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The Journal of Neuroscience, October 15, 1999, 19(20):9117-9125
Sensory Loss by Selected Whisker Removal Produces Immediate
Disinhibition in the Somatosensory Cortex of Behaving Rats
M. Kathleen
Kelly1,
George E.
Carvell1,
Judith
M.
Kodger2, and
Daniel J.
Simons2
1 Department of Physical Therapy, School of Health and
Rehabilitation Sciences, and 2 Department of Neurobiology,
School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
15260
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ABSTRACT |
This study used extracellular unit recordings in behaving animals
to evaluate thalamocortical response transformations in the rat
whisker-barrel system. Based on previous acute studies using
controlled whisker stimulation, we hypothesized that in a cortical
barrel adjacent (non-principal) whiskers exert a net inhibitory
effect. In contrast, in thalamic barreloid neurons, the effects of
neighboring whiskers should be net facilitatory. We evaluated these
hypotheses by recording unit activity at 21 sites in17 animals trained
to explore a wire mesh screen with their whiskers. In the middle of the
recording session, selected vibrissae were clipped close to the skin
surface. The absence of whiskers surrounding the principal whisker was
associated with a mean 20% increase in cortical activity and,
conversely, a 37% decrease in the thalamic activity. Removal of the
principal whisker resulted in a 50% decrease in cortical unit firing.
Findings are consistent with the idea that, in the behaving animal,
each barrel uses multi-whisker thalamic inputs and local inhibitory
circuitry to sharpen the receptive field properties of its constituent
neurons. Cortical disinhibition as a consequence of selective whisker
removal is likely to be an important factor underlying altered
receptive field properties in sensory-deprived animals.
Key words:
barrel; whiskers; tactile behavior; EMG; inhibition; sensory deprivation; plasticity; active touch
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INTRODUCTION |
The rodent somatosensory system
provides a number of advantages for addressing issues related to the
development and maintenance of normal sensory function. Simple whisker
trimming in neonatal animals leads to permanent abnormalities in the
cortical anatomy (Micheva and Beaulieu, 1995 ; Keller and Carlson, 1999)
(but see Akhtar and Land, 1991), cortical receptive field properties
(Simons and Land, 1987; Fox, 1992), and whisker-based discriminative
behavior (Carvell and Simons, 1996). In adult animals, alterations in
cortical receptive fields can be produced after a few days of whisker
removal (Diamond et al., 1993). Elucidating the mechanisms responsible for these and other related phenomena (Buonomano and Merzenich, 1998)
requires an understanding of local circuitry at different levels of the
somatic afferent system.
Previously, we described differences in receptive field properties of
thalamic "barreloid" and cortical "barrel" neurons (Simons and
Carvell, 1989). The former had relatively large, excitatory multi-whisker receptive fields (Nicolelis et al., 1993) with weak inhibitory surrounds. In contrast, presumed excitatory neurons within
barrels displayed smaller excitatory receptive fields and relatively
strong inhibitory effects of adjacent whiskers (Brumberg et al., 1996).
These results suggest that whisker removal should disinhibit neurons in
neighboring cortical barrels but result in no net effect, or even a
reduction in activity, in the corresponding thalamic barreloids. This
idea is consistent with findings in 2-deoxyglucose (2DG) studies in
freely exploring mice (McCasland and Woolsey, 1988). Metabolic labeling
was greater in the C3 cortical column of mice acutely deprived of all
but the principal whisker (C3) compared with levels in the C3 column of
non-trimmed animals.
We interpret the above to mean that, within a barrel, the net effect of
adjacent (non-principal) whiskers is normally inhibitory in behaving
animals. This conclusion is tempered, however, by two lines of
evidence. First, some single-unit studies have shown that, unlike
effects we observed in fentanyl-sedated animals, adjacent whisker
excitatory responses in the barrels of urethane-anesthetized rats are
robust and of long duration (Armstrong-James and Fox, 1987;
Armstrong-James et al., 1992). Hence, between-whisker interactions within a barrel might be facilitatory. Second, in the barrel cortex of
behaving hamsters, GABAergic neurons are more heavily 2DG-labeled than
presumed excitatory cells (McCasland and Hibbard, 1997). Elevated
metabolic activity in the C3 column of C3-only mice could therefore
reflect increased cortical inhibition after adjacent whisker removal
and not an increase in the activity of excitatory barrel neurons.
Here, we used neurophysiological approaches in behaving rats to test
two hypotheses. If the net effect of adjacent whiskers is inhibitory,
their removal should result in increased spike activity. Conversely, if
the net effect of adjacent whiskers is excitatory, their removal should
result in decreased activity. We assessed these alternatives by
recording unit activity in animals trained to whisk a wire mesh screen.
In the middle of the recording session, selected whiskers were clipped
short. The first hypothesis was supported by the cortical unit data,
whereas the second was supported by thalamic data. These results are
important for understanding operations of local circuits in normal and
in sensory-deprived animals.
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MATERIALS AND METHODS |
Animal training
The purpose of the behavioral task was to promote extended
periods of whisker system activation during a natural behavior. Adult
female Sprague Dawley rats were trained to whisk and explore actively a
wire mesh screen to search for a metal-tipped wand (3.5 mm in diameter)
that protruded 1-2 cm through the mesh. Animals were rewarded with a
small amount of powdered rat chow mixed with water and peanut butter.
Details of apparatus. The rat stood on an elevated platform
and stretched across a gap of 7.5 cm to palpate the screen. The platform was 18.5 cm high, 24 cm long, and 18 cm wide at the back end,
narrowing to 8 cm at the front end. The screen, which was supported in
a wooden frame, consisted of wire mesh (grid size 6 × 6 mm)
measuring 25.5 cm in width and 10.5 cm in height. A horizontal bar
placed 8-9 cm above the platform and in front of the screen provided a
means for the animal to stabilize its forepaws so that it could freely
use its face to explore the full extent of the screen, combining
whisking with lateral and vertical head movements. A Panasonic AG-530
video camera was positioned 30 cm above the screen to obtain an
overhead view of the animal while it explored the screen. The shutter
speed was set at  sec. A time-date generator marked each
video frame with the elapsed time of the experiment.
