordings and anatomical tracing to show that like-CF regions of ACx and MG interconnect (Imig and Morel 1984; Winer et al. 1999). Also, cross-correlated unit recordings of MG and ACx neurons indicate functional connectivity when CFs are within one-third of an octave (Miller et al. 2001). Thus thalamocortical afferents convey to cortex information regarding frequencies preferentially at or near CF.
Using muscimol to distinguish thalamocortical from intracortical processes
In theory, inhibition of cortical activity by muscimol does not prevent thalamocortical afferents from releasing transmitter, but the resulting monosynaptic EPSPs would be small amplitude due to sustained shunting of the postsynaptic neuron by open Cl– channels and less likely to elicit spikes. The inhibition of postsynaptic spiking would preclude polysynaptic (intracortical) activity. The effect on LFP responses elicited by stimulation of afferents entering the inhibited region would be to reduce amplitudes completely except for the earliest (monosynaptic) portion of the response, which would have an amplitude that was reduced (though not completely) and no change in onset latency. In the present study, muscimol, in the volumes and concentrations used, was expected to diffuse several millimeters from the injection site and produce significant inhibition of neurons over a large portion of primary ACx (Edeline et al. 2002; Martin and Ghez 1999). CF stimulus-evoked LFPs were reduced as would be expected for preferential inhibition of polysynaptic over monosynaptic activity (i.e., without change in onset latency, with partial reduction of early response components, and with complete suppression of later response components). Moreover, the presence of a presumed monosynaptic LFP component, along with the minimal effects of muscimol on response threshold at CF, suggest that muscimol did not diffuse so far as to reach the MG and inhibit thalamocortical relay neurons. Thus the use of muscimol should help distinguish thalamocortical from intracortical processes.
Because muscimol delivery in the present study involved injection of microliter volumes into ACx, it was necessary to demonstrate that the effects attributed to muscimol did not result from the volume of fluid injected. In addition to the slow rate of injection (0.5–1.0 µl over 1–2 min) and the 15–20 min delay after injection before data collection was begun (to ensure that compression effects dissipated), several results attest to the pharmacological nature of muscimol's actions. First, muscimol reduced neural response amplitude 74%, whereas saline injections of the same volume produced only 7% reductions. Second, in one animal, surface bath application of muscimol produced inhibition similar to that produced by intracortical microinjections in other animals. Third, neither muscimol nor saline significantly affected response threshold—presumably a vulnerable response because of its small amplitude—and saline did not affect response amplitude at threshold (6% reduction). Fourth, the inhibitory effects of muscimol were reversed by picrotoxin after sequential injections of saline and muscimol, whereas damage to the cortex would have resulted in progressively smaller responses after each injection. Together, these results demonstrate that the muscimol's effects were largely due to actions at receptors and not to damage from injected volumes.
In this context, it is not entirely clear why reversal by picrotoxin varied with intensity (Fig. 9B). One possibility is that damage to the recording site from muscimol injections may be more evident at lower intensities, although the lack of significant changes to response threshold after saline or muscimol injections argues against such damage. Alternatively, more intense stimuli may activate greater numbers of neurons and thus may be more likely to include neurons affected by the diffusion of picrotoxin from the recording pipette. In contrast, the few neurons activated at threshold may not include those neurons closest to the recording pipette and the picrotoxin diffusing from it.
Functional connectivity inferred from responses to non-CF stimuli: the basis of broad receptive fields
LFP recordings demonstrated responses to non-CF stimuli 5 octaves from CF, with onsets occurring progressively later than the onset of responses to CF stimuli. We consider three hypotheses to explain these data, and their implications for functional connectivity in ACx.
