University Laboratory of Physiology, Oxford University, Oxford OX1 3PT, United Kingdom
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McAlpine, David, Russell L. Martin, Jennifer E. Mossop, and David R. Moore. Response properties of neurons in the inferior colliculus of the monaurally deafened ferret to acoustic stimulation of the intact ear. J. Neurophysiol. 78: 767-779, 1997. Response properties of neurons in the central nucleus of the inferior colliculus (ICC) were investigated after unilateral cochlear removal at various ages during infancy. Nineteen ferrets had the right cochlea surgically ablated, either in adulthood or on postnatal day (P) 5, 25, or 40, 3-18 mo before recording. Adult ablations were made on the same day as ("acute," n = 3), or 2-3 mo before ("chronic," n = 3), recording. Two ferrets were left binaurally intact. Single-unit (n = 702) and multiunit (n = 1,819) recordings were made in the ICC of barbiturate-anesthetized ferrets ipsilateral (all ages) or contralateral (P5 and acute adult only) to the intact ear. In binaurally intact animals, tonal stimulation of the contralateral ear evoked excitatory activity at the majority (94%) of recording loci, whereas stimulation of the ipsilateral ear evoked activity at only 33% of recording loci. In acutely ablated animals, the majority of contralateral (90%) and ipsilateral (70%) loci were excited by tonal stimulation of the intact ear. In chronically ablated animals, 80-90% of loci were excited by ipsilateral stimulation. Single-unit thresholds were generally higher for low-best frequency (BF) than for high-BF units, and higher in the ipsilateral than in the contralateral ICC. Analysis of covariance showed highly significant differences between all of the ipsilateral and contralateral groups, but no effects of age at ablation or survival time following ablation, other than that the group ablated at P25 had higher mean ipsilateral thresholds than the groups ablated at P5 or, acutely, in adulthood. Cochlear ablation at P5, 25, or 40 resulted in a significant increase in dynamic ranges of ipsilateral ICC unit rate-intensity functions relative to acutely ablated animals. Dynamic ranges of units in the contralateral ICC of P5-ablated ferrets were also significantly increased compared with those of acutely ablated animals. Cochlear ablation at P5, 25, or 40 resulted in a significant increase in single-unit spontaneous discharge rates in the ICC ipsilateral but not contralateral (P5 only) to the intact ear. These data show that unilateral cochlear removal in adult ferrets leads to a rapid and dramatic increase in the proportion of neurons in the ICC ipsilateral to the intact ear that is excited by acoustic stimulation of that ear. In addition, the data confirm that, in ferrets, cochlear removal in infancy leads to a further increase in responsiveness of individual neurons in the ipsilateral ICC. Finally, the data show that responses in the ICC contralateral to the intact ear are largely but not completely unchanged by unilateral cochlear removal.
Maturation of central auditory system neurons and their projections is known to be influenced by manipulations of sensory input. Levi-Montalcini (1949) Twenty-one pigmented ferrets (Mustela putorius furo) were used in this study. All but three of the animals were born in the Departmental animal house after timed matings. Each experimental animal (n = 19) had the right cochlea surgically destroyed, either in the postnatal period (P5, 25, or 40) or in adulthood. Animals that had the cochlear surgery as neonates were raised to maturity before recordings were made. Animals that had the cochlear surgery as adults were operated either on the day recordings were begun ("acute"), or >3 mo before recordings were made ("chronic"). Data were obtained from nine different groups (normal contra, normal ipsi, acute contra, acute ipsi, chronic ipsi, P5 ipsi, P25 ipsi, P40 ipsi, and P5 contra) defined by whether the animal was binaurally intact, the age at which the cochlea was removed, and the ICC (relative to the intact ear) in which recordings were made. Data from some normal and acute adults and P5-ablated animals were analyzed in two groups.
Cochlear removal
Infant ferrets were anesthetized with Saffan (Glaxovet; 0.5-2.0 ml/kg im) and animals in the adult groups were anesthetized with pentobarbital sodium (Sagatal; 40 mg/kg ip). The right cochlea was surgically destroyed as described previously (Moore 1990a Stimulus presentation and measurement
Two methods were used to generate the stimuli used in this study. In earlier experiments, tones (100 Hz-30 kHz) were generated with the use of an analog system (see Moore et al. 1983 Recording procedures
Adult ferrets were prepared for IC recordings by the general methods described by Moore et al. (1983) Histology
On completion of an experiment, animals were perfused through the heart with 0.1 M phosphate-buffered saline and a solution of either mixed aldehydes in phosphate-buffered saline or 10% formal-saline. The brain and the right temporal bone (where lesioned) were removed and trimmed. For the formalin-fixed brains, 40-µm frozen frontal sections were cut through the brain stem, mounted, and Nissl stained. Camera lucida drawings were made of sections containing electrode tracks or lesions. All recording locations reported in this paper were in the ICC. Within the ICC, dorsoventral penetrations were widely spaced across the nucleus and no systematic attempt was made to sample from, or to exclude, any particularpart of the ICC. After decalcification, wax-embedded sections(10 µm) of the right temporal bone were made in a midmodiolar plane to determine the success of the cochlear lesion (see Moore and Kowalchuk 1988 The data presented in this paper were derived from 1,819 recording loci in ICC. Single-unit recordings were made at 702 of these sites, and the remainder included a mixture of evoked activity (both clear but undiscriminated spike activity and "swish" IC responses ipsilateral and contralateral to the intact ear following acute and chronic unilateral cochlear removal in the adult period
RECORDING LOCI.
