Absence of plasticity of the frequency map in dorsal cochlear nucleus of adult cats after unilateral partial cochlear lesionsкод для вставкиСкачать
THE JOURNAL OF COMPARATIVE NEUROLOGY 399:35–46 (1998) Absence of Plasticity of the Frequency Map in Dorsal Cochlear Nucleus of Adult Cats After Unilateral Partial Cochlear Lesions R. RAJAN1* AND D.R.F. IRVINE2 of Physiology, Monash University, Clayton, Victoria 3169, Australia 2Department of Psychology, Monash University, Clayton, Victoria 3168, Australia 1Department ABSTRACT In adult animals, lesions to parts of the auditory receptor organ, the cochlea, can produce plasticity of the topographic (cochleotopic) frequency map in primary auditory cortex and a restricted or patchy plasticity in the auditory midbrain. This effect is similar to the plasticity of topographic maps of the sensory surface seen in visual and somatosensory cortices after restricted damage to the appropriate receptor surface in these sensory systems. There is dispute about the extent to which subcortical effects contribute to cortical plasticity. Here, we have examined whether topographic map plasticity similar to that seen in the auditory cortex and the midbrain is observed in the adult auditory brainstem. When partial cochlear lesions were produced in the same manner as those that were produced in the cortex and midbrain studies, we found no plasticity of the frequency map in the dorsal cochlear nucleus (DCN). Small regions of the DCN that were deprived of their normal, most sensitive frequency (characteristic frequency; CF) input by the cochlear lesion appeared to have acquired new CFs at frequencies at or near the edge of the cochlear lesion. However, examination of thresholds at the new CFs established that the changes simply reflected the residue of prelesion input to those sites: The patterns of CF thresholds were very well predicted by simple calculations of the patterns that were expected from such residual input. The results of this study suggest that the DCN does not exhibit the type of plasticity that has been found in the auditory cortex and midbrain; therefore, it does not account for the changes in responsiveness observed in the higher level structures under similar experimental conditions. J. Comp. Neurol. 399:35–46, 1998. r 1998 Wiley-Liss, Inc. Indexing terms: tonotopic maps; subcortical plasticity; cochlea; cortical plasticity; adults When the neural outflow from restricted parts of sensory epithelia in adult animals is eliminated by damage either to neurons or to receptors, neurons in appropriate regions of the topographic cortical representations (maps) of the receptor surface dynamically acquire sensitivity to receptor surface regions adjacent to the damage. Such plasticity, resulting in an expanded cortical representation of the adjacent receptor surface regions, occurs in visual (Kaas et al., 1990; Heinen and Skavenski, 1991; Chino et al., 1992; Gilbert and Weisel, 1992; Darian-Smith and Gilbert, 1995; Schmidt et al., 1996), somatosensory (see, e.g., Merzenich et al., 1983, 1984; Rasmusson, 1982), and auditory (Robertson and Irvine, 1989; Rajan et al., 1993; Schwaber et al., 1993) systems. In the latter, restricted lesions of the tonotopically organized cochlea can produce plasticity of the cochleotopic frequency map in primary auditory cortex (AI). AI neurons that are deprived of their normal, most r 1998 WILEY-LISS, INC. sensitive frequency (characteristic frequency; CF) input acquire sensitivity to frequencies represented at cochlear sites adjacent to the lesion (Robertson and Irvine, 1989; Rajan et al., 1993; Schwaber et al., 1993). Critically, consideration of thresholds at the new CFs in the reorganized map established that the effects reflected plastic changes rather than simply being the residue of prelesion input (Rajan et al., 1993). Furthermore, the fact that new CFs following reorganization of the cortical map after a Grant sponsor: National Health and Medical Research Council of Australia; Grant number: 920483. *Correspondence to: Dr. R. Rajan, Department of Psychology, Monash University, Clayton, Victoria 3168, Australia. E-mail: email@example.com Received 22 January 1998; Revised 7 May 1998; Accepted 11 May 1998 36 R. RAJAN AND D.R.F. IRVINE long survival period can differ from those seen immediately after the lesion indicates that the plastic changes in cortex do not involve merely reduced thresholds at postlesion CFs (Irvine and Robertson, 1990). There is dispute about the extent to which cortical plasticity reflects subcortical effects. In the visual system, either a limited plasticity has been found at the thalamus (Eysel et al., 1980), or little change was seen in the thalamic lateral geniculate nucleus (LGN) in association with substantial cortical plasticity (Gilbert and Weisel, 1992; Darian-Smith and Gilbert, 1995). In the somatosensory system, subcortical plasticity has been suggested (Pons et al., 1991) or observed in the spinal cord (Basbaum and Wall, 1976; Devor and Wall, 1981), brainstem (Millar et al., 1976), or thalamus (Garraghty and Kaas, 1991; Rasmusson, 1996). However, other studies have failed to find plasticity in the spinal cord (see, e.g., Pubols and Goldberger, 1980; Pubols and Brenowitz, 1982). In the auditory system, we found a ‘‘patchy’’ plasticity in the midbrain nucleus, the inferior colliculus (IC), such that some parts of the central nucleus of the IC expressed plasticity, whereas others did not (Irvine and Rajan, 1994). The only other study on adult subcortical auditory plasticity reported that post-cochlear-lesion changes in the frequency map in the brainstem dorsal cochlear nucleus (DCN) could be explained as residue of prelesion input and did not account for cortical plasticity (Kaltenbach et al., 1992, 1996). This conclusion must be qualified for two reasons. First, in the study by Kaltenbach et al. (1992), cochlear damage was produced with loud sound, which has not yet been demonstrated to induce plasticity of frequency maps anywhere in the auditory pathway. Second, auditory cortical plasticity appears to be expressed only when certain boundary conditions