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The Journal of Neuroscience, October 15, 2001, 21(20):8129-8135
Primordial Rhythmic Bursting in Embryonic Cochlear Ganglion Cells
Timothy A. Jones, Sherri M. Jones, and Kristina C. Paggett Department of Surgery, Division of Otolaryngology, University of Missouri School of Medicine, Columbia, Missouri 65212
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
This study examined the nature of spontaneous discharge patterns in cochlear ganglion cells in embryonic day 13 (E13) to early E17 chicken embryos (stages 39-43). Neural recordings were made with glass micropipettes. No sound-driven activity was seen for the youngest embryos (maximum intensity 107 dB sound pressure level). Ganglion cells were labeled with biotinylated dextran amine in four embryos. In two animals, primary afferents projected to hair cells in the middle region along the length of the basilar papilla in which, in one cell, the terminals occupied a neural transverse position and, in the other, a more abneural location. Statoacoustic ganglion cells showing no spontaneous activity were seen for the first time in the chicken. The proportion of "silent" cells was largest at the youngest stages (stage 39, 67%). In active cells, mean spontaneous discharge rates [9.4 ± 10.4 spikes (Sp)/sec; n = 44] were lower than rates for older embryos (19 ± 17 Sp/sec) (Jones and Jones, 2000
). Embryos at stages 39-41 evidenced even lower rates (4.2 ± 5.0 Sp/sec). The most salient feature of spontaneous activity for stages 39-43 was a bursting discharge pattern in >75% of active neurons (33 of 44). Moreover, in 55% of these cells, there was a clear, slow, rhythmic bursting pattern. The proportion of cells showing rhythmic bursting was greatest at the youngest stages (39-42) and decreased to <30% at stage 43. Rate of bursting ranged from 1 to 54 bursts per minute. The presence of rhythmic bursting in cochlear ganglion cells at E13-E17 provides an explanation for the existence of such patterns in central auditory relays. The bursting patterns may serve as a patterning signal for central synaptic refinements in the auditory system during development.
Key words: functional ontogeny; bird; spontaneous activity; embryonic development; primary afferents; chicken; audition; hearing
INTRODUCTION
Spontaneous rhythmic bursting of retinal ganglion cells may provide a critical signal for refinements in developing central binocular processing circuits. Indeed, modifications of retinal spontaneous afferent discharge patterns can result in altered synaptic configurations in thalamic and cortical relays (Galli and Maffei, 1988
Could development of binaural processing circuits require a patterned activity similar to rhythmic retinal activity? Unfortunately, little is known about spontaneous activity derived from the embryonic or neonatal cochlea. There are a few descriptions of spontaneous discharge patterns in developing central and peripheral auditory circuits. Low spontaneous discharge rates were described in the neonatal pigeon (Richter et al., 1996
MATERIALS AND METHODS
Methods for in vivo recordings of the statoacoustic ganglion in chicken embryos have been published elsewhere (Jones and Jones, 1995a
Beak and toe lengths were measured and used to determine the developmental stage of each animal. Ages are reported as stages or corresponding days of incubation as outlined by Hamburger and Hamilton (1951)
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Table 1. Staging and incubation day equivalence, according to Hamburger and Hamilton (1951) Beveled glass micropipettes, filled with 10% biotinylated dextran amine (BDA; 3000 molecular weight; Molecular Probes, Eugene, OR) in 0.5 M KCl and 0.05 M Tris, were lowered into scala tympani in 0.5 µm steps with the tip directed toward the ganglion. Silver chloride wire electrodes were used for the reference (neck) and ground (extraembryonic fluid). Electrode impedance ranged from 5 to 15 M
and was measured in situ using an electrometer (WPI 767-B; World Precision Instruments, Sarasota, FL).
Electrophysiological activity was amplified (gains ranged from 50 to 500×), filtered (bandpass 100-3000 Hz, or 100-10,000 Hz,
6 dB points), and recorded on videotape (Vetter 420G). Signals were also amplified and led to a speaker so that the activity of neurons was audible. Detailed analysis of spontaneous activity was accomplished off-line. Activity was digitized (40 or 50 µsec/point) and saved on diskette. Then, the recording was systematically analyzed to determine the onset time of each spike occurrence. A voltage threshold criterion was used to detect spikes initially, and each spike detected was displayed at high resolution and visually confirmed on screen (Fig. 1). In Figure 1, records from two neurons illustrate the range of signal-to-noise ratios found typically in the present study.
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Figure 1. The primary digitized records (40 µsec per point) of two neural spike trains are shown here. The records illustrate the range of signal-to-noise ratios encountered in this study. The process of expanding traces for high resolution computerized analysis is shown for neuron 88tm01. Spike detection was accomplished using an initial voltage threshold criterion. Records were divided into contiguous data blocks in which for each block, the voltage threshold could be adjusted to accommodate fluctuations in baseline. The entire record was examined on screen at high resolution for falsely detected spikes and for failed detection of spikes. Each action potential was individually confirmed.