The proportion of recording loci at which acoustic stimulation produced excitatory activity is shown in Fig. 1. Recording loci were characterized as excitatory if tonal stimulation elicited a qualitative increase in spike activity, even if this was limited to the period just after the stimulus onset. Data for the normal contra and normal ipsi groups (Fig. 1A) were obtained from 251 loci. Of these, the vast majority (94%, 235 of 251) was excited by stimulation of the contralateral ear, but only a third (33%, 83 of 251) were excited by stimulation of the ipsilateral ear, and this difference was significant (
DISCHARGE PATTERNS.
Discharge patterns of single units that were excited during a BF-tone stimulus were characterized as either "onset" or "sustained" according to the form of their peristimulus time histogram (Fig. 2). Examples of onset units are shown in Fig. 2, A and E. The sustained category included units that displayed both more phasic (Fig. 2, B and C) and more tonic (Fig. 2D) discharge patterns, but with at least some discharges above the spontaneous level occurring after the onset epoch. Many spontaneously active onset units were inhibited after the stimulus onset, usually for the duration of the stimulus (Fig. 2E). A small number of offset units that were excited only at the termination of the stimulus were sampled, but were not included in any further analysis.
SINGLE-UNIT THRESHOLDS.
Figure 4A shows single-unit thresholds as a function of BF for the normal (
R/I FUNCTIONS.
The relation between unit discharge rate and stimulus intensity was compared between the acute contra and acute ipsi groups. Units were divided into four categories depending on the shape of their R/I functions: 1) monotonic saturating
DYNAMIC RANGES.
The R/I functions described above were used to calculate the unit dynamic ranges, defined as the stimulus intensity range, in dB, over which the evoked discharge rate increased from 10 to 90% of maximum. All saturating monotonic, saturating nonmonotonic, and other units were included in this analysis. Units with nonsaturating R/I functions were included in the analysis only if the dynamic range over the range of intensities investigated was
SPONTANEOUS DISCHARGE RATES.
Single-unit spontaneous discharge rates were calculated as described in the METHODS section. Only units for which R/I functions were obtained were included in this analysis. The distribution of spontaneous rates in the acute contra, and acute and chronic ipsi groups is shown in Fig. 8A. The majority of units in each group (acute contra, 71.7%; acute ipsi, 86.9%; chronic ipsi, 65.5%) had spontaneous discharge rates <5 spikes/s and, for the acute groups, most of these were <1 spike/s. Very few units in any group had spontaneous discharge rates >20 spikes/s. No significant differences were found in the distribution of spontaneous discharge rates between the acute groups (
Effect of neonatal cochlear removal on IC responses ipsilateral to the intact ear
In this section we compare ipsilaterally evoked single-unit responses from the P5, 25, and 40 ipsi groups with those of the acute ipsi group. Recording loci data are also compared with those of the normal ipsi group, and recording loci, thresholds, and discharge patterns are compared with those of the chronic ipsi group.
RECORDING LOCI.
The proportion of loci at which acoustic stimulation of the intact ear produced excitatory activity in the ipsilateral IC is shown in Fig. 1B. All of the neonatally ablated ipsi groups showed a considerably greater proportion of loci with excitatory activity than was found in the normal ipsi group (Fig. 1A; see above). In addition, a significantly greater proportion of loci in the P5 ipsi group responded with excitation compared with the acute ipsi group ( DISCHARGE PATTERNS.
Figure 3B shows the proportion of onset and sustained units (see Fig. 2) in each of the acute, chronic, P5, P25, and P40 ipsi groups. Although the proportion of units with sustained discharge patterns was higher in the P5 ipsi group than in the other ipsi groups, this difference was not significant.
SINGLE-UNIT THRESHOLDS.
Single-unit thresholds at BF for each of the ipsi groups are shown in Fig. 4B. As in the adult groups (Fig. 4A), there was a wide distribution of BFs, and thresholds for all groups followed the shape of the ferret audiogram. Comparisons of thresholds between groups, with the use of the analysis of covariance described above (Table 1), showed no significant difference between any of the groups, except the P25 ipsi group, which (at P < 0.05) had higher thresholds than the acute ipsi and P5 ipsi groups. Note that all ipsi group thresholds were higher than those for all contra groups. Thus neonatal cochlear removal did not lead to an increase in sensitivity of IC neurons relative to cochlear removal in adulthood.