Initial training consisted of instituting the food deprivation schedule
and acclimating the rat to handling. Over a period of a week, the
animal was familiarized with the training apparatus by affording it
access to food mash ad libitum while on the raised platform.
During the second phase of training, the animal was introduced to the
task itself. Trial onset was signified by a white noise audio signal.
At first, the animal was encouraged to explore the screen by placing a
small quantity of food mash on the wand. Contact of the animal's mouth
with the wand completed an electrical circuit, terminating the white
noise and presenting a tone that signaled availability of a food reward
at the side of the platform. Eventually there was no need to place food
on the wand because the animal would immediately initiate palpation of
the screen upon hearing the white noise.
Once an animal learned the basic task, it was fitted with a removable
blindfold (see below). Training continued 5 d/week until the animal
routinely explored the screen for the wand, which was presented to the
animal after progressively longer times after the start of the trial.
Once the probe was introduced through the screen, animals easily
located it within a few seconds. Eventually, animals would explore the
screen continuously for 20-30 sec, performing ~30 such trials during
a single training session. This typically required 3-4 weeks.
Surgical preparation
Rats underwent two surgeries. In the first, a dental acrylic
appliance was attached to the skull for holding an amplifier base,
microdrive, and blindfold. Two to 3 weeks later, a second surgery was
performed to insert EMG electrodes in the mystacial pad and to position
the electrode assembly over the appropriate part of the brain.
Anesthesia was induced with metofane followed by halothane at 1-2%.
All surgical procedures were performed under sterile conditions.
During the first surgery, a skin incision was made over the skull, the
underlying connective tissue was cleared, and the skull was thoroughly
cleaned with 100% H2O2.
Small stainless steel screws, one of which was attached to a ground
wire, were inserted into the bone to serve as an anchor for an acrylic
base. In addition to the amplifier connector, which was placed over the
occipital bone, one or two stainless steel threaded posts were placed
as far anteriorly as possible. These were used to hold a removable custom-fitted plastic (Orthoplast) blindfold. After surgery, the animal
was administered a subcutaneous injection of Torbugesic (2 mg/kg; Fort Dodge Laboratories Inc., Fort Dodge, IA), and crushed baby
aspirin was added to the water bottle in its home cage. An oral
antibiotic was administered for 7-10 d after surgery.
EMG electrode placement. During the second surgery, a pair
of Teflon-coated stainless steel wires (0.0045 inches) was inserted through a small skin incision in the cheek and tunneled subcutaneously to the deep intrinsic muscles of the mystacial pad (Carvell et al.,
1991). Appropriate placement of the wires was determined by the ability
to elicit small movements of one to three neighboring whiskers using
low-threshold stimulus currents. The proximal ends of the electrode
wires were tunneled under the skin to the back of the head and soldered
to the amplifier connector on the skull. The skin incision on the cheek
was sutured using 4-0 silk, and wound margins were treated with
bacitracin ointment.
Microdrive placement. While still anesthetized, the animal
was placed in a stereotaxic frame with non-traumatic ear bars. A small
craniectomy, leaving the dura intact, was made over the ventrobasal
thalamus or the cortical barrel field; both sites were approached from
the skull dorsum. Receptive field-mapping procedures were used to
locate the representation of rostral (i.e., arcs 3-5) whiskers in one
of the midventral rows (C or D) (see Fig. 2 for whisker nomenclature),
because these whiskers were most likely to contact the screen during
the whisking task and because they were surrounded by other whiskers
(e.g., rows C and E for a row D recording site). A miniature microdrive
assembly was positioned over the appropriate area (for review, see
Carvell et al., 1996). For cortical recordings, the microdrive was
positioned so as to target neurons in middle cortical depths, and the
electrode tip was retracted to lie just outside the dura. For thalamic
recordings, the electrode was advanced into ventral posteromedial
nucleus during initial mapping and then withdrawn ~1 mm dorsal
to the nucleus. A thin layer of bacitracin ointment was applied to the craniectomy site and covered with a thin layer of sterile bone wax. A
protective shield made of lightweight plastic was placed over the
apparatus. The animal was treated after surgery as above. In four
animals, two experiments were conducted several weeks apart, one in
each hemisphere.
Recording and data collection
Data collection occurred after the animal was fully recovered
and was again performing the behavioral task, usually 2-5 d after the
second surgery. EMG and unit recordings were obtained through
dual-channel differential amplifiers that were incorporated into a head
stage that plugged into the amplifier base. Conventional secondary
amplification and filtering stages were used. The microelectrode was
again advanced into the whisker representation while aurally monitoring
responses evoked by manual whisker stimulation. Once the representation
of an appropriate whisker was located, the position of the electrode
tip was adjusted carefully over a period of several minutes to isolate
a small number of units responding crisply to stimulation of the
whisker. Considerable care was taken to identify the whisker evoking
the strongest response, which is hereafter denoted as the principal
whisker (PW). This delineation was always confirmed by at least two
observers before the beginning of the recording experiment. From this
point in the experiment, no adjustments were made to the position of
the electrode.
EMG and unit records were stored on the two audio channels of the video
recorder along with the video images of the behavior. Data were
collected for 10-15 trials during which all of the whiskers on the
face were intact. Subsequently, selected whiskers were trimmed to
within 1-2 mm of the skin surface. The animal was gently restrained in
an experimenter's hands, the PW was reconfirmed, and whiskers were
carefully trimmed using blunt surgical scissors. In all but three
experiments, the eight whiskers surrounding the PW were trimmed (Fig.
1); the other cases involved trimming the PW alone or, inadvertently, in combination with some adjacent whiskers
(see Results). After a 10-15 min rest, the rat performed an additional
10-15 trials.
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Figure 1.