NON-CF INPUT IS CARRIED BY THE SAME THALAMOCORTICAL AFFERENTS AS CF INPUT, BUT THALAMIC NEURONS SPIKE AT LONGER LATENCIES TO NON-CF STIMULI THUS PRODUCING LONGER-LATENCY SYNAPTIC ONSETS IN ACX. At all levels of the auditory system, neurons spike to non-CF stimuli at longer latencies than to CF stimuli (Brugge et al. 1969; Eggermont 1996; Hind et al. 1963; Kitzes et al. 1978; Phillips and Hall 1992). Thus a thalamocortical neuron would relay non-CF information at longer latencies, resulting in longer latency synaptic (and LFP) onsets in ACx. This scenario, while undoubtedly correct, does not seem to account for the onset latencies evoked by non-CF stimuli in the present study. Published quantitative examples of single unit responses to CF and non-CF stimuli indicate approximate changes in minimum spike latency of 12–60 ms/octave for ACx (10–30 dB above threshold, data for intervals <1 octave are extrapolated) (Brugge et al. 1969; Eggermont 1996; Phillips and Hall 1992), 4–8 ms/octave for inferior colliculus (10 dB above threshold) (Hind et al. 1963), and 8–15 ms/octave for cochlear nucleus (50–60 dB above threshold) (Kitzes et al. 1978). These latency ranges are generally much longer than the 0.7–4.3 ms/octave for 60–10 dB above threshold in the present study (LFP responses in Fig. 3C). Also, the reduction of bandwidth by intracortical muscimol, and the differential disinhibition of responses to CF stimuli over responses to non-CF stimuli by picrotoxin suggests that non-CF information is not carried by the same afferents that relay CF information. Together, these observations indicate that even though thalamic neurons may spike to non-CF stimuli at long latencies, those spikes do not mediate the earliest arrival of non-CF input at the cortical recording site.
NON-CF INPUT IS VIA DIVERGENT THALAMOCORTICAL PROJECTIONS DELIVERING CF INPUT TO OTHER SITES (FIG. 5A). In this scenario, broadly divergent thalamocortical projections provide CF input to one cortical site and non-CF information to other sites. The divergent terminal arbor could produce slightly longer latencies for responses to non-CF stimuli relative to responses to CF stimuli, i.e., the longer path length of thalamocortical collaterals may increase conduction delay by a few milliseconds. There is insufficient information available about thalamocortical afferents and collaterals to evaluate this idea on the basis of conduction delay. However, the hypothesis is inconsistent with the effects of muscimol and picrotoxin in ACx. Specifically, if responses to non-CF stimuli were produced by monosynaptic thalamocortical input, then muscimol would not affect receptive field bandwidth, and picrotoxin at the recording site would restore responses to CF and non-CF stimuli equally. In contrast, muscimol decreased bandwidth, and picrotoxin had little effect on inhibited responses to stimuli three octaves below CF. These data indicate that bandwidth does not depend on divergent thalamocortical projections.
NON-CF INPUT TO A SITE IS VIA INTRACORTICAL PROJECTIONS (FIG. 5B). In this scenario, thalamocortical CF input to a given site is subsequently relayed intracortically to provide non-CF input to other sites. The intracortical relay would account for the non-CF stimulus-evoked response's greater sensitivity to muscimol, lesser sensitivity to picrotoxin, and delayed onset latency relative to CF stimulus-evoked responses. The delay in onset latency should increase progressively for responses to stimuli both higher and lower than CF because spectral distance from CF would be related monotonically to physical distance between frequency representations in the cortex (Doron et al. 2002; Sally and Kelly 1988). We consider this hypothesis to be the best supported by the data. Further support is provided by preliminary data on tone-evoked current-sourcedensity (CSD) analyses: whereas CF stimulus-evoked current sinks always are found in the middle layers (layers 3 and 4) where thalamocortical inputs terminate (Roger and Arnault 1989; Romanski and LeDoux 1993), non-CF stimulus-evoked sinks lie either above or below the CF stimulus-evoked sink in 6/7 animals (Lazar and Metherate, unpublished observations). Similarly, the proposed intracortical flow of information has been confirmed using the auditory thalamocortical brain slice preparation (Cruikshank et al. 2002; Rose et al. 2003): electrical stimulation of the MG results in a focused, short-latency LFP in layer 4 and longer-latency LFPs at more distant cortical sites (also recording within layer 4 but across presumed isofrequency bands). Laminar recordings reveal a current sink in layer 4 at the site of the shortest-latency LFP, and current sinks generally outside of layer 4 at the more distant cortical sites. Together, these data suggest that CF information from MGv is relayed through layer 4 to other regions of primary ACx, contributing to the synaptic integration underlying broad receptive fields.
