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Absence of plasticity of the frequency map in dorsal cochlear nucleus of adult cats after unilateral partial cochlear lesions

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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: ramesh.rajan@med.monash.edu.au
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. We have also shown (Irvine and
Rajan, 1994) that similar cochlear lesions and survival
times lead to a patchy plasticity in the midbrain inferior
colliculus (IC), such that some parts of the central nucleus
of the IC express plasticity, whereas others show effects
that are consistent with the residue argument. The present results also show that, if this patchiness in the IC is a
reflection that plasticity is expressed in only some of the
multiple brainstem pathways to the IC, then it is not due
to inputs from the DCN conveying plastic, tonotopic reorganization from this brainstem structure.
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