Recording site identification. A
shows cortical barrels in a 60 µm tangential section from an
experiment in which the PW was identified as D4. An electrolytic
lesion made at the recording site (arrow) is located
just superficial to the cytochrome oxidase-rich center of the D4
barrel. Top, Anteromedial. B-D show
histology from a thalamic recording experiment in which the PW was
identified physiologically as C3 (see Fig. 7). B and
C show consecutive 60 µm cytochrome oxidase-stained
sections cut in an oblique horizontal plane (from dorsomedial to
ventrolateral), a plane in which thalamic barreloids can be visualized
(Land and Simons, 1985b, their Fig. 1C).
Top, Dorsolateral; right, posterior. In
B, an electrolytic lesion is visible in the C3 barreloid
(arrow), and the electrode track is visible in C2
(immediately below the letter C). The
arrangement of barreloid rows and arcs are more evident in
C, which is the superficially adjacent section.
D shows the same section as in C overlaid
with a line drawing illustrating the overall orientation of barreloid
rows B-E; row A can only be observed in deeper sections. The split in
the tissue, partially transecting the row C barreloids, is an artifact
of tissue processing, not an electrode track. Scale bars, 500 µm.
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At the conclusion of the experiment, an electrolytic lesion (7 µA for 7 sec) was made to mark the recording site (Fig. 1). Forty-five to 60 min later, the animal was deeply anesthetized with
pentobarbital sodium, and the electrode was carefully withdrawn. The
rat was then perfused for cytochrome oxidase histochemistry (Land and
Simons, 1985a). Subsequently, the brain was frozen and cut in 60 µm
sections. For cortical experiments, the brain was sectioned tangential
to the pial surface overlying the barrel field. For two of three
thalamic experiments, the thalamus was sectioned in a standard coronal
plane. In one case, the diencephalon was oriented in an oblique
horizontal plane during sectioning so that individual thalamic
barreloids could be visualized (Land and Simons, 1985b).
Data analysis
To identify periods of time when the rat's face was in
immediate proximity to the screen and vigorously exploring it for at least 10 sec, each videotape was viewed at normal speed and on a
frame-by-frame basis. This was done while listening to the simultaneous audio recordings of the neural records to verify that the spike activity correlated with screen exploration and that it clearly decreased when the animal moved away from the screen. Spikes were carefully inspected using a digital oscilloscope and amplitude discriminator to obtain an estimate of the number and shapes of isolatable units. Multi-unit and EMG records were then digitized at 50 kHz and 500 Hz, respectively, using DataWave software (Data Wave
Technologies Corp., Longmont, CO). Unit waveforms, which were always
initially negative, were parsed from the continuous record by acquiring
32 points of the waveform centered around an amplitude threshold
crossing of the negative-going phase. Thresholds were set
conservatively to acquire data from typically the one to three largest
amplitude units. Further analyses were performed using custom software.
Spike sorting. To extract single-unit data from the
multi-unit record, we modified the procedure described by Fee et al.
(1996). Parsed waveforms were examined visually to determine which
segment of the 32 sample points contained the most stable region of the action potentials and at what time point in the sample the peak amplitude should be set to best capture the action potential waveforms. Unused sample points at the beginning and end of the original parsed
record were discarded. Using cubic spline interpolation, the true peak
of the action potential was estimated, and the waveform was
resampled to 32 points so as to place the peak at a chosen sample time
in the interpolated waveform. This procedure eliminates jitter in the
aligning of waveforms that have been digitally sampled.
Spike waveforms were sorted using a variant of the method described by
Fee et al. (1996) for stereotrode recordings (64 sample points
across two electrodes). For the single-electrode data used in the
present study, spike waveforms were treated as 32 element vectors. A
subset (~4000) of all of the spike waveforms (i.e., spikes taken from
one behavioral trial) were initially sorted into a large number of
clusters (usually 16) by recursive bisection. For the first bisection,
a small amount of gaussian noise was added to an average of all the
waveforms to produce a second mean waveform. Each waveform was
subsequently assigned to the one (of two) mean waveform that was
closest to it in shape, updating the mean as each waveform was added.
The assignment and updating procedure was repeated three times to allow
the means to attain an equilibrium. Other bisections proceeded
similarly. The resulting clusters were then combined into final
single-unit clusters based on similarity of waveform shape and on a
minimal interspike interval of 2.0 msec, corresponding to the
refractory period. The final clusters were then used to form spike
waveform templates to which we attempted to assign all parsed waveforms
in the full data set. Waveforms that could not be assigned to one of
the templates were discarded or, occasionally, resorted to identify
infrequently spiking units.
In the method of Fee et al. (1996), spike waveforms are first sorted
into initial clusters solely on the distance between the waveform
vector and the cluster mean; the interspike interval criterion is
applied only at the final stage of cluster aggregation. In our
implementation of the method, after the first bisection and before each
subsequent one, all spikes in the data subset were reassigned to the
initial clusters on the basis of both waveform and timing criteria; a
spike could be assigned to a cluster only if its waveform fell within a
set distance from the cluster mean (based on a user selectable
criterion ranging from 1.5 to 2.5 SDs) and only if the spike
occurred at least 2.0 msec later than any previously assigned spike.
Similarly, both variance-based limits and interspike interval criteria
were used in the final aggregation of the initial clusters and in the
subsequent assignment of spikes to the final templates.
Data reduction. Spike occurrence times (saved at 100 µsec
resolution) and EMG data were analyzed in two ways. In the first, each
electrophysiological record, corresponding to individual behavioral
trials, was divided into sequential 100 msec epochs. For each epoch, we
summed the total number of spikes and computed the root-mean-square
value of the EMG (Basmajian and DeLuca, 1985). The second analysis used
an algorithm for detecting EMG bursts to distinguish periods of active
whisking from periods in which whisking was of low amplitude or absent
altogether. EMG signals were rectified and then smoothed by computing,
for each sample point, a mean based on the sample point and the four
points before and after it (±8 msec). The mean and variance of the
rectified, smoothed EMG was computed for the entire trial. These values
were used to establish thresholds for determining epochs during which the amplitude of the EMG signal remained within a chosen range of
values (typically between 0.5 and 5.0 SDs above the mean). Successive
EMG sample points occurring within this range were summed, and, after
examining the distribution of these sums and the corresponding EMG
traces, a criterion was chosen reflecting a minimal acceptable amount
of integrated within-burst activity. In addition to the amplitude and
size criteria, a valid burst could not begin within 25 msec of the end
of a previous one.