Implications of below-CF "boosting"
Although we expected LFPs evoked by CF stimuli to exhibit greater peak amplitudes than LFPs evoked by other frequencies, this often was not the case. Response boosting occurred at high intensities in most animals, 3 octaves below CF (never at frequencies above CF), and at both mid- and high-frequency sites. Because boosted responses at times were associated with weak responses to isointensity CF stimuli, it seemed possible that neurons with nonmonotonic rate-level (intensity) functions may contribute to them, i.e., boosted responses might actually reflect reduced responses to CF stimuli rather than enhanced responses to below-CF stimuli. However, LFP intensity functions at CF were monotonic. Also, single-unit studies have shown that neurons with nonmonotonic intensity functions have enclosed (circumscribed) response areas (e.g., Phillips et al. 1985b); we find no evidence in the literature that these neurons have enhanced responses to stimulus frequencies below CF. Nonetheless, because the relationship of LFP and unit activity is unclear, it is possible that neurons with nonmonotonic intensity functions may contribute to boosted responses (or, more precisely, to weakened responses to CF stimuli) in the present study. Boosting may help equalize spike latencies to CF and non-CF stimuli for some neurons or contribute to the propagation of activity from low- to high-frequency regions observed with optical recording methods (Hess and Scheich 1996); the functional relevance of this activity, however, is unclear. As muscimol reduces, but does not abolish, boosting, it appears to originate subcortically and be amplified in ACx. In fact, auditory nerve fibers with CFs >1 kHz exhibit responses that qualitatively resemble boosting at higher intensities (Rose et al. 1971), but the effect is weaker than that seen in ACx both in terms of the spectral distance from CF of the boosted response (e.g., <1 octave) as well as the degree of boosting.
How broad are frequency receptive fields in primary ACx?
Intracellular and LFP receptive field bandwidths measured 5 octaves at moderate to high intensities, and averaged 2–3 octaves 20 dB above threshold. At the mid-frequency site, the average LFP bandwidth 20 dB above threshold of 2.4 octaves (Fig. 7C) corresponds to an approximate bandwidth measure of 2.71 kHz0.5 using the square-root transformation and 0.54 using a "Q" measure similar to Q10, but 20 dB above threshold [square-root transformation = 
where f2 and f1 are the high and low limits of the receptive field 20 dB above threshold (Calford et al. 1983); Q10 = CF/bandwidth 10 dB above threshold (Kiang 1965)]. These numbers indicate remarkable breadth of tuning, and yet our estimates may underestimate maximum breadth of tuning at higher intensities because our stimulus set only spanned 5 octaves. Indeed, LFP receptive fields extended 5 octaves below CF at some high-frequency sites (CF 40 kHz). These bandwidths are much broader than estimates of bandwidth in primary ACx that are based on spike activity [e.g., average square root score of 0.39 kHz0.5 (Calford et al. 1983) and 1.0 kHz0.5 (Eggermont 1996); Q10 values average 6–7 for CF of 8–12 kHz (Phillips and Irvine 1981)], and undoubtedly indicate that substantial portions of receptive fields are subthreshold. Simultaneous recordings of LFPs and spike activity explicitly demonstrate that LFP-based bandwidths are broader than spike-based bandwidths (Galvan 2001; Norena and Eggermont 2002), and prior intracellular studies have shown that subthreshold receptive fields extend beyond the boundaries of suprathreshold receptive fields (Ojima and Murakami 2002; Ribaupierre et al. 1972; Volkov and Galazjuk 1991; Wehr and Zador 2003).
The remarkable breadth of intracellular and LFP receptive fields raises the intriguing possibility that some primary ACx neurons may integrate information across much of the animal's audible spectrum. A recent study of gerbil primary ACx reached a similar conclusion based on the enhancement of multiunit responses by stimuli several octaves above the conventionally defined receptive field (Schulze and Langner 1999). Other LFP (Eggermont 1996; Galvan et al. 2001; Norena and Eggermont 2002), multiple-unit (Phillips and Hall 1992; Phillips et al. 1994), and optical-imaging (Bakin et al. 1996; Hess and Scheich 1996; Horikawa et al. 1996) studies also provide evidence for very broad spectral integration in primary ACx.