R/I FUNCTIONS AFTER NEONATAL COCHLEAR REMOVAL.
Single-unit R/I functions were classified into one of the four categories (monotonic saturating, nonsaturating, nonmonotonic, and others) defined above. The distribution of R/I functions was similar for the acute and neonatal ipsi groups (Fig. 5B), and no significant difference was found ( DYNAMIC RANGES AFTER NEONATAL COCHLEAR REMOVAL.
R/I functions were used to calculate the dynamic ranges of single units in each of the acute and neonatal ipsi groups (Fig. 7B). The R/I profile criteria used for inclusion in this analysis were as outlined in the first section of RESULTS. Overall, significant differences were observed ( SPONTANEOUS DISCHARGE RATES AFTER NEONATAL COCHLEAR REMOVAL.
The spontaneous discharge rates of single units for which R/I functions were obtained in the acute and neonatal ipsi groups were calculated and divided into the five categories described in the first section of RESULTS (Fig. 8B). Significant differences were found between the groups ( Effect of P5 cochlear removal on IC responses contralateral to the intact ear
In general, IC responses contralateral to the intact ear were little changed by cochlear removal on P5. The proportion of loci at which excitatory activity was recorded in the P5 contra group was almost identical to that of the acute contra group (Fig. 1B). The proportion of units in the P5 contra group that responded to BF tones with a sustained discharge was also similar to that found in the acute contra group (Fig. 3C). Unit thresholds (Fig. 4C) did not differ significantly (Table 1) between the P5 contra group and either the acute contra or normal contra groups. R/I function shapes of the acute and P5 contra groups are shown in Fig. 5C. Despite the lower proportion of monotonic saturating to nonmonotonic saturating units in the P5 contra group, the overall difference between these groups was not significant ( Cochlear removal in adults
A main finding of this study was that cochlear removal in adulthood produced a rapid and dramatic increase in the responsiveness of the IC on the side of the intact ear to stimulation of that ear. The number of loci at which excitatory activity could be recorded increased from one-third in intact animals to over two-thirds in animals that had one cochlea removed on the day recording commenced. In addition, the yield of ipsilaterally excited single units increased dramatically after acute cochlear removal. These results provide evidence for rapid changes in the function of mature central auditory system neurons that parallels the evoked potential results of Popelar et al. (1994) Cochlear removal in infancy
The second main finding of this study was that cochlear removal in the neonatal period further increased IC responsiveness to ipsilateral stimulation, and that this increase was dependent on the age at which the surgery was performed. After unilateral removal on P5, the proportion of excited recording loci was higher and unit dynamic ranges were wider than in acutely lesioned adults. These findings are consistent with those of Kitzes and Semple (1985) Changes in the contralateral IC after P5 cochlear removal
Most of the alterations in response properties of units in the IC ipsilateral to the intact ear were not found in the IC contralateral to that ear. Previous studies of the IC have examined the effects of unilateral deafening in infancy on the physiology of only the nucleus ipsilateral to the intact ear (Kitzes 1984 Mechanisms of change after cochlear removal
The different results obtained after cochlear removal in infancy and adulthood, and after survival for varying periods, suggest multiple mechanisms of change. There are at least three general mechanisms by which changes in physiological responses in the IC might be produced; 1) unmasking of existing synapses, 2) formation of new synapses without axogenesis, and 3) axonal sprouting.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
first showed that removal of the chick otocyst during the embryonic period resulted in a progressive shrinkage and loss of neurons throughout the deafferented nucleus magnocellularis. Subsequent investigations in a variety of species have confirmed and extended these findings (chick: Born and Rubel 1985
; Parks 1979
; mouse: Trune 1982
; gerbil: Hashasaki and Rubel 1989
; ferret: Moore 1990a
). In addition to changing target neuron number and size, cochlear removal produces an immediate cessation in the production of action potentials in the nucleus magnocellularis (Tucci et al. 1987
) and in its mammalian homologue, the anteroventral cochlear nucleus (CN) (Koerber et al. 1966
). Studies in which tetrodotoxin was applied to the round window of the cochlea (Born and Rubel 1988
; Pasic and Rubel 1989
) suggest that the cessation of activity triggers the cascade of cellular events in the nucleus magnocellularis and anteroventral CN that rapidly follow cochlear removal. These events include a decrease of cytoplasmic protein synthesis (Born and Rubel 1988
; Sie and Rubel 1992
; Steward and Rubel 1985
), a disaggregation of ribosomes (Rubel et al. 1991
), a biphasic change in ribosomal RNA (Garden et al. 1994
), and an increase, followed by a decrease, of oxidative metabolic enzymes (Durham et al. 1993
) and mitochondrial volume (Hyde and Durham 1994
). In mature animals, cochlear removal does not result in neuron loss in the CN, although a metabolic downregulation of neurons appears to persist as a consequence of cochlear removal at any age (Moore 1990a
; Rubel et al. 1990
; Tierney et al. 1997
).