Fluid was wicked out of the middle ear, and sound stimuli were delivered using an ER-2 earphone that was sealed at the external auditory meatus. Clicks (0.1 msec; 1.0 V square wave pulses), pure tones (1.0 V peak to peak; 100-4000 Hz), and pure-tone or noise bursts (50 msec duration; 5 msec rise-fall times; 50% duty cycle) were used as stimuli to determine whether individual cells responded to sound. All stimuli were routed through an attenuator (Med Associates, St. Albans, Vermont), amplifier (Med Associates), and equalizer (Pioneer, Long Beach, CA) before output at the earphone. Maximum stimulus intensity at the output of the earphone was 107 dB sound pressure level (SPL) (or dB peak equivalent SPL for clicks across the frequencies tested).
Once single primary afferents were isolated, up to 4 min of continuous spontaneous activity was recorded on analog tape and analyzed off-line. If the neuron could be sound activated, an estimate of best frequency was obtained audiovisually (Jones and Jones, 1995a
We use the expression "rhythmic bursting" here to describe recurring periodic and generally sudden increases in neural discharge rate. When present, bursts of activity are heralded by a flurry of spikes (at least two in number, but usually many more) separated by relatively long silent periods that reoccur at somewhat regular intervals. The striking character of ideal regular bursting is easily recognized. However, in the case of less than ideal rhythmic bursting patterns or less prevalent long silent periods, (as is the case in late embryonic periods) it becomes harder to characterize the regularity and hence the rate of bursting. We addressed this issue in the present study by evaluating spike trains using autocorrelation and the fast Fourier transform (FFT). As described in earlier work (Jones and Jones, 2000
Spontaneous discharge patterns not showing rhythmic bursting based on the ACF were also tested for levels of irregular bursting. Irregular bursting patterns are characterized by bouts of neural activity that occur at irregular intervals separated by relatively long periods of silence. To objectively quantify the level of irregular bursting activity ("burstiness"), we used a numerical "burst factor" (BF) as described in a previous report (Jones and Jones, 2000
After physiological recordings, BDA was ejected from the pipette using pressure (~300 kPa). One to two hours after the injection, the cochlea was fixed and processed. Several fixation and processing protocols were used to increase the likelihood of successful label. The following protocol has thus far been the most successful. The tympanic membrane was opened, the columella was removed, and the cochlea was perfused slowly with 3 ml of 4% paraformaldehyde/1% glutaraldehyde in 0.1 M phosphate buffer. Immediately after cochlear perfusion, the embryo was decapitated, the head was hemisected, and an additional 3-5 ml of fixative was perfused into the opened labyrinth. The medial wall of the cochlea was also opened, and the head was stored in fixative overnight. Our experience suggests that initial perfusion of the cochlea must occur in an intact viable animal. We have not seen successful label in any case in which cochlear perfusion was initiated in a physiologically compromised animal (slow or irregular electrocardiogram or immediately after decapitation).
Dissected cochleas were processed as whole mounts. Processing began with four rinses in PBS (10 min each). The final PBS rinse contained 1% Triton X-100. Rinses were followed with pretreatment in 0.5% H2O2 in PBS (20 min to block endogenous peroxidase) and three additional rinses in PBS (10 min each). Then, cochleas were soaked overnight in avidin-HRP (Vector Laboratories, Burlingame, CA):PBS containing 1% Triton X-100 (1:250). The next day, cochleas were rinsed again with PBS (three times, 10 min each) and soaked in 0.03% DAB for 20-30 min. At this point, 0.03% H2O2 was added, one drop every 1-2 min until desired background stain was achieved (usually an additional 5-8 min). Processed cochleas were embedded in plastic (JB-4) and viewed with light microscopy.
RESULTS
Data used for analysis were obtained from embryos in good physiological condition (i.e., stable brain temperatures and regular heart rate >250 beats per minute). Studies were terminated, or data were excluded for embryos that did not meet these criteria because they were judged to be physiologically compromised. Sixty-one statoacoustic ganglion cells were isolated for study in 51 embryos. All but 17 of the neurons were spontaneously active. The 17 "silent" neurons produced trains of action potentials with current injections ranging from 0.1 to 25 nA.