Potential cortical mechanism of acoustic processing
Because spike-based receptive fields have bandwidths that are similarly narrow throughout the lemniscal auditory system (Calford et al. 1983; Edeline et al. 1999), it is worth considering whether the broad, subthreshold receptive fields observed in the present study distinguish primary ACx from subcortical auditory nuclei [for now, we do not consider the nonlemniscal auditory regions within which broad receptive fields are, of course, more common (Calford and Webster 1981; Calford et al. 1983; Edeline et al. 1999), nor do we consider how inhibitory subfields are created (Sutter and Loftus 2003)]. If, for example, neurons in all auditory nuclei have broad subthreshold receptive fields and narrow suprathreshold receptive fields, then the results of the present study do not reflect a unique feature of ACx. Alternatively, if subcortical nuclei have subthreshold receptive fields that are nearly as narrow as their suprathreshold receptive fields, then the breadth of cortical subthreshold receptive fields may indicate a unique cortical function.
There is evidence that subthreshold receptive fields in subcortical nuclei are narrower than those in cortex. For example, local application of the GABAA receptor antagonist bicuculline produces substantial expansion of receptive fields in primary ACx (Foeller et al. 2001; Muller and Scheich 1988; Wang et al. 2000, 2002) but reportedly lesser or no expansion in subcortical regions (Caspary et al. 1994; LeBeau et al. 2001; Palombi and Caspary 1992). The distinction between cortical and subcortical receptive fields applies to other sensory modalities as well. In the somatosensory and visual systems, bicuculline similarly expands cortical, but not thalamic, receptive fields (Dykes et al. 1984; Hicks et al. 1986; Sillito 1975), and intracellular recordings have demonstrated substantial subthreshold ("nonclassical" or "surround") receptive fields in cortex (Bringuier et al. 1999; Li and Waters 1996; Smits et al. 1991). Intracortical projections are thought to relay information for subthreshold receptive fields in somatosensory and visual cortex (Fox et al. 2003; Gilbert 1998) as is being proposed in the present study for primary ACx. These data suggest that subthreshold receptive fields are broader in each primary sensory cortex than in corresponding subcortical relays (although intracellular recordings in thalamic relay neurons will be needed to resolve this question fully).
Thus broad subthreshold receptive fields may distinguish ACx from subcortical relays within the lemniscal pathway and exist because they are created by intracortical circuitry (3rd hypothesis, see NON-CF INPUT TO A SITE IS VIA INTRACORTICAL PROJECTIONS; Fig. 5B). If intracortical circuitry mediates integration across frequency representations, e.g., to generate responses to spectrally complex stimuli (Schulze et al. 1997; Whitfield and Evans 1965), then conventional spike-based receptive fields might actually reflect responses to suboptimal stimuli, i.e., pure tones. The present results predict one kind of optimal stimulus. The changes in onset latency with increasing spectral distance from CF ranged from 1–4 ms/octave, depending on stimulus intensity. One prediction is that responses to multiple stimuli of different frequencies would sum optimally if their onsets coincided, i.e., if the stimuli were staggered in time with non-CF stimuli appearing before CF stimuli. The optimal stimulus may therefore be a sequence of stimuli— or, in the limit, a frequency-modulated (FM) sweep—moving toward CF from either higher or lower non-CFs, as shown previously (Heil et al. 1992; Phillips et al. 1985a). Complex stimuli such as FM sweeps are important features of natural sounds, including speech, to which ACx neurons respond (Fitch et al. 1997; Nelken et al. 1999; Steinschneider et al. 1999). Conversely, the inability to discriminate spectrally complex stimuli following ACx lesions may underlie deficits in auditory perception such as "pure word deafness" in humans (Phillips 1998b).
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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GRANTS
This study was supported by the National Institutes of Health Grants DC-02967 and DA-12929 and by the California Tobacco-Related Disease Research Program (8RT-0059).
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. Metherate, Dept. of Neurobiology and Behavior, University of California, 2205 McGaugh Hall, Irvine, CA 92697–4550. (E-mail: rmethera{at}uci.edu).
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REFERENCES |
|---|
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
|---|
Barth DS and Di S. Three-dimensional analysis of auditory-evoked potentials in rat neocortex. J Neurophysiol 64: 1527–1536, 1990.
Blanton MG, LoTurco JJ, and Kriegstein AR. Whole cell recording from neurons in slices of reptilian and mammalian cerebral cortex. J Neurosci Methods 30: 203–210, 1989.[CrossRef][Web of Science][Medline]
Bringuier V, Chavane F, Glaeser L, and Fregnac Y. Horizontal propagation of visual activity in the synaptic integration field of area 17 neurons. Science 283: 695–699, 1999.