are met (cf. Rajan and Irvine, 1996). Principal among these conditions is that, in the case of damage to restricted parts of the cochlea, some parts of the cochlea have suffered severe damage to, or degeneration of, the receptor epithelium and cochlear afferent fibers sufficient to deprive cortical regions of all or most of their prelesion input (Rajan and Irvine, 1996). In the DCN study, in which cochlear damage was quantified solely by histology of receptors, only one case (see Fig. 2 in Kaltenbach et al., 1992) showed severe histological damage sufficient to suggest that the boundary conditions for (cortical) plasticity had been met. Furthermore, in this one case, significant histological damage to particular receptor cells was seen in apical cochlear regions, yet there appeared to be no effect on the DCN map for the low frequencies represented in the cochlear apex. The adequacy of the histological index must also be questioned when it is noted that significant changes in a DCN map were observed with minimal histological damage to receptors (see Fig. 3 in Kaltenbach et al., 1992). To resolve these issues, we examined whether plasticity of DCN maps occurred after cochlear lesions that were very similar to lesions that produced cortical plasticity. This would also help determine whether the plasticity found in the IC reflected, at least in part, plasticity expressed in the DCN, which provides a separate and distinct pathway of the multiple brainstem inputs to the IC. MATERIALS AND METHODS Experiments were carried out on adult domestic cats by using the procedures approved by the Monash University Standing Committee on Ethics in Animal Experimentation and by conforming to guidelines set out in the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the policy of the Society for Neuroscience. Animals were allocated to two groups: one group of three normal animals in which no procedures were carried out prior to the terminal experiment to record from DCN and one group of four test animals in which mechanical lesions were made to the left cochlea some months prior to DCN recording. All experimentation was carried out in a shielded, sound-attenuating room. Anesthesia was induced by an intraperitoneal injection of sodium pentobarbitone (Nembutal; 40 mg/kg body weight), and the animal was given a single intramuscular injection of atropine sulfate (0.2 ml of 600 µg/ml solution) to reduce mucous secretion. The animal was wrapped in a thermostatically controlled heating blanket, and rectal temperature was monitored continuously. In the lesioning phase (test animals only) of this study, only the single dose of Nembutal was given: Surgery was completed within 1 hour, and the animal was allowed to recover as detailed elsewhere (Rajan et al., 1993). Procedures for cochlear lesions and recovery in test animals were carried out as described previously (Rajan et al., 1993). In brief, the left round window (RW) was exposed surgically, and a glass micropipette was advanced through the RW and basilar membrane a number of times to create a loss in hearing sensitivity. This loss was assessed by measuring visual detection thresholds (VDTs) for the compound action potential (CAP) audiogram at frequencies from 0.5 kHz to 40 kHz (Rajan et al., 1991) prior to and after the lesion. Animals recovered for 2 months (CML 9420 and CML 95105), 5 months (CML 9418), or 5.5 months (CML 9466). In the terminal DCN recording phase in all animals, after induction of a surgical level of anesthesia, a radial vein was cannulated to administer a single dose of Decadresson (sodium dexamethasone phosphate) and for subsequent administration of Nembutal at approximately 2–3 mg/kg/hour to maintain deep anesthesia. Depth of anesthesia was monitored through continuous recording of the rectal temperature, the electrocardiogram, and the electromyelogram activity from forearm muscles and by regular checks of pupillary dilatation and the pinch-withdrawal reflex. Body temperature was maintained at 37.5 6 0.5°C by a thermostatically controlled warming blanket wrapped around the animal and was regulated by feedback through a rectal temperature probe. Surgery was carried out to implant stainless-steel electrodes against the RW membrane of both cochleas to measure the CAP audiogram bilaterally in all control animals and in three of the four test animals (Rajan et al., 1991). In one test animal, the audiogram was measured only from the lesioned ear. A posterior craniotomy was made (Rajan, 1997) to expose the DCN. In all three control animals and in two test animals (CML 9466 and CML 95105), the craniotomy was made unilaterally to eventually expose the left cochlear nucleus (CN). In the other two test animals (CML 9418 and CML 9420), the craniotomy was made large enough to expose both CN. The cerebellum overlying the CN was removed by suction. To record from the DCN, a glassinsulated tungsten microelectrode (2–5 MV at 1 kHz) was aligned 37° off the midsagittal plane and 37° off the coronal plane (see Fig. 1 in Spirou et al., 1993) to penetrate the ABSENCE OF PLASTICITY IN ADULT DORSAL COCHLEAR NUCLEUS 37 Fig. 1. Cochlear sensitivity in lesioned and unlesioned cochleas of test animals at the time of dorsal cochlear nucleus (DCN) mapping, with respect to normal cochlear sensitivity. Data shown are the visual detection thresholds (VDTs) for the compound action potential (CAP) of the auditory nerve to tone bursts. The hatched region represents the range 6 1.64 standard deviations from the mean of a large database of normative CAP VDTs from the laboratory (cf. Rajan et al., 1991), and the dotted line represents the 20 dB . mean normative CAP VDT. A: Data from the lesioned left (LT) cochleas of all four test animals (CML 9418, 9420, 9466, and 95105). B: Data from the unlesioned right (RT) cochleas of the three test animals from which these data were obtained (CML 9418, 9420, and 95105). Each symbol represents data from one animal, identified at the top left of the plot. NR, no response. DCN near its dorsomedial tip and to run along the long strial axis of the nucleus. With this approach, the electrode traverses