; Sanes et al. 1992
) and ferrets (Moore 1990b
, 1992
). In addition, increases have been found in the number of CN neurons retrogradely labeled by injections of horseradish peroxidase in the ipsilateral inferior colliculus (IC), following removal of the contralateral cochlea in gerbils (Nordeen et al. 1983
) and ferrets (Moore 1994
; Moore and Kowalchuk 1988
). An exuberance of projections on the side of the intact ear has also been shown in the gerbil by anterograde techniques. Moore and Kitzes (1985)
found an increased density of axon terminals from CN neurons in the ipsilateral IC, and aberrant termination zones around and within each of the principal superior olivary complex (SOC) nuclei on both sides of the brain have recently been reported (Kitzes et al. 1995
; Russell and Moore 1995
). However, some brain stem projections may not be changed by cochlear removal. Retrogradely labeled neuron numbers in the gerbil medial superior olive (Nordeen et al. 1983
) and the ferret lateral superior olive (Moore et al. 1995b
) following horseradish peroxidase injections in the IC on the side of the intact ear appear to remain stable.
and Kitzes (1984)
observed that the proportion of ipsilaterally excited IC recording loci was substantially increased, from ~30% in adult gerbils raised with both cochleas intact to 90% in adult gerbils that had one cochlea removed on postnatal day (P) 2. Subsequently, Kitzes and Semple (1985)
showed that ipsilaterally excited single units in the IC had lower thresholds, wider dynamic ranges, higher peak discharge rates, and more sustained discharge patterns in P2-operated than in binaurally intact control animals. These ipsilaterally evoked responses were qualitatively and quantitatively similar to the more robust responses normally evoked by stimulation of the ear contralateral to the recording site (e.g., Semple and Kitzes 1985
).
). The proportion of AI responsive loci on the side of the intact ear was significantly increased (from 65 to 95% of loci) and the mean single-unit threshold was significantly reduced compared with values in animals raised with both cochleas intact. Response properties of AI units on the same side as the removal to stimulation of the intact ear (contralateral stimulation) were unaffected by the lesion. A small number of animals receiving cochlear removal as adults and surviving for 24 h (Reale et al. 1987
), or for many months (Nordeen et al. 1983
), did not appear to exhibit such marked changes.
lesioned the left CN of adult gerbils and recorded response properties in the right IC to stimulation of the right ear. The ventral CN provides a large number of direct and indirect projections to the IC. Response properties of IC units in either acutely or chronically operated animals were unaffected by the lesion, suggesting that physiological changes following cochlear removal are age dependent and not simply related to CN degeneration.
reported that the reduction in the number of CN neurons was restricted to removals performed early in the postnatal period (<P24). The reduction in CN neuron soma area, on the other hand, was about equal at all ages tested (P5-180). The early cessation of the sensitive period for CN neuron loss also contrasted with the longer period of sensitivity and more gradual reorganization of the CN-to-IC projection following unilateral cochlear removal. Removal at P24 produced a gradual increase in the number of CN neurons retrogradely labeled by tracer injections in the ipsilateral IC on the intact side of the brain. This increase was significant by 30 days after the removal (Moore and Kowalchuk 1988
), but continued beyond 3 mo after the removal (Moore 1994
). Later removals (at P90) were also found to produce an enhanced CN-to-IC projection if very long (2.5 yr) survival times were allowed (Moore 1994
). No single-unit studies of the effects of cochlear removal at different ages have been performed. Such studies are of interest because they should show some of the functional consequences of the various anatomic changes cited above and thereby provide further insight into the mechanisms underlying the response of the auditory system to deafness. Thus one aim of this study was to investigate the effects of unilateral cochlear removal, performed at a variety of postnatal ages, on the response properties of units in the ferret central nucleus of IC (ICC).
; Irvine and Rajan 1995
; Kaas 1991
) showing that adult sensory systems are affected by peripheral perturbations and sensory experience in adulthood. The second aim of this study was to examine the effects of unilateral cochlear removal in adulthood on the responses of units in the ICC and to compare cochlear removal in infancy with cochlear removal in adulthood.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
; Moore and Kowalachuk 1988). Briefly, the cochlea was exposed through the ventral bulla and macerated with jewelers' forceps and/or aspirated with a Pasteur pipette. All chronically operated animals (including all the infants) recovered from the surgery and spent a further 3-18 mo in the animal house before ICC recording.