Spike counts were made for a 200 msec period bracketing the EMG burst,
beginning 50 msec before the EMG signal crossing the lower amplitude
threshold. Rectified, integrated EMG activity was summed over the same
time periods. Note that, because whisking occurs at frequencies of
7-10 Hz, overlap can exist between the end of one such epoch and the
beginning of the next. A "periburst time histogram" was constructed
across all bursts and trials by accumulating spikes in 2 msec bins, and
averages were made of the EMG signals. Periods without whisking were
identified as follows. The EMG record was sequentially examined to
identify 200 msec epochs during which no valid EMG burst occurred, and
this was repeated every 50 msec along the record until a burst was
encountered. The search resumed at a randomly selected data point
50-100 msec after the end of a burst. The variable starting time was
used to avoid introducing periodicities into the non-burst associated spike and/or EMG data attributable to preceding periods of
rhythmic bursting. Because of the variability in EMG signal
amplification, which we optimized but did not calibrate for each
recording session, all EMG data will be presented in arbitrary units of magnitude.
Data were analyzed to compare pre-trim and post-trim spike count and
EMG measures. For each animal, this typically involved mean data
obtained from several thousand time epochs. Within-animal comparisons
were made using t tests. Groups of animals were categorized according to recording location (thalamus and cortex) and whisker trimming [PW and adjacent whiskers (ADJ)]. Within-group comparisons of pre-trim and post-trim data were made using paired t
tests. Between-group comparisons were performed as follows. For each unit, we calculated the proportional change in unit activity as the
ratio of post-trim to pre-trim values (hereafter denoted as Post/Pre
ratios) and used t tests to compare the mean values between groups. For all statistical tests, p  0.05 (two-tailed) was used as the criterion for significance. Error measures
are presented as SDs.
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RESULTS |
General observations
Date were obtained from 21 experiments in 17 animals. Recordings
yielded 48 single units, which were studied under the following conditions of recording location and whisker trimming: cortex-PW trim
(n = 9 units in 4 experiments); cortex-ADJ trim
(n = 33 in 14 experiments); and thalamus-ADJ trim
(n = 6 units in 3 experiments). EMG recordings were
obtained for all but one (thalamic) experiment. Results are based on
the analysis of 14,410 and 16,568 sec of pre-trim and post-trim data,
respectively. Of the 42 cortical units, 20 and 17 were determined
histologically to have been recorded in layers III and IV,
respectively. Two recording sites (one unit each) were in the
infragranular layers. Three units from one experiment could not be
definitively located because of poor histology. None of the data
analyses indicated laminar-dependent differences in the obtained
results, and therefore data are pooled across layers for statistical
analyses. Differences in receptive field properties across cortical
layers might be revealed in a larger sample of units distributed more
equally throughout the cortical depths.
Figure 2 illustrates the basic
experimental paradigm and one of the main findings. In this animal,
units were recorded from the C4 cortical column during eight trials
when all whiskers were intact. Then, all of the immediately adjacent
whiskers were trimmed to within a few millimeters of the skin
surface, and the animal performed an additional eight trials. Graphs
show, on a trial-by-trial basis, the mean spike count per 100 msec
epoch of one unit (Fig. 2C) and two measures of the muscle
activity recorded in the mystacial pad (A, B).
After trimming, the unit activity increased. Trial-by-trial comparisons
indicate that spike counts are correlated with relative levels of EMG.
This suggests that, in general, as whisking increases, there is more
stimulus-evoked activity and that our methods are sensitive enough to
detect it. Average EMG values (B) during pre-trim and
post-trim trials did not differ, indicating that the increased unit
activity cannot be accounted for by changes in the overall level of
whisker muscle activity. There was no difference in the distribution of
interburst intervals for pre-trim and post-trim trials
(A), and in both cases the modal value was 100 msec.
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Figure 2.
Schematic of experimental paradigm showing spike
counts and EMG activity during pre-trim and post-trim trials. The
figurines of the face illustrate whisker nomenclature. In the
right figurine, the central solid circle
indicates C4, the PW, and the open circles indicate the
immediately adjacent whiskers, which were trimmed before obtaining
post-trim data. Graphs show mean ± SE spike counts
(C) and integrated EMG (B)
averaged over all consecutive 100 msec epochs during each trial. In
this experiment, the animal performed eight pre-trim and eight
post-trim trials. Note that the mean unit activity (indicated by the
dashed line) increased after removing the whiskers
surrounding the PW, but the overall EMG activity remained unchanged.
Time stamps show the time course of the experiment. Histograms in
A show the distribution of intervals between successive
EMG bursts.
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Figure 3 illustrates the nature of the
raw data. The bottom two traces show cortical unit and
electromyographic activity obtained during a 1 sec period when an
animal was actively whisking the screen. Comparison of the two
traces reveals an overall correspondence between the occurrence of
EMG bursts and spike discharge (Fig. 4A). The expanded
traces at the top show individual action
potentials. The spike-sorting program distinguished three units from
this experiment, representative waveforms of which are shown.
Synchronized EMG and spike data from one of these units (Fig. 3,
asterisks) is shown in Figure 4A. The
left panel shows average EMG burst traces and corresponding
periburst time histograms, and the right panel shows
activity obtained during periods without EMG bursting. A clear
correspondence between EMG bursts and unit discharge is apparent.
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Figure 3.
