1Department of Cell and Molecular Physiology, 2Department of Biomedical Engineering, and 3Dental Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
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ABSTRACT |
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Whitsel, B. L.,
O. Favorov,
K. A. Delemos,
C.-J. Lee,
M. Tommerdahl,
G. K. Essick, and
B. Nakhle.
SI neuron response variability is stimulus tuned and NMDA receptor
dependent. Skin brushing stimuli were used to evoke spike discharge activity in single skin mechanoreceptive afferents (sMRAs) and anterior parietal cortical (SI) neurons of anesthetized monkeys (Macaca fascicularis). In the initial experiments 10-50
presentations of each of 8 different stimulus velocities were delivered
to the linear skin path from which maximal spike discharge activity
could be evoked. Mean rate of spike firing evoked by each velocity
(MFR) was computed for the time period during which spike discharge activity exceeded background, and an across-presentations estimate of
mean firing rate () was generated for each velocity. The magnitude of the trial-by-trial variation in the response (estimated as
CV; where CV = standard deviation in MFR/
) was
determined for each unit at each velocity.
for both
sMRAs and SI neurons (
sMRA and
SI, respectively) increased monotonically
with velocity over the range 1-100 cm/s. At all velocities the average estimate of intertrial response variation for SI neurons
(
SI) was substantially larger than the
corresponding average for sMRAs (
sMRA).
Whereas
sMRA increased monotonically over the
range 1-100 cm/s,
SI decreased progressively
with velocity over the range 1-10 cm/s, and then increased with
velocity over the range 10-100 cm/s. The position of the skin brushing
stimulus in the receptive field (RF) was varied in the second series of
experiments. It was found that the magnitude of CVSI varied
systematically with stimulus position in the RF: that is,
CVSI was lowest for a particular velocity and direction of
stimulus motion when the skin brushing stimulus traversed the RF
center, and CVSI increased progressively as the distance
between the stimulus path and the RF center increased. In the third
series of experiments, either phencylidine (PCP; 100-500 µg/kg) or
ketamine (KET; 0.5-7.5 mg/kg) was administered intravenously (iv) to
assess the effect of block of
N-methyl-D-aspartate (NMDA) receptors on SI
neuron intertrial response variation. The effects of PCP on both
CVSI and
SI were transient,
typically with full recovery occurring in 1-2 h after drug injection.
The effects of KET on CVSI and
SI were similar to those of PCP, but were
shorter in duration (15-30 min). PCP and KET administration
consistently was accompanied by a reduction of CVSI. The
magnitude of the reduction of CVSI by PCP or KET was
associated with the magnitude of CVSI before drug
administration: that is, the larger the predrug CVSI, the
larger the reduction in CVSI caused by PCP or KET. PCP and
KET exerted variable effects on SI neuron mean firing rate that could
differ greatly from one neuron to the next. The results are interpreted
to indicate that SI neuron intertrial response variation is
1) stimulus tuned (intertrial response variation is lowest
when the skin stimulus moves at 10 cm/s and traverses the
neuron's RF center) and 2) NMDA receptor dependent
(intertrial response variation is least when NMDA receptor activity
contributes minimally to the response, and increases as the
contribution of NMDA receptors to the response increases).
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INTRODUCTION |
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The magnitude of the anterior parietal cortical (SI) response to a
mechanical skin stimulus undergoes prominent fluctuations from one
stimulus presentation to the next. Trial-by-trial fluctuations of the
SI response to the same stimulus (intertrial response variation) are
obvious regardless of the recording method employed; that is, the SI
neuron population response recorded with a large surface electrode, the
action potential train of a single SI neuron recorded with a
microelectrode from an extracellular location, and the change in
transmembrane potential change recorded intracellularly from a
neuron's dendrite or soma all exhibit substantial
trial-by-trial variability despite extensive precautions to ensure
constancy of stimulus and experimental conditions. A large
trial-by-trial variability is not unique to the stimulus-evoked
response of SI cortex or of individual SI neurons. For example,
prominent trial-by-trial variation of the response of both single
neurons and neuron populations of other primary sensory cortical
regions has been described (for recent descriptions of the large
variability in the visual cortical response see Arieli et al.