). Later experiments employed tonal stimuli generated, shaped, and gated by a PC-based programmable digital stimulus system. The Auditory Laboratory Digital Stimulus System (ALDISS) consisted of a fast digital-to-analogue conversion card housed in a PC and a number of controlling routines written in Turbo Pascal and native assembler languages. The digital-to-analogue conversion was carried out by the QDA2 board supplied by Tucker-Davis Technologies (TDT, Gainesville, FL). The QDA2 provided an output bus to control a TDT attenuator (PA3) with programmable attenuation (resolution 0.1 dB). Antialiasing was achieved with the TDT FLT2 filter (corner frequency 30 kHz).
. After induction of anesthesia with Sagatal (40 mg/kg ip), the left brachial vein was exposed and cannulated. Further anesthetic (Sagatal 1:5 in saline iv) was administered as indicated by reflex withdrawal to a pinch of the forepaw.
) were advanced through the nucleus, in a dorsal-to-ventral trajectory, by a microdrive under remote control. Multiple penetrations were made in each animal.
).
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
audible, sustained increases in activity without visually obvious spikes) and loci at which no excitatory drive was recorded. The undiscriminated spike activity and swish were used to examine the proportion of recording loci at which excitatory drive could be evoked. For all other analyses, only discriminated, single-unit responses were considered.
).
2 = 194.08, df = 1, P < 0.001). After cochlear removal, the proportion of recording loci at which ipsilateral stimulation elicited an excitatory response increased dramatically and significantly in both the acute ipsi (70%, 178 of 254;
2 = 69.25, df = 1, P < 0.001) and chronic ipsi (92%, 123 of 134;
2 = 121.10, df = 1, P < 0.001) groups. In addition, the proportion of excitatory loci was significantly greater (
2 = 23.77, df = 1, P < 0.001) in the chronic ipsi group than in the acute ipsi group, suggesting that the length of time between cochlear removal and recording had an effect on IC responsiveness. By contrast, acute cochlear removal had little or no effect on the proportion of contralaterally evoked excitatory loci (acute contra: 90%, 131 of 146). The single-unit data confirmed these multiunit observations. Thus acute, unilateral cochlear removal produced a rapid (within hours) enhancement of driven activity in the IC ispilateral to the intact ear.
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FIG. 1.
A: proportion of excited inferior colliculus (IC) recording loci for binaurally intact animals (normal contra and normal ipsi), and for 3 adult-ablated groups (acute contra, acute ipsi, and chronic ipsi). B: proportion of excited IC recording loci for neonatal contra and ipsi groups. P, postnatal day.
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FIG. 2.
Examples of peristimulus time histograms (20-ms bins) evoked by 20 repetitions of 310-ms tone burst at best frequency (BF) classified as onset (A and E) and sustained (B-D). Black bar beneath each histogram: duration of stimulus.
). However, in the acute contra group, only 67% (74 of 110) of units contralateral to the stimulated ear showed sustained discharge patterns, and this difference was significant (
2 = 9.65, df = 1, P < 0.002). Nevertheless, the proportion of sustained units in the acute contra group was still significantly higher (
2 = 17.52, df = 1, P < 0.001) than that in the acute ipsi group, where only 38% of excited units showed sustained discharge patterns. A similar proportion (28%) of units in the chronic ipsi group showed sustained responses. Because of the poor responsiveness of units in the normal ipsi group, we did not obtain sufficient data (n = 16) from this group to enable quantitative comparison with the other groups. However, those units that were recorded tended to be predominantly onset.
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FIG. 3.
Proportion of onset and sustained IC single units for comparisons of (A) normal contra and ipsi, acute contra and ipsi, and chronic ipsi groups; (B) acute and chronic ipsi and 3 neonatal ipsi groups; and (C) adult contra and P5 contra groups. See text for details of onset/sustained criteria.
) and acute (
) contra groups, and the chronic (
) and acute (×) ipsi groups. For all groups, there was a clear relationship between BF and threshold. Low-BF units had the highest thresholds, and, as BF increased, thresholds initially decreased (up to ~10 kHz) and then increased. These threshold-frequency relations followed the general shape of the behavioral audiogram for the ferret (see Kelly et al. 1986
) and are consistent with a previous report from this laboratory of ferret ICC thresholds (Moore et al. 1983
). To compare thresholds between the groups, it is therefore necessary to control for both threshold and sampling differences with respect to BF. To perform this control, an analysis of covariance (S-Plus, v0.3.3, StatSci, Seattle, WA) was used. Initially, a cubic model was found to fit the normal contra data. This was then tested against all the other groups (including the neonatally ablated animals), and was found to fit them if a logarithmic transformation was performed on the threshold data. Finally, the significance of the difference between the threshold intercept of this model, applied to each group, was tested. The results (Table 1) showed that the mean threshold of neurons did not differ significantly in either the two contra groups or the two ipsi groups, whereas both contra groups had significantly lower thresholds than both ipsi groups.