Representative raw data. The bottom two
traces show EMG and neural traces during a 1 sec period of
whisking. Note overall correspondence of spike discharges with EMG
bursts. Three units were isolated from the neural records; two
occurrences of each are shown in the expanded view above
the continuous neural record (note 2 msec scale). Top
traces show 100 consecutive waveforms from each unit along with
the templates (thick dark lines) to which the waveforms
were assigned. Units were recorded at the site of the lesion in the D4
barrel shown in Figure 1A.
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Figure 4.
Periburst time histograms. Each
panel shows averaged EMG activity
(traces) and corresponding unit activity accumulated in
time histograms having 2 msec bins. Data on the left are
taken from 200 msec epochs containing EMG bursts and are aligned with
respect to burst onset, which occurs at the 50th msec bin. EMG averages
(scales in arbitrary units not shown) were made from rectified signals,
and bursts were identified using threshold and magnitude criteria (see
Materials and Methods). Data on the right were obtained
during periods of screen contact without EMG bursting. Pre-trim
(black) and post-trim (light gray) data
are shown for representative units under the three experimental
conditions. Note the opposite effects on cortical and thalamic unit
activity with ADJ trimming.
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In this experiment, the PW was identified as the D4 whisker on the
basis of manual stimulation applied while the rat was awake and gently
restrained by hand. Subsequent histological reconstruction confirmed
that recordings were obtained from the D4 column at the layer III/IV
border (Fig. 1A). After obtaining baseline data (pre-trim), the PW was trimmed. As illustrated in Figure
4A, unit activity was profoundly diminished both
during periods of active whisking (measured as EMG burst) and during
screen contact without whisking (measured as the absence of EMG
bursts). The average EMG traces are virtually indistinguishable during
pre-trim and post-trim trials, suggesting that changes in the behavior
cannot readily account for the pronounced decrease in unit activity.
Representative data from the other two experimental conditions are
shown in Figure 4, B and C. Results in
B were obtained from a cortical recording during which the
eight whiskers surrounding the PW were trimmed. In contrast to removal
of the PW, removal of adjacent whiskers led to a 45% increase in unit
activity during both whisking and non-whisking epochs. In this animal,
average EMG values were actually lower during the post-trim trials.
Opposite effects of adjacent whisker removal are observed in the
thalamic unit, whose results are illustrated in C. Post-trim
neural activity was 77% lower than pre-trim activity, despite
virtually no difference in overall EMG.
An interesting aspect of the data in the left panels of
Figure 4 is the temporal relationship between (pre-trim) unit activity and EMG burst. Both cortical units displayed temporally focused activity peaks that occurred near maximal whisker protraction (as
inferred from the EMG record; Carvell et al., 1991). Based on the video
and audio records, these peaks correspond to contact of the whiskers
with the screen. The response profile for the thalamic unit (Fig.
4C) differs in two respects; relative to the peak of the EMG
burst, unit activity occurs later, and it is more temporally dispersed.
Such temporally offset peaks were not unique to thalamic units, because
they were observed also in some cortical recordings. Differences in
peak response time may be related to the directional sensitivity of the
individual units, but we were unable to assess this accurately in the
loosely restrained animal. Cortical units also varied with respect to
the temporal dispersion of their response peaks. Approximately 60%
displayed profiles similar to those in Figure 4, A and
B, with the remaining unit profiles being weakly modulated
or completely unmodulated by presumed whisker contact. Even in the
latter cases, however, the total neural activity at the chosen
recording sites was always clearly related to manual whisker
deflections. In contrast, the smaller sample of thalamic units were
less strongly modulated. In fact, the data shown in Figure
4C represent the most strongly modulated profile of the four
thalamic units for which EMG records were obtained.
Quantitative analyses
The principal issue addressed in the present experiments concerns
the immediate effects on a barrel-related column of removing adjacent
whiskers while leaving the principal whisker intact. Quantitative data
for the cortical and thalamic neurons studied using this experimental
manipulation are presented in Figure 5. A presents findings based on average spike counts obtained
in all 100 msec epochs during pre-trim and post-trim trials. With all
whiskers intact, cortical units discharged at a mean rate of 27.6 ± 21.0 Hz, which increased to 32.1 ± 23.8 Hz after adjacent whisker removal (p = 0.001; n = 33). Thalamic units fired at an average of 46.0 ± 29.9 Hz with
all whiskers present, and decreased their firing after whisker trimming
to 35.0 ± 32.4 Hz (p = 0.02; n = 6). B presents average
root-mean-square values for EMG activity in the same 100 msec
bins; the number of observations is smaller than in A
because the same EMG data were used for all units in a given
experiment. Mean pre-trim and post-trim EMG values (in arbitrary units)
are highly similar for both cortical (3.64 ± 2.05 vs 3.61 ± 2.06; n = 14) and thalamic experiments (1.51 ± 0.96 vs 1.54 + 0.96; n = 2).
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Figure 5.
Scatterplots showing effects of adjacent whisker
trimming on cortical and thalamic units. Average spike
(A) and EMG (B) activities
measured in consecutive 100 msec epochs. Spike counts are converted to
frequency; EMG is measured in arbitrary units. Spike activities
measured during 200 msec burst (C) and non-burst
(D) epochs (see Fig. 4, left and
right). Dotted lines represent a 1:1
correspondence. Note that, overall, spike activities are highest in
C (burst), lowest in D (non-burst), and
intermediate in A (undifferentiated).