the tonotopic axis of the DCN (Spirou et al., 1993; Fig. 2A in the present study). The electrode was advanced rapidly in a ventral direction into the depth of the DCN, with only random sampling of activity during this forward penetration, until the neuronal clusters that were most sensitive to a low frequency (,4–8 kHz) were first encountered. The electrode was left in this position for <10 minutes to allow any compression of tissue to settle. Then, the most sensitive frequency (characteristic frequency; CF) and the threshold at CF of the neuronal cluster (‘‘cluster’’ recording) were determined audiovisually. Finally, quantitative data to tone bursts over a range of frequencies and intensities were obtained to define the boundaries of the excitatory response area (ERA) and response strength within the ERA, as detailed previously (Rajan et al., 1993; Rajan, 1997). The electrode was then moved back out of the DCN in steps of 50 µm, and recordings from neuronal clusters were made every 100– 200 µm. When possible, data were obtained from a number of such penetrations. Stimuli were pure tone bursts (50 msec duration, 4 msec rise-fall times) that were presented at 2/second to the ear ipsilateral to the DCN from which recordings were made. Methods of stimulus generation, delivery, and calibration were as described previously (Rajan et al., 1991, 1993). In two test animals, data were obtained from the DCN ipsilateral and that contralateral to the lesioned cochlea. In the other two test animals, data were obtained only from the DCN ipsilateral to the lesioned cochlea. For convenience, in all lesioned animals, the DCN ipsilateral to the lesioned cochlea will be referred to as ipsilesional and the DCN contralateral to the lesioned cochlea will be referred to as contralesional. The experiment was terminated with an overdose of Nembutal, which was administered through the i.v. cannula. In some experiments, one or both cochleas from the test animals were then removed for histology (Rajan et al., 1993). In some experiments from control and test animals, prior to the overdose, the tungsten microelectrode was readvanced into the DCN, and electrolytic lesions were made at selected points along the length of a successful track. In these cases, the DCN was also recovered postmortem for histology. RESULTS Effect of lesions on cochlear hearing sensitivity in test animals CAP audiograms in the lesioned left cochleas of the test animals, which are illustrated in Figure 1A, show that all four animals had CAP threshold losses commencing at some intermediate frequency and increasing to higher frequencies. Generally, the threshold losses consistently commenced from a frequency of about 12–15 kHz, with large losses ($ 20 dB relative to normal thresholds; one of the boundary conditions we have shown to be necessary for cortical plasticity; Rajan and Irvine, 1996) commencing from about 15–19 kHz and with losses increasing at higher frequencies. In two animals (CML 9420 and CML 9466), no CAP could be recorded at frequencies $ 24 kHz. In the other two animals (CML 9418 and CML 95105), the CAP was absent at frequencies of $ 30–32 kHz. This pattern of CAP thresholds is very similar to those recorded in our cortex study (Rajan et al., 1993). In contrast, thresholds in control animals and in the unlesioned cochleas of the test animals consistently lay within the normative range. This is illustrated in Figure 1B for the unlesioned cochleas of three test animals. Histological examination of the cochleas showed effects similar to those described previously with such lesions (Rajan et al., 1993; Rajan and Irvine, 1996): A quite sharp edge extending over a few hundred microns separated the region of normal cochlea (as determined by light microscopy) located apically from a basal region in which the organ of Corti had collapsed completely, with destruction of all hair cells and with only a few spiral ganglion cells surviving (, 5–10% of the normal complement). In the intermediate region, there was graded 38 R. RAJAN AND D.R.F. IRVINE Fig. 2. Progression of characteristic frequency (CF) with distance in the left dorsal cochlear nucleus (DCN) in control animal NCN 9457 (A) and in test animal CML 9420 (B), in which a lesion was made in the left cochlea 2 months prior to the DCN mapping. The hatched region labeled A indicates neuronal clusters that were responsive to tone-burst stimulation but very weakly, such that a clear CF could not be assigned. The shaded region labeled X indicates neuronal clusters that were unresponsive to tone-burst stimulation. Each symbol indicates data from a single penetration along the strial axis of DCN. Symbols surrounded by rectangles indicate that neuronal clusters at that point were broadly tuned for frequency even near threshold; in such cases, the symbol has been placed at the frequency that elicited the strongest response at threshold, whereas the box indicates the range of frequencies over which the cluster responded within 5 dB of threshold. Each plot is to be read from right to left to see the CF progression from low CFs ventral in the penetration and high CFs dorsally. damage to the hair cells. Given the similarity of these histological effects to those described previously (Rajan et al., 1993; Rajan and Irvine, 1996), these data are not presented here. about 18 kHz was recorded in any of the five penetrations in this animal. The CF gradient in the ipsilesional DCN in all four test animals is shown in Figure 3E–H and can be compared with the gradient seen for two control animals (Fig. 3A,B) and for the contralesional DCN of two lesioned animals (Fig. 3C,D). In each animal, the different penetrations were aligned with respect to one another at the distance at which a CF of 10 kHz was first encountered. By comparing Figure 3A with Figure 2A, it can be seen that, when this alignment procedure is carried out, the tonotopic gradients in different penetrations in the one animal overlie very well with respect to the CF recorded along the strial axis of DCN. In the two normal cases and the two contralesional cases illustrated in Figure 3A–D, there is a