Brugge JF, Dubrovsky NA, Aitkin LM, and Anderson DJ. Sensitivity of single neurons in auditory cortex of cat to binaural tonal stimulation; effects of varying interaural time and intensity. J Neurophysiol 32: 1005–1024, 1969.
Calford MB and Webster WR. Auditory representation within principal division of cat medial geniculate body: an electrophysiological study. J Neurophysiol 45: 1013–1028, 1981.
Calford MB, Webster WR, and Semple MM. Measurement of frequency selectivity of single neurons in the central auditory pathway. Hear Res 11: 395–401, 1983.[CrossRef][Web of Science][Medline]
Caspary DM, Backoff PM, Finlayson PG, and Palombi PS. Inhibitory inputs modulate discharge rate within frequency receptive fields of anteroventral cochlear nucleus neurons. J Neurophysiol 72: 2124–2133, 1994.
Cruikshank SJ, Rose HJ, and Metherate R. Auditory thalamocortical synaptic transmission in vitro. J Neurophysiol 87: 361–384, 2002.
Doron NN, Ledoux JE, and Semple MN. Redefining the tonotopic core of rat auditory cortex: physiological evidence for a posterior field. J Comp Neurol 453: 345–360, 2002.[CrossRef][Web of Science][Medline]
Dykes RW, Landry P, Metherate R, and Hicks TP. Functional role for GABA in primary somatosensory cortex: shaping receptive fields of cortical neurons. J Neurophysiol 52: 1066–1093, 1984.
Edeline JM, Dutrieux G, Manunta Y, and Hennevin E. Diversity of receptive field changes in auditory cortex during natural sleep. Eur J Neurosci 14: 1865–1880, 2001.[CrossRef][Web of Science][Medline]
Edeline J-M, Hars B, Cotillon N, and Hennevin E. Muscimol diffusion after intracerebral microinjections: a re-evaluation based on electrophysiological and autoradiographic quantifications. Neurobiol Learn Mem 78: 100–124, 2002.[CrossRef][Web of Science][Medline]
Edeline JM, Manunta Y, Nodal FR, and Bajo VM. Do auditory responses recorded from awake animals reflect the anatomical parcellation of the auditory thalamus? Hear Res 131: 135–152, 1999.[CrossRef][Web of Science][Medline]
Eggermont JJ. How homogeneous is cat primary auditory cortex? Evidence from simultaneous single-unit recordings. Aud Neurosci 2: 79–96, 1996.
Eggermont JJ and Smith GM. Synchrony between single-unit activity and local field potentials in relation to periodicity coding in primary auditory cortex. J Neurophysiol 73: 227–245, 1995.
Evans EF. The frequency response and other properties of single fibers in the guinea pig cochlear nerve. J Physiol 226: 263–287, 1972.
Fitch RH, Miller S, and Tallal P. Neurobiology of speech perception. Annu Rev Neurosci 20: 331–353, 1997.[CrossRef][Web of Science][Medline]
Foeller E, Vater M, and Kossl M. Laminar analysis of inhibition in the gerbil primary auditory cortex. J Assoc Res Otolaryngol 2: 279–296, 2001.[Medline]
Fox K, Wright N, Wallace H, and Glazewski S. The origin of cortical surround receptive fields studied in the barrel cortex. J Neurosci 23: 8380–8391, 2003.
Galvan VV. Long-Term Stability of Frequency Tuning and Consolidation of Learning-Induced Receptive Field Plasticity in the Primary Auditory Cortex (PhD dissertation). Irvine, CA: University of California, 2001.
Galvan VV, Chen J, and Weinberger NM. Long-term frequency tuning of local field potentials in the auditory cortex of the waking guinea pig. J Assoc Res Otolaryngol 2: 199–215, 2001.[Medline]
Gilbert CD. Adult cortical dynamics. Physiol Rev 78: 467–485, 1998.
Heil P and Irvine DRF. First-spike timing of auditory-nerve fibers and comparison with auditory cortex. J Neurophysiol 78: 2438–2454, 1997.