1996; Azouz and Gray 1999
; deRuyter et
al. 1997
; Ferster 1996
; Shadlen and
Newsome 1994
, 1995
, 1998
; for
divergent view see Gur et al. 1997
).
The fact that the trial-by-trial fluctuations in the mean firing rate
response of a single SI neuron to a repeated, identical mechanical skin
stimulus typically are 10-30 times larger than the variations in the
response of a skin mechanoreceptive afferent fiber (sMRA) studied in
the same way (Essick and Edin 1995; Lee and
Whitsel 1992
; Whitsel et al. 1993
,
1977
; Young et al. 1978
) suggests that
CNS mechanisms account for the largest fraction of the response
variation observed at the level of SI cortex. Unfortunately, little or
no detailed information is available concerning the mechanisms that, on
a trial-by-trial basis, could modify the efficacy of transmission of
stimulus-evoked neuroelectrical activity over the projection pathways
that link sMRAs and SI neurons. The dearth of information about the CNS
mechanisms responsible for the large variability of the SI response to
repetitive sensory stimulus was the major impetus for this study.
Previous studies of information processing by SI cortex have assumed
that 1) randomness in the processes that underlie
synaptic transmission at each level of the sMRA-to-SI projection path, and in the processes that generate the spike train responses of individual sMRAs underlies the prominent trial-by-trial fluctuations in
both the SI cortical responses and perceptual experiences evoked by
sensory stimuli; 2) the magnitude of the trial-by-trial
fluctuations in signal transmission over the sMRA-to-SI neuron
projection path does not change systematically or substantially with
changing stimulus conditions; and 3) the sources that
contribute to sMRA and CNS somatosensory neuron response variation act
collectively to impose a fixed upper limit on the capacity of SI cortex
to detect and respond differentially to somatic stimuli. To the
contrary, the observations obtained in this study suggest that the CNS
mechanisms that determine SI neuron response variation are not
invariant, but operate dynamically to minimize response variation over
the same range of conditions of skin brushing stimulation optimal for
human tactile motion perceptual discrimination (Essick
1997; Essick and Whitsel 1985a
,b
; Whitsel
et al. 1972
).
Some of the findings were communicated previously (Prince et al.
1994; Whitsel et al. 1993
).
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METHODS |
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Skin brushing stimuli
A computer-controlled DC torque motor (Cantek) was used to deliver skin brushing stimuli. The skin path contacted by the brush was defined by a rectangular opening in an aperture plate in stationary contact with the skin. This stimulator permits the delivery of brushing stimuli at velocities between 0.1 and 250 cm/s with a high degree of accuracy (±1% for velocities between 1 and 100 cm/s). Software allows a number of parameters of brushing stimulation to be specified from a computer keyboard: velocity, direction, interstimulus interval (ISI), and number of stimulus presentations in a "run." Other stimulus parameters (orientation, location within the RF, traverse length, traverse width, force) are determined by adjusting the position of the stimulator (orientation and location within the RF), by using an aperture plate with an opening with the desired dimensions (traverse length and width), and by using a brush with the desired stiffness (force). In the experiments of this study, these "other" parameters of skin brushing stimulation were adjusted to optimize the response of each SI neuron and sMRA studied. The range of traverse lengths used was 2.0-8.5 cm; traverse width was either 0.5 or 1.0 cm. No stimulus exerted a force on the skin >10 g.
Neurophysiological recording
SI NEURON RECORDING.
Macaca fascicularis monkeys of either sex were studied.