fairly monotonic progression of CF along the strial axis of DCN. Although the full CF sequence in DCN (Spirou et al., 1993) was not recorded in all penetrations in all four cases, CFs up to about 32 kHz were always obtained. In contrast to this normal tonotopic CF gradient, the CF gradient in ipsilesional DCN of the four test animals (Fig. 3E–H) was clearly abnormal in DCN dorsal to the 10 kHz CF point. Low CFs were always found in ventral DCN, and there was a normal CF progression as the electrode was moved more dorsally. In two animals (CML 9420 and CML 95105; Fig. 3E,F), this progression was maintained until a CF of about 16 kHz was first encountered. Thereafter, the CF-distance plot in these two animals flattened out, indicating that a CF of about 16 kHz was obtained over some distance, or it dipped down to even lower CFs. This effect occurred over a distance of , 1 mm that varied between the two animals and between different penetrations in the one animal, then it was followed by more dorsal DCN regions, where neurons were either broadly tuned for frequency (A points) or, most often, unresponsive to sound (X points). In CML 9418 (Fig. 3G), the CF-distance map flattened out at about 20–22 kHz for some distance in two penetrations before unresponsive points were recorded Tonotopic order in DCN of control and test animals In control animals, as described by Spirou et al. (1993), neuronal clusters in ventral DCN had low CFs and clusters in dorsal DCN had high CFs, with a generally monotonic increase in CF in between. This is illustrated in Figure 2A for the four penetrations in control animal NCN 9457. Although all four penetrations did not record the entire CF range represented in DCN (Spirou et al., 1993), a tonotopic gradient of CFs from 8 kHz to at least 32 kHz was always obtained. The differences in the depth at which any particular CF was obtained across the four penetrations reflects the change in shape and curvature of the DCN and, thus, the exact starting point of the penetration along the tonotopic axis of DCN (Spirou et al., 1993; Fig. 3 of present study). In three penetrations, after CFs of 32–40 kHz had been obtained dorsally in DCN, more dorsally located neuronal clusters were broadly tuned for frequency (‘‘A’’ points) or unresponsive (‘‘X’’ points). In the fourth penetration, the most dorsal recording site yielded a CF of 32 kHz. The tonotopic sequence in the ipsilesional left DCN in one test animal (CML 9420) is illustrated in Figure 2B. Again, low CFs were obtained in ventral DCN, with a CF of , 5 kHz obtained in at least two of the five penetrations. A tonotopic CF sequence was obtained in each penetration as the electrode was moved dorsally, until a CF of about 12–18 kHz was first encountered. Thereafter, more dorsally, the CF-distance plot flattened out in each penetration as CFs of about 10–16 kHz were obtained for some distance, the extent of which varied between different penetrations but was between 0.5 mm and 1 mm. More dorsal to this area, neuronal clusters did not respond to auditory stimuli at all (X points). No CF greater than ABSENCE OF PLASTICITY IN ADULT DORSAL COCHLEAR NUCLEUS more dorsally. In the third penetration (Fig. 3G, open circles), the flattening out of the CF-distance plot was mixed with dips to much lower CFs in the plot, particularly at the most dorsal locations. Finally, in CML 9466 (Fig. 3H), the CF-distance plot for each of two penetrations flattened out at about 22 kHz for some distance before unresponsive points were recorded more dorsally. The differences between the normal CF sequences (from both control left DCN and from the contralesional DCN of test animals) and sequences in the ipsilesional DCN of test animals can be appreciated more easily by comparing the overall CF gradients in these different cases. This was done by fitting a line of best approximation to all data in each of the two subcategories of ipsilesional DCN data (the two ipsilesional DCN cases with CF-distance plot flattening at about 16 kHz and the two cases with CF-distance plot flattening at about 22 kHz, as detailed above) and the tonotopic sequence in the total normal DCN set (four control DCN and two contralesional DCN). To fit the line in each of these categories, CF data from all penetrations, aligned to the 10-kHz CF point, were overlaid and sorted according to distance. The CF-distance relationship in each category was then approximated by a Beiter-spline function, using a low spline parameter (kept constant across all three categories) to keep smoothing to a minimum. The qualitative Beiter-spline function was preferred to a more quantitative function, such as a polynomial, because, although polynomials were good descriptors when CF-distance plots were monotonic, they were poor descriptors when there were dips in the CF-distance relationship, as in CML 9418 and, to a lesser extent, CML 9420. In fitting this spline function, A and X points in all three data sets were not used, i.e., only points with clearly assignable CFs were used to determine the CF-distance relationship. To illustrate the fact that the Beiter-splines were a good approximation of the overall aligned CF gradients for each group, Figure 3I–K shows the spline functions fitted to each of the three groups. Finally, to compare the tonotopic sequences across the three groups, the spline fits alone are shown in Figure 3L. Commencing ventrally in DCN, the tonotopic sequence in the two subcategories of ipsilesional DCN in test animals initially corresponds closely to that of DCNs receiving input from unlesioned ears (the ‘‘normal’’ DCNs, consisting of the control, unlesioned animals, and the contralesional DCNs in the test animals). However, at distances about 0.5–1.0 mm more dorsal to the 10-kHz CF point, the CF-distance plots of the two subcategories of ipsilesional DCNs diverge from the normal tonotopic sequence as the CF-distance plots in the former cases flatten out at about 16 kHz, or about 22 kHz. In the case in which the CF-distance plot flattens out at about 16 kHz, this effect is seen for only a relatively short distance of up to about 1.25 mm