Discharge rates [spikes (Sp) per second] for spontaneously active individual ganglion cells are plotted as a function of developmental stage in Figure 2. Rates were based on recordings with an average duration of ~87 sec, with the lowest rate based on 8 spikes in 90 sec and the highest rate based on 406 spikes in 10.23 sec. The total number of action potentials per record ranged from 8 to 2184 spikes. The longest continuous record of spontaneous activity was 4 min. To establish a broader context, we have added data from earlier work for stages 44 and 45 (Jones and Jones, 2000
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Figure 2. Discharge rates (spikes per second) for individual ganglion cells are plotted as a function of developmental stage. Data for stages 44 and 45 are from earlier work (Jones and Jones, 2000
Five examples of discharge patterns from stages 39-43 are represented in Figure 3. These records reflect the slow rhythmic discharge patterns or bursting found in animals younger than E18. The frequency of bursting was generally quite low (<1 Hz, ranging from 0.0167 to 0.9 Hz; mean ± SD = 0.27 ± 0.19; n = 18). Figure 4 illustrates the results of autocorrelation and Fourier analysis on some of these neurons. Neuron 80tm01 demonstrates modest spike discharge rates overall (3.9 Sp/sec) and is featured at the top of Figure 4. The ACF array for 80tm01 reveals a strong periodicity in firing, whereas the FFT demonstrates a corresponding f0 of 0.228 Hz. The burst rate in bursts per minute is calculated as BR = f0 × 60 sec/min, or ~13.4 bursts per minute in this case. A second rhythmically bursting neuron from Figure 3 is shown in Figure 4 (91tm01). Despite relatively low overall spike rates (0.45 Sp/sec), the ACF reveals a clear periodicity and a significant FFT fundamental at f0 = 0.163 Hz or ~9.8 bursts per minute. The neuron at the bottom of Figure 4 (76tm01) is an example in which rhythmic bursting is absent. No periodicity is apparent in the ACF, and the FFT has no significant peaks. This neuron, although not a rhythmically bursting cell, was classified as irregularly bursting, having a BF = 1.99. All neurons of Figure 3 had robust rhythmic patterns. There were examples of neurons in the present study that displayed evidence of very weak periodicities, and it was necessary to adopt an objective conservative criterion distinguishing rhythmic from nonrhythmic patterns. Activity patterns producing spectral peaks with magnitudes less than twice baseline levels were classified as nonrhythmic (irregular bursting). Those producing spectra with a clear fundamental frequency peak that was two or more times that of the background levels were judged to be regularly bursting neurons.
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Figure 3. Bursting spontaneous discharge patterns. Five examples of discharge patterns are represented at progressively later stages of development from stage 39 to 43 (top to bottom, respectively). Eighteen of the 44 spontaneously active ganglion cells produced rhythmic bursting patterns. Each vertical line represents a single action potential. Total time represented is 60 sec. Over these developmental stages, the rate of bursting ranged from 1 to 54 bursts per minute. Burst rates for each neuron were based on the FFT spectrum of the ACF (Fig. 4). Rates in bursts per minute for neurons shown were 9.78 for 91tm01, 5.88 for 89tm01, 5.88 for 87tm01, 13.68 for 80tm01, and 15.6 for 84tm02. Five cells that demonstrated regular bursting patterns (all at stages 42-43) also responded to sound.
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Figure 4. Autocorrelation functions (ACF; also referred to as probability density functions) and their fast Fourier transforms (FFT) are shown for three representative neurons. The ACF of spike discharge activity was examined for evidence of periodicities. Neuron 80tm01 (top) shows a robust periodicity, and the FFT spectrum demonstrates a fundamental frequency (f0) of 0.228 Hz. A portion of the spike train for neuron is shown in Figure 3. Similarly, the spike activity of neuron 91tm01 of Figure 3 was subjected to ACF and FFT analysis, revealing a clear periodicity at 0.163 Hz, despite the low spike rate in this case. Neuron 76tm01 exhibited no rhythmic bursting, and as can be seen in the ACF, there were no periodicities present. FFT amplitudes are represented in arbitrary units.
The average rhythmic burst rate (Fig. 5) increased during stages 39-43. Burst rate increased from 9.8 bursts per minute at stage 39 to 35 bursts per minute at stage 43 (linear regression slope, 5.68 bursts per minute per stage; p < 0.01; r2 = 0.3; n = 18). In many cases, the bursting was quite regular and contrasted markedly with irregular bursting patterns described in detail for a substantial number of primary afferents in animals older than E18 (Jones and Jones, 2000
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Figure 5. Rhythmic discharge rates (bursts per minute) are plotted as a function of developmental stage (top). Rate of rhythmic bursting increased on average with increasing developmental stage. The range of burst rates was 1-54 bursts per minute. The regression slope for data shown was 5.68 bursts per minute per stage (p < 0.01; r2 = 0.3). At stages 40-43, both rhythmic and irregular bursting patterns were present. Rates indicated here are for rhythmic bursting only. Bursting patterns are irregular when present at stages beyond 43. The relative number of neurons exhibiting rhythmic bursting decreased with increasing stage (bottom). Circles represent both rhythmic and nonrhythmic bursting patterns, whereas triangles represent proportions of rhythmically bursting neurons only. The fraction of rhythmically bursting cells decreases at later stages. * indicates that in the case of stage 39, most cells were silent. The two cells that were active had very low spike rates, and only one had a sufficient number of spikes to evaluate for bursting patterns. This cell exhibited rhythmic bursting. The other cell generated only eight spikes in 90 sec, thus precluding a determination of bursting status.