Under deep general anesthesia (1-4% halothane in oxygen) and after intramuscular injection of a glucocorticoid (SoluMedrol, 5-10 mg),
a 2-cm diameter circular opening was made in the skull overlying SI
cortex and a recording chamber installed over the opening with dental
acrylic. A catheter was inserted in a hindlimb vein to allow
intravenous (iv) administration of drugs and maintenance solutions
(0.9% NaCl and 5% dextrose). All surgical sites were infiltrated and
topically dressed with long-lasting local anesthetic and closed with
sutures. After the surgical procedures had been completed,
neuromuscular block was achieved by administration of vecuronium
bromide (Norcuron, 0.1 mg/kg iv loading dose, 1 µg · kg1 · min
1 thereafter), positive pressure
respiration was provided, and end-tidal CO2 was maintained
between 3.0 and 4.5% by adjustments of respirator rate and volume.
sMRA RECORDING.
Records of the spike trains evoked in large-diameter sMRAs by skin
brushing stimuli were available as part of a database of single and
multineuron recordings obtained in previous experiments. This database
was the source of all the sMRA data to be presented in this paper.
Because the methods used to record stimulus-evoked spike discharge from
individual sMRAs were described previously (Lee and Whitsel
1992; Whitsel et al. 1972
; Young et al.
1978
), they will be described only briefly.
General procedures
Subjects were killed by administration of PB (40 mg/kg iv),
followed by intracardial infusion of 0.9% saline and, in turn, by 10%
neutral buffered Formalin. After intracardial infusion, the cortical
region traversed by microelectrode penetrations was removed, blocked,
and postfixed before histological processing. Each cortical block was
infiltrated with 30% sucrose and sectioned in the sagittal plane at 30 µm. Sections were stained with cresyl fast violet, mounted on glass
slides, and coverslipped. The sections were scanned microscopically to
identify 1) the tracks created by the recording
microelectrodes and 2) the locations of electrolytic lesions
created by passing DC current through the recording microelectrode. The
cytoarchitectonic areas from which single-unit recording were obtained
were identified using the criteria of Powell and Mountcastle (1959) for differentiation of areas 3b, 1, and 2, and
Jones and Porter (1980)
for identification of area 3a.
All recordings were obtained from layers III-V of areas 3b and 1.
Neural spike train data processing and analysis
Raster plots of spike trains and peristimulus (PST) histogram plots were generated from the data obtained from each unit. The index of stimulus-evoked, single-trial response magnitude used for both SI neurons and sMRAs was the average frequency of neural spike discharge (overall mean firing rate, MFR) during the entire period over which the response exceeded the background level of spike discharge activity. For most sMRAs and SI neurons, and at most stimulus velocities, this period corresponded closely to the time during which the brush was in contact with the RF. At the highest stimulus velocities, however, it was not unusual for the stimulus-evoked response to continue for a time after the brushing stimulus had broken contact with the skin. When the times of initial and final brush contact with the skin did not match the period during which a unit's response was elevated (never observed at velocities <50 cm/s), the response period was considered to start at the point at which discharge activity first exceeded background (background was defined as the average level of discharge activity present before stimulus delivery), and to continue until spike discharge activity first returned to background. Background firing rate ("spontaneous activity") was not subtracted from the mean firing rate during stimulation.
Magnitude of intertrial variability of the stimulus-evoked response of
an sMRA or SI neuron was estimated by the coefficient of variation in
MFR (CV), computed as
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(1) |
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(2) |
Stimulus protocol and sample size
The same protocol (the "standard protocol") was used to obtain data from each sMRA (n = 25) and SI neuron (n = 25) studied in the initial series of experiments. This protocol delivered eight different velocities of brushing stimuli (1, 2.5, 5, 10, 25, 50, 75, and 100 cm/s) to the path in the RF from which the most vigorous spike discharge activity could be evoked (the optimal skin path). The other characteristics of the standard protocol were as follows: each of the two available (opposing) directions of motion was delivered at every velocity; 10-50 presentations of each velocity were applied in each direction; order of brushing stimulus presentation was randomized for velocity and direction of motion; and ISI was 3.5-5 s.