dorsal to the 10-kHz CF point (a distance corresponding in the normal CF-distance plot to a normal CF of about 30 kHz) before cells that are unresponsive to auditory stimuli are encountered more dorsally. In the case in which the curve flattens out at about 22 kHz, this is followed by the CF-distance plot dipping down to much lower CFs (due specifically to one penetration in one animal, CML 9418). Thus, in this subcategory (and, specifically, in CML 9418), CFs appear to be recorded over the same extent of DCN as in normal DCN, although there is a marked difference in the tonotopy in this subcategory compared with the nor- 39 mal DCN tonotopy, which extends to 40 kHz (the upper frequency limit in our testing system). In summary, the tonotopy in ipsilesional DCN in test animals shows features that are somewhat similar to some effects in contralateral AI (Rajan et al., 1993) after mechanical cochlear lesions of the same type used here, producing destruction or desensitization of high-frequency regions of the cochlea. In ipsilesional DCN regions in which high CFs (corresponding to frequencies represented in the damaged portion of the cochlea) would be found normally, there is (in most cases) an ‘‘expanded’’ representation of lower frequencies, generally of frequencies close to or at the edge of the cochlear lesion. Thresholds at CF in DCN in control and lesioned animals To establish whether the postlesion changes in the CF map are a manifestation of plasticity or simply reflect the residue of prelesion input (Rajan et al., 1993; Rajan and Irvine, 1998), it is necessary to consider thresholds at the ‘‘new’’ CFs. In the residue argument, the flattening of the CF-distance plot reflects the fact that, normally, there is convergence and divergence between different frequency channels in central auditory pathways. In CF regions in which the normal CF input has been destroyed or desensitized by the cochlear lesion, the ‘‘new’’ CF could simply be the most sensitive input remaining after elimination of the former CF input. The fact that ‘‘new’’ CFs were always at frequencies lower than those expected in the DCN regions corresponding to the lesion reflects the facts that the low-frequency slopes of ERAs are shallower than highfrequency slopes and that our cochlear lesions produced losses that commenced at some intermediate frequency and increased with increasing frequency. This would result in the observed ‘‘expanded’’ representation of a low frequency near the edge of the cochlear lesion. It is to be noted that, according to the residue argument, the residual responses (due to inputs from frequencies other than the normal CF inputs), by definition, would not be the prelesion inputs to which the neuron was most sensitive. Thus, thresholds at these postlesion residual CFs should be higher than those expected of neurons for which this was the normal CF. Furthermore, if all high-CF neurons lost their CF input and were left with a similar residual input from a cochlear lesion-edge frequency, then it would be possible, from the ERAs (see Materials and Methods) in normal neurons, to predict the progression of CF thresholds expected to be encountered across the DCN regions expressing the ‘‘new’’ residual CF. In our AI, study we have shown how this procedure could be applied (Rajan et al., 1993). Here, we apply the same procedure to the present DCN data. Threshold data at CF from all four ipsilesional DCNs are shown in Figure 4A–D, in which they are plotted with penetrations aligned at the 10-kHz CF point, like the CF-distance data in Figure 3. In all penetrations in all four ipsilesional DCNs, CF thresholds remained low (# 20 dB) only up to and for short distances beyond the 10-kHz CF point. From distances of ,0.5 mm more dorsal to this point progressing to even more dorsal DCN, CF thresholds rise steeply and, for the most part, monotonically. These effects can be contrasted with CF-threshold data from the DCN in two control animals (Fig. 4E,F) and from the contralesional DCN in two test animals (Fig. 4G,H; note that Fig. 4E–H illus- Figure 3 ABSENCE OF PLASTICITY IN ADULT DORSAL COCHLEAR NUCLEUS trates the same cases shown in Fig. 3 for CF-distance plots). In all four plots, CF thresholds remain low (# 20 dB) for distances up to at least 1.0 mm more dorsal to the 10-kHz CF point. Thereafter, although CF thresholds increase, the rate of increase in normal DCN (control DCNs and contralesional DCNs in two test animals) generally appears to be much shallower than that in the ipsilesional DCN of test animals. Direct comparison of the threshold-distance gradient in the ipsilesional DCN against that in the normal pool was attempted by using the same analysis that was applied to the CF-distance data in Figure 3. A line of best approximation was fitted to all data in each of the two subcategories of ipsilesional DCN data (the two ipsilesional DCN cases with CF-distance plot flattening about 16 kHz and the two cases with CF-distance plot flattening about 22 kHz) and to the data in the total normal DCN set (control and contralesional DCNs). The Beiter-spline functions fitted to each of the three groups are shown in Figure 4I–K to illustrate the fact that the spline functions were a good approximation of the overall, aligned, CF-threshold gradients for each group. Figure 4L compares the three spline fits. Ventral to the 10-kHz CF point, the spline fits to the threshold-distance data in all three categories of DCN data overlie quite well. This congruity holds true with dorsal progression in DCN until a position almost 0.5 mm more dorsal to the 10-kHz CF point. Thereafter, the lines fitted to the two subcategories of ipsilesional DCN data diverge markedly from the line fitted to the total normal DCN pool, as thresholds in ipsilesional DCN increase much more steeply than in normal DCN. Comparison of Figure 4L and Figure 3L shows that, in the region of the ipsilesional DCN in which the CF-distance plot diverges from the normal CF-distance plot, CF thresholds also increase steeply. Fig. 3. Progression of characteristic frequency (CF) with distance in normal and ipsilesional dorsal