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FIG. 4.
Single-unit thresholds plotted as function of BF for (A) normal and acute contra, and acute and chronic ipsi groups; (B) acute, P5, 25, and 40 ipsi groups, and (C) acute and P5 contra groups. See keys for details.
View this table:
TABLE 1.
Results of the analysis of covariance comparing mean thresholds in each group
units whose discharge rate at intensities greater than that required to evoke the maximum rate did not fall below 75% of the maximum; 2) monotonic nonsaturating
units whose discharge rate at the highest intensity examined was >10% greater than for the next highest intensity; 3) nonmonotonic
units that showed a reduction in discharge rate of
25% of the maximum at intensities greater than that needed to evoke the maximum; and 4) "others"
units whose R/I functions showed fluctuations in discharge rate >10% of the maximum at intensities below that required to evoke the maximum. Figure 5A shows the proportion of units with R/I functions in each of these categories. In both groups, the most common R/I function shape was monotonic and saturating, with just under half the units (49.1%) in the acute contra group and just over half the units (57%) in the acute ipsi group. No significant differences in the distribution of R/I function shapes were found between these groups (
2 = 6.96, df = 3, not significant).
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FIG. 5.
Proportion of each type of rate-intensity (R/I) function described in text, in each of (A) acute contra and acute ipsi groups, (B) acute ipsi and 3 neonatal ipsi groups, and (C) acute contra and P5 contra groups.
2 = 6.78, df = 1, P < 0.01).
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FIG. 6.
Distribution of single-unit peak discharges for (A) acute contra and acute ipsi groups, (B) acute ipsi and 3 neonatal ipsi groups, and (C) acute contra and P5 contra groups for 20 repetitions of 310-ms tone burst at BF.
30 dB (this placed such R/I functions in the final group of the analysis, which included all dynamic ranges of
30 dB). The dynamic range of units classified as others was calculated over the widest range of intensities for which the R/I function contained no fluctuations in discharge level >10% of the maximum.
2 = 17.12, df = 3, P < 0.001). Specifically, the proportions of units with dynamic ranges between 20 and 30 dB (
2 = 10.86, df = 1, P < 0.001) and >30 dB (
2 = 5.37, df = 1, P < 0.05) were significantly higher in the acute contra group than in the acute ipsi group.
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FIG. 7.
Distribution of single-unit dynamic ranges for (A) acute contra and acute ipsi groups, (B) acute ipsi and 3 neonatal ipsi groups, and (C) acute contra and P5 contra groups. See text for details.
2 = 2.88, df = 2, not significant).
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FIG. 8.
Distribution of single-unit spontaneous discharge rates for (A) acute contra and acute and chronic ipsi groups, (B) acute ipsi and 3 neonatal ipsi groups, and (C) acute contra and P5 contra groups.
2 = 2.88, df = 2, P < 0.05) than in the acute ipsi group, with more units having spontaneous rates >5 spikes/s.
2 = 12.45, df = 1, P < 0.01) but not the chronic ipsi group. The proportion of excited loci gradually declined with advancing age at the time of the removal, and none of the other intergroup differences were significant.
2 = 12.85, df = 9, not significant).
2 = 20.02, df = 9).
2 = 23.94, df = 9, P < 0.005). A greater proportion of units in the acute ipsi group showed dynamic ranges <10 dB compared with all of the neonatal ipsi groups (
2 = 17.45, df = 1, P < 0.001). The proportion of units with dynamic ranges in each band was also related to the age at which cochlear removal was perfomed. Both the P5 ipsi (
2 = 3.94, df = 1, P < 0.05) and P25 ipsi (
2 = 5.46, df = 1, P < 0.05) groups, but not the P40 ipsi group, had a higher proportion of units with dynamic ranges >30 dB compared with the acute ipsi group.
2 = 67.36, df = 12, P < 0.0001). Whereas nearly two-thirds of units in the acute ipsi group had spontaneous rates <1 spike/s, only about one-fifth of units in each of the neonatal ipsi groups had such low rates. In contrast, spontaneous rates in the top two categories (10-20 and >20 spikes/s) accounted for just 3% of units in the acute ipsi group, but >30% of units in the P5, 25, and 40 ipsi groups. Statistically, a greater proportion of units in the neonatal ipsi groups had spontaneous rates in the three highest ranges (5-10 spikes/s,
2 = 12.17, df = 1, P < 0.001; 10-20 spikes/s,
2 = 13.62, df = 1, P < 0.001; >20 spikes/s,
2 = 13.56, df = 1, P < 0.001) compared with the acute ipsi group. In addition, a higher proportion of units had spontaneous rates <1 spike/s in the acute ipsi group than in the neonatal ipsi groups (
2 = 22.42, df = 1, P < 0.001). No significant differences were observed in the distribution of spontaneous discharge rates between the P5, 25, and 40 ipsi groups. Finally, all the neonatal ipsi groups had significantly higher spontaneous discharge rates compared with the chronic ipsi group (
2 = 4.86, df = 3, P < 0.01), with more units showing spontaneous rates >5 spikes/s.