The 25 sMRAs studied included 13 slowly adapting (SA) afferents, 10 rapidly adapting (RA, hair) afferents, and 2 Pacinian (PC) afferents;
all had an RF on hindlimb hairy skin. This representation of the
different classes of sMRAs in the sample population does not differ
substantially from the proportions of large-diameter cutaneous
mechanoreceptive afferent types found within nerves that innervate
hairy skin in human subjects (Vallbo et al. 1995). To
ensure that the standard protocol was completed in 45-60 min, each
stimulus velocity <10 cm/s was presented 10 times, each velocity between 10 and 25 cm/s was repeated 25 times, and each velocity above
25 cm/s was delivered 50 times. The higher velocity stimuli were
delivered a larger number of times to compensate for the progressive
decrease in the reliability of estimates of unit response magnitude
with increasing velocity of skin brushing stimulation; because the
duration of a brushing stimulus decreases with increasing velocity,
neuron response duration also decreases, and this, in turn, decreases
the reliability of the measure of the stimulus-evoked response that is
obtained on each stimulus trial. For technical reasons (e.g., early
termination of the protocol due to loss of unit isolation, or to
stimulator/controller malfunction) an incomplete set of observations
was obtained from 11 of the 25 SI neurons and from 3 of the 25 sMRAs
studied using the standard protocol.
A less time-consuming protocol (the "reduced protocol") was used to study the effects on SI neurons 1) of place of brushing stimulation in the RF (9 neurons: the series 2 experiments), and 2) of centrally acting drugs (38 neurons: the series 3 experiments). The reduced protocol also was used to determine whether changes in SI neuron RF properties accompanied the trial-by-trial fluctuations in the mean firing rate response to repeated applications of the same brushing stimulus (10 neurons were studied to evaluate the relationship between intertrial response variation and RF properties; these neurons were among those studied in the 2nd and 3rd series of experiments).
Drug dosage and route of administration
It was anticipated that the doses of ketamine (KET; 0.5-7.5
mg/kg) and phencylidine (PCP; 100-500 µg/kg) that were used would achieve CNS concentrations that would block ~50% of cortical
N-methyl-D-aspartate (NMDA) receptors (for
recent reviews of noncompetitive NMDA receptor antagonists, see
Iversen and Kemp 1994; Iversen et al.
1989
; Lodge et al. 1994
). This estimate
of drug effectiveness is based on 1) the concentrations in
the cerebrospinal fluid and the cortical extracellular compartment
achieved at these doses, and 2) on the ability of PCP and
KET to antagonize [3H]MK-801 binding in the rat cortical
slice (Wong et al. 1986
). At these doses, PCP
and KET do not cause either synchrony in cortical neuron
"spontaneous" activity or regular oscillations in single neuron
response to sensory drive; these outcomes are encountered routinely
with higher doses and would prevent meaningful evaluation of intertrial
response variation.
Approaches for localized drug delivery (microiontophoresis, pressure injections) were not employed because it was felt that such methods could not effectively or reliably eliminate NMDA receptor-mediated influences that undoubtedly 1) arise at multiple sites in somatosensory cortex and 2) are conveyed to different compartments of the target neurons via multiple, indirect, and spatially distributed routes. A second reason for systemic (intravenous) administration of the drugs was that this approach, unlike the approaches for applying drugs directly to the neurons under study, permits an effective drug concentration to be maintained in the cortical network over the lengthy time period needed to characterize the response of an SI neuron to repetitive skin brushing after drug administration. However, one should be aware that intravenous administration has the considerable disadvantage that one cannot be certain of the site(s) of drug action responsible for any effect(s) the drug might have on SI neuron response.
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RESULTS |
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Effects of stimulus velocity on sMRAS and SI neurons
The raster plots of Fig. 1 show
spike trains recorded from an sMRA (top panel) and SI neuron
(bottom panel) during the delivery of four velocities (5, 25, 50, and 100 cm/s) of a skin brushing stimulus that, on every trial,
moved in the same direction across the same skin path. The first 10 responses of each unit to each velocity are illustrated. It should be
evident that, for both units, each increase in stimulus velocity was
accompanied by an increase in mean rate of spike firing
(), and by a decrease in the number of stimulus-evoked
spikes. Similar effects of increasing velocity were obtained from all
25 sMRAs studied with the standard protocol, and from 25 of the 29 SI
neurons studied in the same way.