Heil P, Langner G, and Scheich H. Processing of frequency-modulated stimuli in the chick auditory cortex analogue: evidence for topographic representations and possible mechanisms of rate and directional sensitivity. J Comp Physiol [A] 171: 583–600, 1992.[Medline]
Hess A and Scheich H. Optical and FDG mapping of frequency-specific activity in auditory cortex. Neuroreport 7: 2643–2647, 1996.[Web of Science][Medline]
Hicks TP, Metherate R, Landry P, and Dykes RW. Bicuculline-induced alterations of response properties in functionally identified ventroposterior thalamic neurones. Exp Brain Res 63: 248–264, 1986.[Web of Science][Medline]
Hind JE, Goldberg JM, Greenwood DG, and Rose JE. Some discharge characteristics of single neurons in the inferior colliculus of the cat. II. Timing of the discharges and observations on binaural stimulation. J Neurophysiol 26: 321–341, 1963.
Horikawa J, Hosokawa Y, Kubota M, Nasu M, and Taniguchi I. Optical imaging of spatiotemporal patterns of glutamatergic excitation and GABAergic inhibition in the guinea pig auditory cortex in vivo. J Physiol 497: 629–638, 1996.
Horikawa J, Ito S, Hosokawa Y, Homma T, and Murata K. Tonotopic representation in the rat auditory cortex. Proc Jpn Acad Ser B 64: 260–263, 1988.
Hsieh CY, Cruikshank SJ, and Metherate R. Differential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist. Brain Res 880: 51– 64, 2000.[CrossRef][Web of Science][Medline]
Imig TJ and Morel A. Topographic and cytoarchitectonic organization of thalamic neurons related to their targets in low-, middle-, and high-frequency representations in cat auditory cortex. J Comp Neurol 227: 511–539, 1984.[CrossRef][Web of Science][Medline]
Johnston D and Wu SM-S. Foundations of Cellular Neurophysiology. Cambridge, MA: MIT Press, 1995.
Kiang NY-S. Discharge Patterns of Single Fibers in the Cat's Auditory Nerve. Cambridge, MA: MIT Press, 1965.
Kilgard MP and Merzenich MM. Cortical map reorganization enabled by nucleus basalis activity. Science 279: 1714–1718, 1998.
Kitzes LM, Gibson MM, Rose JE, and Hind JE. Initial discharge latency and threshold considerations for some neurons in cochlear nuclear complex of the cat. J Neurophysiol 41: 1165–1182, 1978.
Langner G, Schreiner C, and Merzenich MM. Covariation of latency and temporal resolution in the inferior colliculus of the cat. Hear Res 31: 197–201, 1987.[CrossRef][Web of Science][Medline]
LeBeau FE, Malmierca MS, and Rees A. Iontophoresis in vivo demonstrates a key role for GABA(A) and glycinergic inhibition in shaping frequency response areas in the inferior colliculus of guinea pig. J Neurosci 21: 7303–7312, 2001.
Li CX and Waters RS. In vivo intracellular recording and labeling of neurons in the forepaw barrel subfield (FBS) of rat somatosensory cortex: possible physiological and morphological substrates for reorganization. Neuroreport 7: 2261–2272, 1996.[Web of Science][Medline]
Martin JH and Ghez C. Pharmacological inactivation in the analysis of the central control of movement. J Neurosci Methods 86: 145–159, 1999.[CrossRef][Web of Science][Medline]
Mendelson JR, Schreiner CE, and Sutter ML. Functional topography of cat primary auditory cortex: response latencies. J Comp Physiol [A] 181: 615–633, 1997.[CrossRef][Medline]
Merzenich MM, Knight PL, and Roth GL. Representation of cochlea within primary auditory cortex in the cat. J Neurophysiol 38: 231–249, 1975.
Metherate R and Aramakis VB. Intrinsic electrophysiology of neurons in thalamorecipient layers of developing rat auditory cortex. Dev Brain Res 115: 131–144, 1999.[CrossRef][Medline]
Metherate R and Ashe JH. Ionic flux contributions to neocortical slow waves and nucleus basalis-mediated activation: whole cell recordings in vivo. J Neurosci 13: 5312–5323, 1993a.[Abstract]
Metherate R and Ashe JH. Nucleus basalis stimulation facilitates thalamocortical synaptic transmission in rat auditory cortex. Synapse 14: 132–143, 1993b.[CrossRef][Web of Science][Medline]
Metherate R and Ashe JH. Facilitation of an NMDA receptor-mediated EPSP by paired-pulse stimulation in rat neocortex via depression of GABAergic IPSPs. J Physiol 481: 331–348, 1994.