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|
For the preceding analyses, data were simply compiled from consecutive
100 msec epochs without regard to the presence or absence of whisking,
as defined by EMG bursts. As shown in Figures 2 and 4, overall neural
activity is higher during periods of EMG bursting. To rule out the
possibility that observed changes in neural activity reflect the
relative incidence of EMG bursts (whisks) during pre-trim versus
post-trim trials, we parsed the data records into burst and non-burst
epochs (see Materials and Methods). Figure 5C shows data
obtained during periods of EMG bursts; values represent average firing
rates computed over a 200 msec epoch bracketing the burst. After
adjacent whisker removal, cortical units increased their activities
during both burst (30.4 ± 23.2 vs 35.4 ± 25.6;
p = 0.001; n = 33) and non-burst epochs
(23.1 ± 20.4 vs 25.9 ± 22.5; p = 0.025). In
the thalamus, EMG records were available for four units only. On
average, their activities decreased but not significantly (burst,
62.0 ± 24.2 vs 49.5 ± 30.0; p = 0.063;
non-burst, 60.6 ± 23.5 vs 50.0 ± 30.5; p = 0.124). As for the 100 msec bin analyses, there were no statistically
significant differences between pre-trim and post-trim EMG activity for
either cortical or thalamic experiments.
Data from cortical and thalamic units were compared directly using mean
ratios of post-trim to pre-trim activity. For each measure, the two
groups of units differed significantly, with cortical units displaying
mean ratios >1.0, indicative of increased activity, and thalamic units
displaying mean ratios <1.0. For the 100 msec bin data, the average
increase in cortical unit activity was 20% compared with a 37%
decrease in thalamic activity (1.20 ± 0.33 vs 0.63 ± 0.31;
p < 0.001; n = 33 and 6). Virtually
identical values were obtained for cortical activity measured during
200 msec burst (1.21 ± 0.34) and non-burst (1.17 ± 0.33)
epochs. For both measures, these values differed significantly from the
smaller set of four thalamic units for which EMG data were available
(burst, 0.72 ± 0.31; p = 0.008; non-burst,
0.74 ± 0.34; p = 0.016).
For each animal, we computed the mean interval between EMG bursts.
Values were similar for pre-trim and post-trim trials (248 ± 71 vs 242 ± 72 msec; p = .28), and Post/Pre ratios
did not differ between thalamic and cortical experiments (0.89 ± .005 vs 0.99 ± 0.18; p = 0.55). The largest
change was observed in a thalamic experiment in which the mean
interburst interval decreased from 337 to 245 msec; despite this
increase in overall whisking frequency, two of the three units recorded
at this site decreased their activities by 13 and 23%, with the other
unit displaying no change. Modal intervals, determined using frequency
histograms having 25 msec bins, averaged 112.5 msec for both pre-trim
and post-trim trials (p = 1.0). For any given
experiment, the modal interburst interval did not vary by more than one
bin before and after whisker trimming.
Data were also analyzed separately for each unit. Two-tailed Student's
t tests were used to determine whether differences existed
between pre-trim and post-trim spike counts. Data compiled from
consecutive 100 msec epochs are presented in Figure
6. Of the 33 cortical units examined
after adjacent whisker removal, 64% displayed significant increases in
unit activity (mean of 38%), 24% showed a significant decrease (mean
of 19%), and 12% were statistically unchanged. Interestingly, at one
recording site, one of the two isolated units significantly increased
its firing, whereas the other significantly decreased its firing. In
contrast, none of the thalamic units studied under these conditions increased its firing. Of the six thalamic units, five (83%)
significantly decreased their activity (mean of 45%), the remaining
unit showing no change. Units were categorized as having increased
activity or not (activity decrease or no change). A
 2 test comparing the frequency of these
categories revealed a significant difference between thalamic and
cortical units (p < 0.001). Removal of the PW
resulted in a decrease in cortical unit firing for eight of nine units
(mean of 59%). One unit showed a statistically significant increase of
20%; this unit was recorded at a site in which a second unit showed a
significant activity decrease.
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|
Figure 6.
Summary of statistical comparisons performed on
individual units. Student's t tests were used to
compare pre-trim and post-trim spike activity (100 msec epochs) for all
units in the three experimental conditions. Shown are percentages of
each population showing statistically significant changes
(p < 0.05; two-tailed).
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|
Determining the principal whisker in awake animals
Interpretation of the present results critically depends on
identification of PW versus adjacent whiskers in the awake animal, using manual stimulation and audio monitoring. For virtually all cortical recording sites, the PW was readily distinguished from its
neighbors by the clearly more vigorous responses its deflection evoked
in the overall neural activity. Histological reconstruction of the
cortical barrel field provided confirmation that the physiologically identified PW corresponded with the anatomical representation of the
whisker. The one exception in the cortical data was a recording site in
which physiological identification of the PW was ambiguous, because the
units responded equally well to a number of neighboring whiskers, one
of which we selected as the PW based on the slightly stronger response
it evoked. This site was subsequently found to be within the
interbarrel septum close to the barrel corresponding to the
physiologically identified PW. We therefore operationally classified
this experiment as a "PW trim." Removal of its neighboring whiskers
resulted in a 56% decrease in unit activity, consistent with the
strong multi-whisker nature of septal receptive fields.
In the thalamic recording experiments, physiological identification of
the PW was considerably more difficult, because the receptive fields of
the overall neural activity were consistently multi-whisker. In the
final experiment, we confirmed the physiological identification of the
PW after the recording session using controlled whisker deflections
while the rat was anesthetized with halothane. In this experiment, we
also sectioned the thalamus in an oblique horizontal plane to identify
the barreloid in which the recordings were obtained. In the awake
condition, neural activity was evoked by several whiskers in the
vicinity of C3, with the C3 and C2 whiskers evoking the most vigorous
responses. After careful testing, we designated C3 as the PW,
subsequently trimming the eight whiskers surrounding it. After the
animal was anesthetized, the receptive field at this recording site
became clearly focused on the C3 and C2 whiskers (Fig.
7B).
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Figure 7.
Data from an identified thalamic barreloid.
A, Effects of adjacent whisker trimming on two thalamic
units recorded at the lesion site in the C3 barreloid shown in Figure
1B. Note decreased activity in both cases after
trimming. B, Confirmation of C3 as the PW. After
behavioral testing, the rat was anesthetized with halothane, and
controlled whisker stimuli (Simons, 1983) were applied individually to
C3 and each of the eight surrounding whiskers. Spike counts were
obtained from the multi-unit record with the amplitude threshold set
high to discriminate the two largest units, which corresponded to the
individual units of A. The C3 whisker was trimmed to the
same length as the previously clipped adjacent whiskers.