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For each sMRA and SI neuron studied with the standard protocol, the
eight across-trial estimates of obtained (1 estimate for each stimulus velocity) were plotted to yield a "velocity versus
plot" (Fig. 2).
Twenty-two sMRAs were studied using opposite directions of motion; thus
each of these 22 sMRAs yielded 2 velocity versus
plots
(1 for each direction; accounting for 44 of the 47 superimposed plots
in bottom left panel in Fig. 2). For three sMRAs, only the
responses to brushing stimuli delivered in one direction of motion were
obtained.
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Figure 2, bottom left panel, reveals that the higher the
velocity of brushing stimulation, the larger was the of
an sMRA. The effect of an increase in velocity on
was
highly consistent: in 136 of the 143 instances in which the responses
of the same sMRA to neighboring velocities were compared (in excess of
96% of the comparisons), the
elicited by the nearest
higher velocity exceeded the
associated with the lower
velocity. The plot in the bottom right panel of Fig. 2 shows
the "pooled" (across unit) velocity versus
relationship generated from the sMRA data.
Velocity of skin brushing also influenced SI neuron mean firing rate in
a way that was relatively consistent from one SI neuron to the next.
The 39 velocity versus plots obtained from SI neurons
are shown in the top left panel of Fig. 2, and the pooled relationship generated from the data obtained from all 25 SI neurons is
shown at the top right. Fourteen of the 25 SI neurons were studied using both (opposite) directions of motion applied to the same
skin path (accounting for 28 of the 39 plots in the top left
panel of Fig. 2); data from the remaining 11 neurons were obtained
using only one direction of motion. In >98% of the instances in which
the responses of the same neuron to neighboring stimulus velocities
were compared (in 156 of 163 instances), the nearest higher-velocity
stimulus was associated with a larger
.
Comparison of SI neuron and sMRA response variation
Although inspection of the spike train raster plots obtained from
each unit (e.g., such as those in Fig. 1) strongly suggested that the
magnitude of intertrial response variation of an SI neuron studied at a
given velocity exceeded that of an sMRA studied at the same velocity,
we sought to ascertain whether this impression could be confirmed
objectively. To this end, the across-unit average CV in the response of
both sMRAs and SI neurons (sMRA and
SI, respectively) to each stimulus velocity
was determined. The plots in Fig. 3 make
it evident that at every velocity
sMRA is
lower than
SI; and statistical evaluation of
the data from which Fig. 3 was generated revealed that at every
velocity the difference between
sMRA and
SI is statistically significant
(P < 0.001; paired t-test).
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Figure 3 also reveals a second major difference between the across-unit
intertrial response variation of sMRAs and SI neurons: sMRA increases monotonically over the entire
velocity range studied (1-100 cm/s), whereas
SI changes nonmonotonically with velocity.
More specifically, unlike
sMRA,
SI decreases with velocity over the range
1-10 cm/s, but then increases with velocity over the range 10-100
cm/s. Linear regression analysis showed that the slope value of each
limb of the
versus velocity relationship for SI neurons
is statistically significant (P < 0.01), as is the
slope value of the entire relationship for sMRAs (P < 0.01). Furthermore, the velocity dependency of
exhibited
by RA, SA, and PC afferents (Fig. 4) is
virtually the same; the slope values of the linear regression equations
determined for the data obtained from RA, SA, and PC fibers were not
statistically different from one another.