cochlear nucleus (DCN). A–D: Normal (i.e., left) DCN, in two control animals (A,B) and contralesional (i.e., right) DCN in two test animals (C,D). E–H: DCN ipsilateral to the lesioned cochlea in test animals. The animal is identified in the top right corner of each plot from A to H. The layout of the ordinate is the same as that described for Figure 2. For the abscissa, in each animal, the different penetrations were aligned with respect to one another at the distance at which a CF of 10 kHz was first encountered. The abscissa plots distance in the DCN relative to this point, with positive depths indicating points farther ventral along the DCN strial axis than the 10-kHz CF point and negative values that indicate more dorsally located points. Otherwise, the layout here is the same as that for Figure 2, with each symbol indicating data from a single penetration along the strial axis of DCN. I–L: Comparison of the CF-distance progression in normal DCN vs. that in each subcategory of ipsilesional DCN. In I–L, the full line presents the Beiter-spline of best approximation for the trend of data (symbols) in that plot. I presents the data for the ipsilesional DCN for the two test animals in which the CF-distance plot flattened out at ,16 kHz (CML 9420, shown in E; CML 95105, shown in F). J presents the data for the ipsilesional DCN for the two test animals in which the CF-distance plot flattened out at ,22 kHz (CML 9418, shown in G; CML 9466, shown in H). K presents data from the four normal DCNs shown in A–D and from another two control animals. Data from the different animals for each plot were aligned at the distance of the 10-kHz CF point and then sorted according to distance. Then, the Beiter-spline approximation was fitted by using a low spline parameter that was kept constant across all three plots (I–K). These fitted lines alone are compared in L, in which CMLs 16 indicates the line fitted in I, CMLs 22 indicates the line fitted in J, and NORMALS indicates the line fitted in K. Note the different abscissa scale in L compared with the other plots. 41 Predictions of CF thresholds by the residue hypothesis The marked divergence of CF thresholds in the dorsal region where the CF-distance plots flattened out in ipsilesional DCN is very different from the effects seen in AI plasticity, in which CF thresholds remain low in the region where the CF-distance plots flatten out (Robertson and Irvine, 1989; Rajan et al., 1993; Rajan and Irvine, 1998). This suggests that the DCN effects are not similar to AI plasticity and could simply reflect the residue of prelesion inputs (Rajan et al., 1993; Rajan and Irvine, 1998). The argument that the CF-distance plots in the ipsilesional DCN in test animals are explicable as the residue of prelesion input is strengthened by comparison of CF thresholds measured in the DCN in these cases with the CF thresholds predicted from the residue argument. The latter thresholds were derived from the ERAs measured in the normal pool (i.e., control DCNs and contralesional DCN in two test animals) in the manner explained below. Figure 5A–D illustrates the CF-threshold predictions for two control DCNs and two contralesional DCNs in test animals for the case in which the residue of prelesion input resulted in an expanded representation of a frequency of 16 kHz. In these plots, for all CFs up to 16 kHz, the thresholds plotted are those measured at CF (i.e., for CFs up to 16 kHz, the data are exactly those shown in the appropriate plots in Fig. 4). Thereafter, for points with CFs . 16 kHz, the threshold plotted is not that at CF but rather threshold at 16 kHz, which was obtained from the quantitative measurements of the ERA for higher-CF clusters. Similar calculations were also made in the other two control animals (not illustrated). Similarly, Figure 5E–H illustrates the CF thresholds predicted by the residue argument in the case in which there is an apparent ‘‘expanded’’ representation of 22 kHz. In these plots, which were also derived from normal data, thresholds plotted for all CFs up to 22 kHz are those at CF (i.e., for CFs up to 22 kHz, data plotted are exactly those in appropriate plots in Fig. 4). Thereafter, for points with CFs . 22 kHz, the threshold plotted is that at 22 kHz, which, again, was obtained from the ERA measured in the higherCF clusters. In both rows, it can be seen that the residue argument would predict that, beyond the ‘‘lesion-edge’’ CF (i.e., 16 kHz for Fig. 5A–D and 22 kHz for Fig. 5E–H), there would be a sharp increase in CF thresholds as recordings were made from neuronal clusters located more dorsally in DCN. These predicted effects can be compared with the actual progression of CF thresholds recorded in the left DCN of the lesioned animals. (In making this comparison, it should be noted that, in the two subsets of test DCN data, in the region where the CF-distance plots ‘‘flattened out,’’ the CF was not always exactly at 16 kHz or exactly at 22 kHz. Hence, the progression of CF thresholds calculated here for cases in which the progression was of CFs at 16 kHz or at 22 kHz should be treated only as approximations of the progression expected in the test DCN subsets.) Like in Figures 3 and 4, this was done by fitting a Beiter-spline function to provide a single approximation of all data in a particular pool. Here, all data for the predictions for a residual 16 kHz ‘‘expanded’’ representation were pooled, and a Beiter-spline function was fitted to those data. A similar procedure was carried out on data for the predictions for a residual 22 kHz ‘‘expanded’’ representa- Figure 4 ABSENCE OF PLASTICITY IN ADULT DORSAL COCHLEAR NUCLEUS tion. Figure 5I compares the spline function fitted in the case of the residual 16-kHz ‘‘expanded’’ representation with the spline functions fitted to the CF-threshold progression seen in the normal data pool (the same spline fit as in Fig. 4K) and in ipsilesional DCN in the two test animals in which the CF-distance plot flattened out at about 16 kHz (the same spline fit as in Fig. 4I). The sequence of 16-kHz CF thresholds predicted by the residue argument matches quite closely