2 = 2.32, df = 3, not significant). In addition, the peak discharge rates of units in the two contra groups (Fig. 6C) were not significantly different from each other (
2 = 3.72, df = 6, not significant). The dynamic ranges of units in the P5 contra group were significantly broader than those in the acute contra group (Fig. 7C), most notably showing a higher proportion of units with ranges >30 dB (
2 = 26.60, df = 1,P < 0.001). Finally, no significant differences in spontaneous discharge rates were found between the acute and P5 contra groups (Fig. 8C;
2 = 3.15, df = 2, not significant).
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
. In that study, adult guinea pigs treated unilaterally with ototoxic drugs showed, within 1-7 days, a decrease in the threshold and latency, and an increase in the amplitude of evoked potentials recorded from large (0.3-0.5 mm) electrodes, implanted in the IC and AI, in response to high-frequency acoustic stimulation of the ipsilateral, untreated ear. Popelar et al. (1994)
found a progressive increase in ipsilateral excitation during the 7-day study period. We found a significant increase in excitation from the acutely deafened ferrets, tested on the day of cochlear removal, to the chronically deafened ferrets, tested
3 mo after the removal.
, little or no change was found in the amplitude of evoked responses in the contralateral IC and, in our study, no change in the overall distribution of excitation or in the threshold of single units was found. However, a significant decrease in the proportion of sustained units was observed, suggesting a possible increase in the level of long-lasting or late inhibition on this side of the brain.
; Merzenich and Reid 1974
; gerbil IC: Kitzes 1984
; Semple and Kitzes 1985
; cat AI: Reale et al. 1987
) was maintained after unilateral cochlear removal, but at a reduced level.
, who reported that, after cochlear removal in P0-2 gerbils, responses of units in the IC on the side of the intact ear were generally stronger than those in adult gerbils raised with both cochleas intact. In the ferret, unilateral cochlear removal on P25 or 40 produced changes in IC responsiveness broadly similar to those produced by cochlear removal on P5, but to a progressively lesser degree. Thus the proportion of excitatory loci decreased progressively with age at removal, with only the P5 group differing significantly from the acute ipsi group. In the comparison of unit dynamic ranges, the P5 and P25 groups, but not the P40 group, had more units with broader ranges than did the acute group. On the other hand, cochlear removal on P25 or 40 still produced a greater proportion of IC units with higher spontaneous rates, compared with acutely or chronically lesioned adult animals. Thus the results from the later-operated animals were intermediate between those of the P5- and adult-operated groups. However, this tendency did not vary uniformly between the indexes examined, suggesting that there are at least two developmental sensitive periods in addition to the acute effects of cochlear removal in adulthood.
in the gerbil. In that study, unit thresholds, peak discharge rates, and the proportion of sustained responses to ipsilateral stimulation all changed to levels normally found for contralateral stimulation. The smaller changes found after cochlear removal in neonatal ferrets may reflect intrinsic species differences or a relative maturity of the neonatal ferret auditory system compared with that of the gerbil. The second point is that we found differences between the neonatal groups and the chronic ipsi group. The most striking of these was the large increase, relative to either of the adult ipsi groups, in the level of spontaneous activity of units in the IC ipsilateral to the intact ear after cochlear removal in all the neonatal groups. This increase was additional to that found to occur after long survival after cochlear removal in adulthood. Thus, although some effects of cochlear removal were found, to about equal degrees, in all three neonatal groups, those effects still had a developmental dependence.
; Kitzes and Semple 1985
; Moore and Kitzes 1986
). However, Reale et al. (1987)
did examine the effects of unilateral cochlear removal in the cat on unit responses in the contralateral AI. They found that the proportion of excitatory loci was similar (>90%) to that recorded in animals raised with both cochleas intact. Unfortunately, Reale et al. (1987)
did not examine single-unit dynamic ranges. The finding in the present study that dynamic ranges of units in the P5 contra group were wider than those in the adult contra group shows that at least one form of induced change occurred in the IC contralateral to the intact ear. Moreover, it may be noted that the direction of this change, associated with a presumed increase in responsiveness, was the opposite to the presumed decrease found in the contralateral IC after cochlear removal in adulthood.