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The prominent tendency (see Fig. 3) for both
sMRA and
SI to
increase with velocity over the range 10-100 cm/s is undoubtedly due
to the decrease in stimulus duration and, more directly, to the
decrease in the duration of the stimulus-evoked response that accompanies an increase in stimulus velocity. In other words, when
stimulus velocity increases, the period of time available for sampling
the stimulus-evoked spike train decreases, and this, in turn, decreases
the reliability of each single-trial estimate of MFR. Similarly,
because an increase in stimulus velocity within the range 1-10 cm/s
also is accompanied (for the same reason indicated above) by a decrease
in the reliability in the estimation of MFR, one expects to find that
for both sMRAs and SI neurons also will increase with
velocity over the range 1-10 cm/s. Figure 3 shows that this
expectation was not realized; the slope of the
versus
velocity relationship for SI neurons between 1 and 10 cm/s is decidedly
negative; moreover, this outcome is unlikely due to noise in the data
because the negative slope value of this initial limb of the
relationship is statistically significant from zero (P < 0.01).
Our suggestion is, therefore, that the negatively sloping part of the
versus velocity relationship for SI neurons (the part
between 1 and 10 cm/s) reflects a process that obscures the tendency
for the error in estimating unit MFR to increase as stimulus velocity
is increased. The functional importance of this observation is that it
suggests a process located within the CNS. A non-CNS explanation for
the negatively sloping initial limb of the
versus
velocity relationship for SI neurons appears very unlikely because
sMRA increases monotonically over the entire
1- to 100-cm/s range of stimulus velocities; this is the expected form
of the relationship if the dominant contributor to response variation is the period of time over which the single trial estimates of MFR were obtained.
Although comparison of the pooled estimates of SI neuron and of sMRA trial-by-trial response variation (Figs. 3 and 4) was valuable because it demonstrated that the velocity dependency of the two type of units is different, combination of the data obtained from different units obscures an impressive, and potentially functionally important heterogeneity of the observations collected from individual SI neurons. This heterogeneity is made apparent by the differences between the velocity versus CV plots (each plot shows the data obtained from a different SI neuron) illustrated in Fig. 5. For example, for some SI neurons the magnitude of CV approximated the low variability characteristic of sMRAs over a relatively wide band of velocities (typically, between 1 and 25 cm/s; see right panels in Fig. 5). In contrast, for other SI neurons (left panels in Fig. 5) the magnitude of CV equaled or approached that of sMRAs only over a very narrow band of velocities. In fact, for some SI neurons of the latter type, the magnitude of CV approached that characteristic of sMRAs at only a single velocity. In striking contrast to the considerable neuron-to-neuron diversity in the velocity dependency of SI neuron response variation, the form of the velocity versus CV relationship for sMRAs studied using the same stimulus conditions was highly stereotyped: i.e., for all sMRAs studied in this way CV increased monotonically and relatively gradually over the velocity range 1-100 cm/s.
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To what extent is SI neuron response variation influenced by direction of motion and stimulus position within the RF?
The finding that the responses of SI neurons to stimulus velocities in the vicinity of 10 cm/s exhibited sMRA-like (low) trial-by-trial response variation led us to ask whether other parameters of skin brushing stimulation (e.g., direction of motion or position in the RF) might also influence the magnitude of SI neuron response variation.
DIRECTION OF STIMULUS MOTION.
The data shown in Fig. 6 were obtained
from four different SI neurons studied by applying opposing directions
of motion to the optimal path in the RF. It should be noted that for
each of these neurons the magnitude of the difference in the
responses to opposing directions of motion applied at
the same velocity is different (the difference in the responses to
opposing directions of same-velocity stimulus motion is least for the
SI neuron that provided the data in the bottom right panel
of Fig. 6, is greatest for the neuron that provided the data in the
top left panel, and is intermediate for the 2 neurons whose
data are shown in the top right and bottom left
panels). Although inspection of data in Fig. 6 reveals that there
is a tendency for the CV associated with a given velocity to be lowest
for the direction of motion that led to the highest mean firing rate
response at that same velocity (this is particularly evident in the
data for the directional selective neurons at the top left, top
right, and bottom left of Fig. 6), it also is evident
that the extent to which a neuron responded differentially to stimulus
direction did not cause fundamental modification of the way in which
velocity influenced the magnitude of intertrial response variation.