the way in which the sequence of CF thresholds actually recorded in the ipsilesional DCN in the two test cases diverged from the sequence in the normal pool. The only marked difference between the predicted function and that observed in the lesion animals is very dorsally in the DCN, where the ipsilesional DCN becomes unresponsive. This must reflect test DCN regions that are completely deprived of any input (where the residue argument still predicts some low-CF input). Similarly, Figure 5J compares the Beiter-spline fit to the CF-threshold predictions of the residual 22-kHz CFs argument against the spline fit to the CF-threshold progression seen in the normal data pool (again, the same spline fit used in Fig. 4K) and in the ipsilesional DCN in the two test animals in which the CF-distance plot flattened out at about 22 kHz (the same spline fit used in Fig. 4J). There is less congruence between the predicted function and the lesion data here than in Figure 5I. However, it should be noted that the CF thresholds that were actually recorded in the ipsilesional cases shown here, in fact, were worse than those predicted by the residue argument. In part, this could reflect the fact that the CF sequence in the ipsilesional DCN in these two test animals (see Fig. 3J) actually shows irregular dips to lower CFs, which would have higher ‘‘residual’’ thresholds than a frequency of 22 kHz in a formerly high-CF neuronal cluster. It could also reflect the fact that the observed CF thresholds in the ipsilesional DCN in these two animals appear to be slightly offset from the normative data, even for lower CFs that are just . 10 kHz (Fig. 5J). If this small offset of about 5–10 dB is Fig. 4. Progression of threshold at characteristic frequency (CF) with distance in normal and ipsilesional dorsal cochlear nucleus (DCN). A-D: DCN ipsilateral to the lesioned cochlea in test animals. E-H: Normal (i.e., left) DCN in two control animals (E,F) and contralesional (i.e., right) DCN in two test animals (G,H). Animal number is in the top right corner in A–H. Abscissa layout is that same as that in Figure 3 and plots distance in DCN relative to the 10-kHz CF point in each penetration in each animal. Positive depths again indicate points farther ventral along the DCN strial axis than the 10-kHz CF point, and negative values indicate more dorsally located points. The ordinate plots threshold at CF, and the shaded region labelled NR indicates neuronal clusters that were unresponsive to tone-burst stimuli. I–L: Comparison of the threshold-distance progression in normal DCN vs. that in each subcategory of ipsilesional DCN. The full line in each case presents the Beiter-spline of best approximation for the trend of data (symbols) in that plot. I presents threshold data for the ipsilesional DCN in which the CF-distance plot flattened out at ,16 kHz (CML 9420, shown in Fig. 3E; CML 95105, shown in Fig. 3F). J presents threshold data for the ipsilesional DCN in which the CF-distance plot flattened out at ,22 kHz (CML 9418, shown in Fig. 3G; CML 9466, shown in Fig. 3H). K presents data for the four normal DCNs shown in E–H and from the third control animal. In each plot, the distance-aligned data from the different animals were sorted; then, the Beiter-spline approximation was fitted by using a low spline parameter that was kept constant across all three plots (I–K). These fitted lines alone are compared in L, in which the CMLs 16 indicates the line fitted in I, CMLs 22 indicates the line fitted in J, and NORMALS indicates the line fitted in K. Note the different abscissa scale in L compared with the other plots. 43 corrected for, then there is quite good correspondence between the 22-kHz CF thresholds predicted by the residue argument and those that were actually recorded in these ipsilesional DCNs in which the CF-distance plot flattens out at about 22 kHz. In any case, the fact that CF thresholds in these two animals are worse than those predicted by the residue argument would at least argue strongly against the idea that the CF gradients observed in these animals reflect plasticity. DISCUSSION Following unilateral, partial cochlear lesions in adult animals, the tonotopic map in the ipsilesional DCN is altered. In at least some penetrations in all lesion animals, neurons in ipsilesional DCN regions where high CFs would normally be found have a new CF, generally at a frequency that is close to or at the edge of the cochlear lesion (lesion-edge frequencies). This results either in a flattening out of the CF-distance plot or a flattening out mixed with irregular dips to much lower frequencies in the CF-distance plot. Thus, in the ‘‘deprived’’ DCN, there is an ‘‘expanded’’ representation of lower frequencies close to the edge of the cochlear lesion, with varying degrees of scatter with regard to the frequency range showing this expanded representation. The distance of deprived DCN over which this change occurs varies between penetrations even in the one animal. This effect is similar to that described by Kaltenbach et al. (1992) after acoustically induced cochlear lesions. The flattening out effect is reminiscent of the flattening out of the CF-distance plot (and expanded representation of lesion-edge frequencies) seen in contralesional AI after similar cochlear lesions (Rajan et al., 1993). However, there are two major respects in which the DCN effect differs from the cortical effect. The first difference is that, over the region in which the CF-distance plot in ipsilesional DCN varies from the normal CF-distance progression, there is a systematic and generally-monotonic increase in thresholds at the ‘‘new’’ CFs. This is very different from the effect seen in contralesional AI, in which thresholds remain low when progressing from normal AI regions into the AI region containing the new CFs at lesion-edge frequencies (Rajan et al., 1993; Rajan and Irvine, 1998) and are not significantly different from normal thresholds for those CFs. This difference in the progression of CF thresholds in ipsilesional DCN and contralesional AI suggests that the DCN effects do not represent plasticity of the