The relative percentage of neurons exhibiting spontaneous bursting changed as a function of developmental stage. At ages younger than stage 42, 10 of the 18 active cells demonstrated rhythmic bursting. The relative number of rhythmically bursting cells decreased with increasing stage as illustrated in Figure 5 (bottom). There was a mixture of neurons displaying regular and irregular bursting patterns at stages 40-43. The proportion of silent cells also decreased progressively from 67% at stage 39 to zero at stages 44 and 45. Figure 5 illustrates the relative number of irregularly and regularly bursting neurons at each stage. At stages 44-45, bursting is evident in ~33% of cells, and the bursting patterns are irregular (Jones and Jones, 2000
Cellular labeling was observed in four embryos. Figure 6 shows the primary afferent terminals for neuron 87tm01 (stage 40-41) of Figure 3. This neuron was located 50% of the distance from apex to base, it terminated toward the abneural edge of the papilla (60% of distance from the neural to abneural edge), it did not respond to sound at levels up to 103 dB SPL, and it generated the rhythmic discharge pattern shown in Figure 3. A second bursting neuron recorded from another embryo at stage 40-41 innervated a similar central region of the papilla but had terminals near the neural edge transversely (10% of distance from neural to abneural edge). The label in the other two cases filled ganglion cell bodies but could not be resolved at the final terminals on hair cells.
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Figure 6. Labeled neuron for animal 87tm01. Spontaneous discharge pattern for this animal is shown in Figure 2. Top, The neural edge; bottom, the abneural edge; right, the base; and left, the apex. Scale bar, 50 µm.
DISCUSSION
The majority of embryonic ganglion cells at stages 39-43 (E13-E17) display regular, rhythmic spontaneous bursting patterns. These data provide the first definitive evidence of primordial regular bursting patterns for primary afferents of the cochlear ganglion. The rate of bursting increases with age and becomes less regular as development proceeds. At stages beyond 43, only 33% of statoacoustic ganglion cells burst, and the bursting pattern is irregular (Jones and Jones, 2000
Five of the rhythmically bursting cells of the present study responded to sound, thus identifying them as auditory fibers innervating the papilla. Two other rhythmically bursting cells did not respond to sound, but BDA labeling identified their cell bodies and showed them to innervate the papilla. These data clearly demonstrate that auditory primary afferents can and do display rhythmic bursting patterns at stages 39-43. In our view, most of the rhythmically bursting cells are likely cochlear afferents, including unlabeled cells that did not respond to sound. This is based primarily on the fact that auditory primary afferents are by far the most numerous cells in the statoacoustic ganglion (~8000) (Fischer et al., 1994
The present study shows that at developmental stages 39-43 in the chicken embryo, statoacoustic ganglion cells also display slow overall spontaneous firing rates that are substantially lower than those published for stages 44-45 (Jones and Jones, 2000
As noted above, in the youngest embryos, many cells appeared to exhibit no spontaneous activity, and yet long spike trains were readily produced with nanoampere levels of current injection in each case. Romand (1984)
Structural immaturity may contribute to the high thresholds and immature activity patterns of stages 38-40. A considerable amount of information has been published regarding this early period of cochlear ontogeny in the chicken (Cohen and Fermin, 1978
The origin of the cochlear bursting pattern is unknown. The rhythmic process does not simply reflect slower discharge rates. If that were the case, then presumably CVs of bursting neurons would not be altered. Mature spontaneous discharge patterns exhibit a quasi-Poisson spike interval distribution reflecting a primary stochastic or random excitatory process (Kiang, 1965
Primordial rhythmic activity has been shown to be of critical import to the development of normal binocular vision (Shatz, 1996
FOOTNOTES Received July 28, 2000; revised July 17, 2001; accepted July 27, 2001.
This research was supported by National Institutes of Health and National Institute on Deafness and Other Communication Disorders Grant R01 DC02753.
Correspondence should be addressed to Dr. Timothy A. Jones, Department of Surgery/Otolaryngology, University of Missouri School of Medicine, Room 202 Allton Building, DC375.00, 301 Business Loop 70W, Columbia, MO 65212. E-mail: JonesT{at}health.missouri.edu.
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Copyright © 2001 Society for Neuroscience 0270-6474/01/21208129-07$05.00/0
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