That is, the general form of the velocity-CV relationship of each
neuron shown in Fig. 6 remains the same when the response is evoked by
opposite directions of stimulus motion across the RF, even in those
instances when the opposing directions evoked very different MFRs.
Moreover, it should be noted that the tendency for CV to be lower for
the direction of motion that led to the highest mean firing rate was
least evident at velocities in the vicinity of 10 cm/s; that is, for
most neurons minimal or near-minimal CV values were obtained at
velocities in the vicinity of 10 cm/s, regardless of the direction of
motion applied to the optimal skin path. Results similar to those shown in Fig. 6 were obtained for all SI neurons studied with the complete standard protocol (n = 14; 6 were directionally
selective).
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POSITION OF THE STIMULUS IN THE RF. The influence of position of the brushing stimulus in the RF was investigated by delivering a repetitive stimulus to the optimal path in the RF, and also to one or more linear paths that paralleled, but did not overlap the optimal path. A different protocol (the reduced protocol) was used in such experiments to minimize the time required to estimate the magnitude of the response variation associated with the neuron's response to stimulation at each RF position. Specifically, the reduced protocol applied 10-25 presentations at a single, preselected velocity of brushing motion (usually between 5 and 25 cm/s) to each path in the RF in each of the opposing directions of motion; ISI was 3.5-5 s. Use of this protocol yielded an estimate of CV for each combination of stimulus path and direction of motion studied. Information about the effects of stimulus position in the RF on CV was obtained from nine SI neurons.
Results obtained from an SI neuron studied by applying the stimulus at different positions in the RF are shown in Fig. 7. The RF of this neuron was on the hairy skin of the lateral, posterior, and medial surfaces of the contralateral calf, with the optimal skin path (the region yielding the highest mean rate firing response) occupying a central position on the medial calf (M. Cen.). A total of five nonoverlapping parallel linear paths (indicated by arrows on the figurine at the top left of Fig. 7) were studied. Twenty-five presentations of each of the opposing directions of motion were delivered to each path; stimulus velocity was always 12.5 cm/s.
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Meaning of SI neuron response fluctuations
We next sought to evaluate the possibility that trial-by-trial changes in the magnitude of the response of an SI neuron to the same brushing stimulus might reflect trial-by-trial changes in the distribution of sensitivity within the skin region contacted by the stimulus. The approach used to investigate this possibility is illustrated in Fig. 8. Figure 8A shows the MFR response of an SI neuron to each presentation of a brushing stimulus (49 stimuli were delivered) that moved at 20 cm/s from proximal-to-distal across the dorsal hairy skin of digits 3 and 4 of the contralateral hindlimb. The scatter of the points along the y-axis in the plot in Fig. 8A indicates the prominent trial-by-trial fluctuations in the MFR response of this neuron (the MFR on this neuron fluctuated between 7 and 70 spikes/s).
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The approach used to ascertain whether, and to what extent, the
response fluctuations of the neuron illustrated in Fig. 8 corresponded
to changes in the distribution of sensitivity within the RF consisted
of the three following steps: 1) the individual responses
were partitioned into three nonoverlapping groups based on magnitude
(see plots at top right; group I includes the largest responses, group III the smallest responses, and the group II responses
are intermediate), 2) a PST histogram (binwidth in cm) was
generated for the trials in each response group, and the histograms for
the different response groups were superimposed to facilitate their
comparison (the histogram for the group II responses is superimposed on
the histogram for the group I responses in C; D
superimposes the histograms for the group III and group I responses), and 3) a ratio plot (Duncan et al. 1982;
Lee and Whitsel 1992
) was computed for each pair of PST
histograms (see Fig. 8, E and F; a value <1.0 in
a ratio plot indicates that at this skin site the unit's sensitivity
to the brushing stimulus was less than it was when the unit's response
magnitude fell within group I, the highest response group; and
conversely, a value >1.0 indicates that at this site the unit's
sensitivity was greater than it was when the unit's response fell
within group I).