tonotopic organization, as in contralesional AI, but simply the residue of preexisting input (Rajan et al., 1993; Robertson and Irvine, 1989; Rajan and Irvine, 1998). The residue argument predicts that, if all high-CF neurons expressed a new CF as a consequence of residual inputs, then thresholds at the postlesion residual CF would be higher than CF thresholds in neurons for which this frequency was the normal CF, as noted above (see Results). Furthermore, if all high-CF neurons exhibited the same ‘‘new’’ CF, then the residue argument would predict a systematic (although not necessarily monotonic) increase in CF threshold from normal AI across the region containing the expanded representation of a lesion-edge frequency (Rajan et al., 1993; Rajan and Irvine, 1998). The observed progression of CF thresholds in AI differed markedly from this prediction from the residue hypothesis (Rajan et al., 1993; Rajan and Irvine, 1998). The same Figure 5 ABSENCE OF PLASTICITY IN ADULT DORSAL COCHLEAR NUCLEUS analysis was applied here. In contrast to AI, in DCN, the CF-threshold progression that was predicted from the residue argument closely matched the progression of CF thresholds in the lesion animals in which there was a flattening out of the CF-distance plot at about 16 kHz. It also matched quite well the progression of CF thresholds in the lesioned animals in which there was a flattening out of the CF-distance plot at about 22 kHz. In the latter case, the mismatch was due to the residue argument underestimating the observed increase of CF thresholds in these two animals. These comparisons make it unlikely that any postlesion flattening out of the CF-distance plot in ipsilesional DCN could account for the effects seen in contralesional AI after very similar cochlear lesions. Unlike the AI effects, which appear to reflect a true plasticity of the tonotopic organization, the DCN effects appear simply to reflect the residue of prelesion inputs. The other major respect in which the postlesion DCN changes differ from AI changes is that, in the DCN, the flattening out (with or without dips) in the CF-distance plot was not found uniformly in all penetrations in all animals. In as many penetrations as those that showed this effect, the CF-distance plot showed a normal progression until a lesion-edge CF was first encountered and then no further auditory drive was encountered more dorsally, i.e., deprived DCN regions simply became unresponsive to tones. In contrast, in contralesional AI, plasticity effects were uniform in all penetrations across the tonotopic axis of AI. The DCN has a highly complex laminar structure both cytoarchitecturally and in terms of neural connectivity (for reviews, see Cant and Morest, 1984; Moore, 1986; Young et al., 1992), such that it has sometimes been considered to have a ‘‘cortex-like’’ physiology (cf. Evans, 1968). It was for this reason that we directed our attention to this subdivision of the cochlear nucleus, because, potentially, it is the most likely to be able to express plasticity of the tonotopic organization after partial cochlear lesions very similar to the lesions that cause plasticity in the adult AI (Rajan et al., 1993). The absence of plasticity in our study and the similar conclusion drawn by Kaltenbach et al. (1992, 1996) show that having such a complex circuitry does not ensure that plasticity occurs. Clearly, the DCN must lack neural Fig. 5. Predictions of the residue hypothesis for the progression of characteristic frequency (CF) thresholds with distance in ipsilesional dorsal cochlear nucleus (DCN). A–D: Data for the case in which an expanded CF representation of 16 kHz occurred as a residue of preexisting input. E–H: Data for the case in which the expanded residual CF representation was at 22 kHz. In these plots, data are from normal DCN (animal numbers are shown at top right). In A–D, data plotted are the CF thresholds for CFs # 16 kHz; thereafter, the thresholds plotted for clusters with CF . 16 kHz are the thresholds at 16 kHz measured in the excitatory response area (ERA). Similarly, in E–H, data plotted are CF thresholds for CFs # 22 kHz; thereafter, the thresholds plotted for clusters with CF . 22 kHz are thresholds at 22 kHz measured from the ERA. I,J: Comparison of Beiter-spline lines of best approximation with CF-threshold data from normal DCN (NORMALS; the same spline fit as in Fig. 4K), from a particular subset of ipsilesional DCN (CML with animal numbers; for I, this is the same spline fit as in Fig. 4I; for J, this is the same spline fit as in Fig. 4J), or for the CF thresholds predicted from the residual hypothesis for the case in which an expanded CF representation of 16 kHz (I, PREDICTED 16 kHz RESIDUE) or 22 kHz (J, PREDICTED 22 kHz RESIDUE) occurred as a residue of preexisting input. Note the different abscissa scale in I and J compared with the other plots. 45 mechanisms that are essential for the occurrence of plasticity of the type observed in the cortex after cochlear lesions. The absence of plasticity in the adult DCN is consistent with the absence of plasticity seen in many (but not all) studies at low subcortical levels in other sensory systems (see above). All of these studies have used partial or total deprivation of the outflow from the receptor surface only for relatively brief periods. In contrast, a long period of survival was used in the study by Pons et al. (1991), who found such extensive cortical plasticity that it was suggested that at least some component of this plasticity must reflect subcortical effects. Although we cannot say whether such long survival times would allow plasticity to occur in the DCN, the survival times after the cochlear lesion in this study ranged from 2.0 months to 5.5 months, and we have shown that AI plasticity can be found with a survival time of 2.0 months, the shortest used in the AI study (Rajan et al., 1993). Thus, at least, we can say that the AI plasticity expressed with a survival time of 2.0–5.5 months after a partial cochlear lesion in adult animals is not due to plasticity at the DCN. 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