), there is an immediate (within minutes) expansion in the receptive fields of neurons, normally representing a lesioned digit, to include areas of the body adjacent to that digit. Unfortunately, although we know that the excitatory changes in the acute ipsi group reported here occurred within a matter of hours, we do not know whether the changes were immediate. Similarly, Popelar et al. (1994)
found changes in high-frequency evoked IC response amplitudes within 24 h of a cochlear lesion, but did not report shorter-term results. We have recently completed a study of single-unit responses in the ferret AI after cochlear removal (Moore et al. 1995a
, 1997). Units having a narrow range of BFs (8-12 kHz), recorded from one ferret during 50 h after cochlear removal, showed a gradual reduction in threshold (at BF) rather than an abrupt decrease, as unmasking would seem to predict. Although preliminary, and derived from a different level of the auditory system, this result suggests that even the most rapidchanges reported here may not be due to an immediate release from inhibition. On the other hand, a longer-term change in synaptic gain (e.g., through an increase in receptor expression) would be consistent with both the AI and IC data.
) produces profound neuron loss in the CN on the operated side, and increases the extent of the projection from the CN on the side opposite the cochlear removal, both to the SOC bilaterally and to the IC on the intact side. Several response changes (excitatory loci, unit thresholds, and dynamic ranges) found in the present study were qualitatively or quantitatively more marked after cochlear removal during this early period. The freeing up of postsynaptic sites in the IC after the removal of the contralateral cochlea, and the death of a large number of CN neurons, may induce the invasion of new, ipsilaterally derived axons on to the vacant sites, thus increasing the influence of ipsilateral excitation in the IC. Later cochlear removal, or ear plugging, still produces a gradual increase in the projection from the CN to the IC on the normally hearing side, but there is no neuron loss in the CN and no clear change in the projection from the CN to either SOC. The changes in ipsilaterally evoked responses after P25 and P40 removals were somewhat smaller than at P5 and are therefore temporally consistent with the more minor changes in connections in the auditory brain stem that have been observed after removals at these ages (Moore 1994
).
), might be to reduce the rate at which the discharge level increases as stimulus level is increased. Thus dynamic ranges could be extended without an increase in peak discharge level. A combination of new, low-threshold excitatory and high-threshold inhibitory inputs might also account for the general increase in excitability, evidenced by the increase in excited recording loci and spontaneous discharge rates in the neonatally ablated groups compared with both binaurally intact and adult-ablated controls.
; Miller et al. 1997; Popelar et al. 1994
). In particular, the level of
-aminobutyric acid decreases within a period of days after deafening. Although it is not yet clear how quickly this occurs, a decrease in local inhibition may explain at least some of the longer-term increase in excitation reported here.
). Thus unilateral cochlear removal in the neonatal period, resulting in degeneration of the CN on the operated side, would produce only a minor, excitatory1 deafferentation of the IC contralateral to the intact ear, in contrast to the much larger deafferentation of the ipsilateral IC discussed above. This could create synaptic space for de novo projections from the CN on the intact side, and may contribute to the observed increase in the contralaterally evoked dynamic ranges of single IC neurons. Surprisingly, a retrograde tracing study (Nordeen et al. 1983
) actually reported a decrease in the size of the CN-to-IC projection on the side of a neonatal cochlear removal, but further anatomic studies of that pathway (Moore 1994
; Moore and Kitzes 1985
) have not found any changes. An alternative possibility is that changes may have occurred in the projections to the contralateral IC that are routed through the SOC or the dorsal nucleus of the lateral lemniscus.
). The limits to increased responsiveness imposed by the availability of additional, unresponsive IC neurons, and by the mechanical and electrical properties of the auditory periphery, would presumably prevent the expression of such widespread changes as those found in the normally less responsive IC.
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ACKNOWLEDGEMENTS |
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We thank D. Fleming and staff for animal care, K. Laman for histological assistance, M. Cortina-Borja for statistical help, A. King and J. Schnupp for critical comments on earlier drafts of the paper, and two anonymous reviewers for helpful criticisms and comments.
This work was supported by a Wellcome Prize Studentship to D. McAlpine, a C. J. Martin Traveling Fellowship of the Australian National Health and Medical Research Council to R. L. Martin, a Canadian Natural Sciences and Engineering Research Council Studentship and an Oxford McDonnell-Pew Cognitive Neuroscience Studentship to J. E. Mossop, and a Medical Research Council Programme Grant to D. R. Moore.
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FOOTNOTES |
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Present address of R. L. Martin: Air Operations Division, Maritime Research Laboratory, Fisherman's Bend, Victoria 3207, Australia.
1
There is also likely to be a more marked, inhibitory deafferentation of the IC on the side of the cochlear removal, produced by neuron loss in the lateral superior olive on that side (Moore 1992; Moore et al. 1995b
).
Present address and address for reprint requests: D. McAlpine, MRC Institute of Hearing Research, University Park, University of Nottingham, Nottingham NG7 2RD, UK.
Received 24 January 1997; accepted in final form 11 April 1997.
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REFERENCES |
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