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Figure 1, B-D, shows histology from this animal. The marker
lesion was appropriately located in the C3 barreloid. The spike-sorting program identified two discriminable units. Results of adjacent whisker
removal on their activities during the behavioral task are presented in
Figure 7A. The EMG wires had apparently become displaced
since their insertion several days previously, so that EMG data are not
available from this animal. For both units, spike counts per 100 msec
epochs decreased significantly after adjacent whisker removal.
| |
DISCUSSION |
A unique feature of the rodent somatosensory cortex is the
anatomic correspondence between barrels and whiskers. Numerous electrophysiological studies using passive whisker stimulation in
immobilized animals, with or without general anesthesia, have demonstrated a functional correspondence as well. Specifically, within
a vertical column centered on a layer IV barrel, neurons at different
cortical depths respond only or maximally to the whisker that is
anatomically appropriate to that barrel (Simons and Woolsey, 1979;
Armstrong-James and Fox, 1987). This correspondence between cortical
anatomy and function has been demonstrated previously in naturally
exploring animals using markers for metabolic activity (Durham and
Woolsey, 1978; McCasland and Woolsey, 1988). In those studies, acute
removal of selected whiskers led to reduced 2DG labeling in their
corresponding barrels. Moreover, subtle changes in the labeling pattern
across the barrel field paralleled adjacent whisker-related inhibitory
gradients observed in neurophysiological studies (McCasland et al.,
1991). The present findings extend these observations by demonstrating
that, in the behaving rat, the spike activity of neurons within the
anatomic map of the whiskers can be clearly ascribed to specific
whiskers. As expected, removal of the principal whisker leads to a
substantial decrease in unit activity in the corresponding barrel and
its associated column. Less intuitively, this manipulation leads to an
increase in unit activity in neighboring columns. We interpret this
latter finding to reflect disinhibition.
Methodological issues
Our motivations for developing the screen exploration task were
twofold. First, the task had to require the rat to use its whiskers
vigorously, providing strong self-activation of the sensory system.
Second, the task had to involve a behavior that was relatively natural,
easy to perform, and minimally stressful. These considerations were
important because activity from the same neurons were to be compared
under conditions when all whiskers were intact and again after the
immediate removal of as many as 25% of the large whiskers on the
mystacial pad. Thus, failure of an animal to perform the task after
trimming, perhaps as a result of stress caused by the absence of
whiskers, would eliminate inclusion of its data from the analyses,
despite a lengthy period of previous preparation. Moreover, whisker
removal is for practical purposes the end point of the experiment,
because several weeks are required for regrowth, a period during which
electrode tracks and marker lesions might disappear.
Previous studies from our laboratory that investigated whisking
behavior involved detailed kinematic reconstructions of video images,
made on a frame-by-frame basis (Carvell and Simons, 1990). To visualize
individual whiskers, these analyses required the animal to behave
within a physically limited field of view while focusing their whiskers
on a relatively challenging set of discriminanda. Because these types
of analyses and behaviors were poorly suited to the present
experimental goals, we opted for extensive, prolonged screen
exploration rather than high-resolution whisker imaging. The explicit
assumption is that data collection spanning multiple trials (each
lasting tens of thousands of milliseconds) would permit a reliable
estimate of unit activity that is relatively independent of
moment-to-moment variations in the extent to which the whiskers contact
the screen. In addition, we used several control measures to ensure
that trimming-induced changes in unit activity did not simply reflect
systematic changes in the behavior. First, the size of the screen was
chosen to permit adequate video resolution for identifying periods
during which the animal was exploring it, and data were analyzed only
during these epochs. Second, we directly measured muscle activity from
the mystacial pad contralateral to the unit recording location and
analyzed the unit data in three related, but different, contexts:
overall EMG activity; the presence of EMG bursts, indicative of active whisker protraction; and the presence of non-bursting low-level activity, corresponding to periods when whiskers were being passively drawn across the screen by head movement. Third, we recorded from another location in the whisker-to-barrel pathway, i.e., thalamic barreloids, and found the effects of adjacent whisker removal to be
different from those in the cortex. Ideally, unit recordings should be
obtained simultaneously from homologous barreloids and barrels in the
same animal, but we were unsuccessful in several attempts to do this.
Fourth, although the 100 msec spike count data of Figure 5 suggest that
the same qualitative results of whisker trimming would have been
observed if we had non-selectively incorporated the two or three
largest amplitude spikes in the measured neural record, the use of a
spike-sorting procedure provides additional evidence that the observed
effects of whisker removal are caused by changes in neural
responsiveness and not by changes in whisking behavior. At several
recording sites, post-trimming activity was observed to be elevated for
one unit but decreased for another.
Comparison with previous characterizations of whisker-related
receptive field organization
Previous single-unit studies of fentanyl-sedated rats (Simons and
Carvell, 1989; Brumberg et al., 1996) have revealed a number of
important differences in the receptive field properties of thalamic
barreloid and cortical barrel neurons. Relevant to the present
findings, thalamic units, as a population, display multi-whisker excitatory receptive fields with weak adjacent whisker inhibitory effects. In contrast, the largest number of recorded barrel neurons (regular-spike units) are excited mainly or exclusively by the principal whisker, which also evokes the strongest inhibition within
its parent barrel. Adjacent whiskers, deflected alone or in
combination, also evoke "cross-whisker" inhibition, but unlike the
PW, they evoke little or no excitation of regular-spike barrel units.