Metherate R, Cox CL, and Ashe JH. Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine. J Neurosci 12: 4701– 4711, 1992.[Abstract]
Metherate R and Cruikshank SJ. Thalamocortical inputs trigger a propagating envelope of gamma-band activity in auditory cortex in vitro. Exp Brain Res 126: 160–174, 1999.[CrossRef][Web of Science][Medline]
Miller LM, Escabi MA, Read HL, and Schreiner CE. Functional convergence of response properties in the auditory thalamocortical system. Neuron 32: 151–160, 2001.[CrossRef][Web of Science][Medline]
Muller CM and Scheich H. Contribution of GABAergic inhibition to the response characteristics of auditory units in the avian forebrain. J Neurophysiol 59: 1673–1689, 1988.
Muller-Preuss P and Mitzdorf U. Functional anatomy of the inferior colliculus and the auditory cortex: current source density analyses of click-evoked potentials. Hear Res 16: 133–142, 1984.[CrossRef][Web of Science][Medline]
Nelken I, Rotman Y, and Yosef OB. Responses of auditory cortex neurons to structural features of natural sounds. Nature 397: 154–157, 1999.[CrossRef][Medline]
Norena A and Eggermont JJ. Comparison between local field potentials and unit cluster activity in primary auditory cortex and anterior auditory field in the cat. Hear Res 166: 202–213, 2002.[CrossRef][Web of Science][Medline]
Oertel D. The role of timing in the brain stem auditory nuclei of vertebrates. Annu Rev Physiol 61: 497–519, 1999.[CrossRef][Web of Science][Medline]
Ohl FW, Scheich H, and Freeman WJ. Topographic analysis of epidural pure-tone-evoked potentials in gerbil auditory cortex. J Neurophysiol 83: 3123–3132, 2000.
Ojima H and Murakami K. Intracellular characterization of suppressive responses in supragranular pyramidal neurons of cat primary auditory cortex in vivo. Cereb Cortex 12: 1079–1091, 2002.
Palombi PS and Caspary DM. GABAA receptor antagonist bicuculline alters response properties of posteroventral cochlear nucleus neurons. J Neurophysiol 67: 738–746, 1992.
Phillips DP. Factors shaping the response latencies of neurons in the cat's auditory cortex. Behav Brain Res 93: 33–41, 1998a.[CrossRef][Web of Science][Medline]
Phillips DP. Sensory representations, the auditory cortex, and speech perception. Semin Hear 19: 319–332, 1998b.[CrossRef]
Phillips DP and Hall SE. Multiplicity of inputs in the afferent path to cat auditory cortex neurons revealed by tone-on-tone masking. Cereb Cortex 2: 425–433, 1992.
Phillips DP and Irvine DR. Responses of single neurons in physiologically defined primary auditory cortex (AI) of the cat: frequency tuning and responses to intensity. J Neurophysiol 45: 48–58, 1981.
Phillips DP, Mendelson JR, Cynader MS, and Douglas RM. Responses of single neurones in cat auditory cortex to time-varying stimuli: frequency-modulated tones of narrow excursion. Exp Brain Res 58: 443–454, 1985a.[Web of Science][Medline]
Phillips DP, Orman SS, Musicant AD, and Wilson GF. Neurons in the cat's primary auditory cortex distinguished by their responses to tones and wide-spectrum noise. Hear Res 18: 73–86, 1985b.[CrossRef][Web of Science][Medline]
Phillips DP, Semple MN, Calford MB, and Kitzes LM. Level-dependent representation of stimulus frequency in cat primary auditory cortex. Exp Brain Res 102: 210–226, 1994.[Web of Science][Medline]
Recanzone GH, Schreiner CE, and Merzenich MM. Plasticity in the frequency representation of primary auditory cortex following discrimination training in adult owl monkeys. J Neurosci 13: 87–103, 1993.[Abstract]
Ribaupierre Fd, Goldstein MH, and Yeni-Komshian G. Intracellular study of the cat's primary auditory cortex. Brain Res 48: 185–204, 1972.[CrossRef][Web of Science][Medline]
Robles L and Ruggero MA. Mechanics of the mammalian cochlea. Physiol Rev 81: 1305–1352, 2001.