Because of the strongly multi-whisker nature of their receptive fields,
inhibitory ("fast-spike") units are thought to mediate cross-whisker inhibitory interactions locally, within their parent barrel (Kyriazi and Simons 1993; Pinto et al., 1996; Goldreich et al.,
1999). Stimulus-evoked inhibition disproportionately diminishes excitatory responses evoked by weakly excitatory stimuli (Brumberg et
al., 1996), as does direct microiontophoretic application of GABA
itself (Kyriazi et al., 1996). For example, deflections of the PW can
completely abolish the otherwise small excitatory responses associated
with adjacent whisker stimulation. In light of these findings, Brumberg
et al. (1996) proposed that, during active touch, simultaneous
palpation of an object by multiple neighboring vibrissae would enhance
signal contrast (e.g., "PW-ness") in barrel regular-spike neurons
by disproportionately diminishing excitatory effects of non-columnar
whiskers. Accordingly, when all whiskers are actively exploring an
object, overall activity in a cortical barrel would be reduced relative
to that evocable by deflections of whiskers singly. The activity that
remains, however, would be more focused on the PW.
Here, we indirectly assessed the contribution of neighboring whiskers
to cortical and thalamic activity by eliminating their influence.
Consistent with the 2DG results of McCasland and Woolsey (1988) in
freely exploring mice, acute removal of adjacent whiskers was
associated with increased cortical unit activity in the barrel representing the intact PW. We interpret the results of these two
studies as follows. In the absence of adjacent whiskers, the PW
provides the nearly exclusive afferent excitatory drive to neurons in
the homologous barreloid and barrel. Because the trimmed adjacent
whiskers can no longer contact the screen, they are unable to
contribute, along with the PW, to excitation in the thalamus and to
"tonic" inhibition within the cortex. This yields PW-evoked responses that are less vigorous in the thalamus and more vigorous in
the cortex, relative to when all whiskers are present. In the cortex,
the disinhibitory effect is so pronounced that, in the present
experiments, cortical neurons increased their activity an average of
20%, despite an average 37% reduction in the firing of thalamic neurons.
Implications for deprivation-induced plasticity
A commonly used paradigm for studying plasticity in the
somatosensory system involves the removal of whiskers by trimming, plucking, or follicle cauterization. When performed in normally reared
adult animals, whisker removal has been associated with an increase in
the activity evoked by the remaining whiskers (Diamond et al., 1993).
In cases in which two adjacent whiskers are left intact, increased
responses to both whiskers are observed within the same barrel after
only a few days of deprivation. This phenomenon has been attributed to
correlated neuronal activities as a result of whisker "pairing."
The present findings indicate that the effect of selected whisker
removal in an otherwise normally functioning animal is one of profound
disinhibition of neurons in neighboring cortical columns, at least in
the short term. Whether, and to what extent, such net disinhibition
persists over time remains to be determined. Nevertheless, even short
periods of disinhibition, lasting a few days, are likely to contribute
substantially to alterations in receptive field properties. Indeed,
reduction of tonic inhibition within local cortical circuits may be the
primary causative factor in the cascade of events leading to synaptic modifications. For example, NMDA-dependent long-term potentiation requires membrane depolarization. Thus, changes in receptive field properties observed when all but two whiskers are chronically removed
may be more a reflection of partial whisker-field removal ("whisker
sparing") than of whisker pairing. In neonatal animals, whisker
removal results in a variety of physiological and behavioral abnormalities that persist despite long-term regrowth of the whiskers during adulthood (Simons and Land, 1987; Akhtar and Land, 1991; Carvell
and Simons, 1996). These effects may reflect, at least in part, the
absence of normal levels of inhibition during periods when sensory
experience refines the cortical circuitry.
| |
FOOTNOTES |
Received April 29, 1999; revised July 22, 1999; accepted Aug. 3, 1999.
This work was supported by National Science Foundation Grant
IBN-9209490, National Institutes of Health Grant NS-19950, and a Viva
J. Erickson scholarship and a Patricia Leahy memorial scholarship to
M.K.K. from the American Physical Therapy Association. We thank Thomas
Prigg for expert technical assistance, William W. Simons for developing
the spike sorting software, and Peter Land and Harold Kyriazi for comments.
Correspondence should be addressed to M. Kathleen Kelly, Department of
Physical Therapy, 6035 Forbes Tower, University of Pittsburgh,
Pittsburgh, PA 15260.
| |
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4428 - 4436.
[Abstract]
[Full Text]
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D. J. Pinto, J. A. Hartings, J. C. Brumberg, and D. J. Simons
Cortical Damping: Analysis of Thalamocortical Response Transformations in Rodent Barrel Cortex
Cereb Cortex,
January 1, 2003;
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33 - 44.
[Abstract]
[Full Text]
[PDF]
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C. E. Brown and R. H. Dyck
Rapid, Experience-Dependent Changes in Levels of Synaptic Zinc in Primary Somatosensory Cortex of the Adult Mouse
J. Neurosci.,
April 1, 2002;
22(7):
2617 - 2625.
[Abstract]
[Full Text]
[PDF]
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N. Laaris and A. Keller
Functional Independence of Layer IV Barrels
J Neurophysiol,
February 1, 2002;
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1028 - 1034.
[Abstract]
[Full Text]
[PDF]
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H. Wallace, S. Glazewski, K. Liming, and K. Fox
The Role of Cortical Activity in Experience-Dependent Potentiation and Depression of Sensory Responses in Rat Barrel Cortex
J. Neurosci.,
June 1, 2001;
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3881 - 3894.
[Abstract]
[Full Text]
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G. Mirabella, S. Battiston, and M. E. Diamond
Integration of Multiple-whisker Inputs in Rat Somatosensory Cortex
Cereb Cortex,
February 1, 2001;
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164 - 170.
[Abstract]
[Full Text]
[PDF]
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A. L. Barth, M. McKenna, S. Glazewski, P. Hill, S. Impey, D. Storm, and K. Fox
Upregulation of cAMP Response Element-Mediated Gene Expression during Experience-Dependent Plasticity in Adult Neocortex
J. Neurosci.,
June 1, 2000;
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4206 - 4216.
[Abstract]
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TOP
ABSTRACT
INTRODUCTION