Roger M and Arnault P. Anatomical study of the connections of the primary auditory area in the rat. J Comp Neurol 287: 339–356, 1989.[CrossRef][Web of Science][Medline]
Romanski LM and LeDoux JE. Organization of rodent auditory cortex: anterograde transport of PHA-L from MGv to temporal neocortex. Cereb Cortex 3: 499–514, 1993.
Rose JE, Hind JE, Anderson DJ, and Brugge JF. Some effects of stimulus intensity on response of auditory nerve fibers in the squirrel monkey. J Neurophysiol 34: 685–699, 1971.
Rose HJ, Kaur S, and Metherate R. Synaptic processing in auditory cortex: data from in vivo intracellular recordings and the auditory thalamocortical slice. Abstr Assoc Res Otolaryngol 26: 314, 2003.
Sally SL and Kelly JB. Organization of auditory cortex in the albino rat: sound frequency. J Neurophysiol 59: 1627–1638, 1988.
Sanes DH and Constantine-Paton M. The sharpening of frequency tuning curves requires patterned activity during development in the mouse, Mus musculus. J Neurosci 5: 1152–1166, 1985.[Abstract]
Schulze H and Langner G. Auditory cortical responses to amplitude modulations with spectra above frequency receptive fields: evidence for wide spectral integration. J Comp Physiol [A] 185: 493–508, 1999.[CrossRef][Medline]
Schulze H, Ohl FW, Heil P, and Scheich H. Field-specific responses in the auditory cortex of the unanaesthetized Mongolian gerbil to tones and slow frequency modulations. J Comp Physiol [A] 181: 573–589, 1997.[CrossRef][Web of Science][Medline]
Shaw NA. The auditory evoked potential in the rat—a review. Prog Neurobiol 31: 19–45, 1988.[CrossRef][Web of Science][Medline]
Sillito AM. The contribution of inhibitory mechanisms to the receptive field properties of neurones in the striate cortex of the cat. J Physiol 250: 305–329, 1975.
Smits E, Gordon DC, Witte S, Rasmusson DD, and Zarzecki P. Synaptic potentials evoked by convergent somatosensory and corticocortical inputs in raccoon somatosensory cortex: substrates for plasticity. J Neurophysiol 66: 688–695, 1991.
Steinschneider M, Volkov IO, Noh MD, Garell PC, and Howard MA, 3rd. Temporal encoding of the voice onset time phonetic parameter by field potentials recorded directly from human auditory cortex. J Neurophysiol 82: 2346–2357, 1999.
Sutter ML and Loftus WC. Excitatory and inhibitory intensity tuning in auditory cortex: evidence for multiple inhibitory mechanisms. J Neurophysiol 90: 2629–2647, 2003.
Talwar SK, Musial PG, and Gerstein GL. Role of mammalian auditory cortex in the perception of elementary sound properties. J Neurophysiol 85: 2350–2358, 2001.
Trussell LO. Synaptic mechanisms for coding timing in auditory neurons. Annu Rev Physiol 61: 477–496, 1999.[CrossRef][Web of Science][Medline]
Volkov IO and Galazjuk AV. Formation of spike response to sound tones in cat auditory cortex neurons: interaction of excitatory and inhibitory effects. Neuroscience 43: 307–321, 1991.[CrossRef][Web of Science][Medline]
Wang J, Caspary D, and Salvi RJ. GABA-A antagonist causes dramatic expansion of tuning in primary auditory cortex. Neuroreport 11: 1137–1140, 2000.[Web of Science][Medline]
Wang J, McFadden SL, Caspary D, and Salvi R. Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons. Brain Res 944: 219–231, 2002.[CrossRef][Web of Science][Medline]
Wehr M and Zador AM. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. Nature 426: 442–446, 2003.[CrossRef][Medline]
Weinberger NM and Bakin JS. Learning-induced physiological memory in adult primary auditory cortex: receptive fields plasticity, model, and mechanisms. Audiol Neurootol 3: 145–167, 1998.[CrossRef][Medline]
Whitfield IC and Evans EF. Responses of auditory cortical neurons to stimuli of changing frequency. J Neurophysiol 28: 655–672, 1965.
Winer JA, Sally SL, Larue DT, and Kelly JB. Origins of medial geniculate body projections to physiologically defined zones of rat primary auditory cortex. Hear Res 130: 42–61, 1999.[CrossRef][Web of Science][Medline]
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