Inspection of the superimposed histograms (shown in the
middle) and ratio plots (shown at the bottom) of
Fig. 8 reveals that the fluctuations in SI neuron response magnitude
were accompanied by substantial and regionally selective changes in the
distribution of sensitivity within the RF. That is, when the response
of the neuron to the skin brushing stimulus did not attain that of
group I, it was not due to a uniform loss of sensitivity at all points within the stimulated skin path, but instead, to a selective loss of
sensitivity at skin points outside the RF center (the RF centerthe skin area exhibiting the maximal response to the brushing stimulus
is designated by the asterisks located above the PST histograms and ratio
plots of Fig. 8). It also should be noted that the sensitivity of the
RF center of the neuron remained essentially undiminished even during
those trials when response magnitude was lowest. Similar findings were
obtained from all SI neurons evaluated using the same approach
(n = 10).
CNS mechanism(s) involving NMDA receptors contribute to SI neuron ITV
The reduced protocol also was used to study the effects on SI neuron trial-by-trial response variation of drugs known to selectively interact with one or another of the multiple classes of receptors that mediate the excitatory actions of synaptically released glutamate. All SI neurons studied for the purpose of evaluating the effects of drug administration (a total of 38 SI neurons) used either of two versions of the reduced protocol: 1) a single velocity of skin brushing stimulation was delivered in both of the available directions of motion (opposing) to the optimal skin path, or 2) a limited number of stimulus velocities (2-4) were applied in opposing directions to the optimal path.
Twenty-six SI neurons were studied both before and at multiple times
after intravenous administration of 100-500 µg/kg of PCP (a
selective noncompetitive antagonist of NMDA receptors) (Iversen
et al. 1989; Lodge et al. 1989). Another 12 neurons were studied before and at multiple times after intravenous
injection of 0.5-7.5 mg/kg of KET (another selective noncompetitive
antagonist of NMDA receptors). Finally, 12 neurons were studied both
before and after intravenous administration of 7-15 mg/kg PB (a
barbiturate anesthetic that exerts actions via different mechanisms
other than NMDA receptor antagonism, including potentiation of the
actions of GABA at GABAA receptors). Whenever possible, a
neuron was studied repeatedly (at selected time points after PCP or KET
administration; usually no less frequently than once every 10 min)
until response magnitude and intertrial variability had recovered to
the levels observed before drug administration (typically 1-1.5 h for
PCP, and 20-30 min for KET; no unit was studied long enough for
recovery from PB). For each neuron studied in this way an estimate of
across-trial mean firing rate (
) and intertrial
variability (CV) was obtained at each time point by repetition of the
exactly the same protocol.
Two representative examples of "raw" spike train data that show
clear effects of intravenous PCP on the SI neuron trial-by-trial response variation associated with repetitive brushing of the optimal
path in the RF are provided in Figs. 9
and 10. Note that, although the effect
of PCP on the CV of both neurons is the same (the CV of both neurons is
decreased after PCP), the effect on MFR is very different from one
neuron to the next. Summarized briefly, for the SI neuron in Fig. 9, CV
decreased and increased following PCP; whereas for the
neuron in Fig. 10 both CV and
decreased after PCP
administration.
|
|
Data completely consistent with those shown in Figs. 9 and 10 were
obtained from three SI neurons (each studied in different subject;
using the reduced protocol) in which PCP was not applied systemically,
but was applied topically to the cortical surface (in these experiments
a concentration of 5 × 106 M in the cerebrospinal
fluid that bathed the cortical surface was achieved by
microinjection of PCP into the recording chamber). In all three neurons
studied in this way, topical PCP application reduced the trial-by-trial
variation in the response to repetitive skin brushing and increased
. Similar effects of PCP on the SI neuron response
variation associated with a quite different mode of skin stimulation
(sinusoidal vertical skin displacement) also were obtained and will be
reported in a subsequent paper. The results obtained using topical PCP
application are viewed as consistent with the idea that the alterations
of SI neuron CV and observed after intravenous administration of PCP or
KET are mainly attributable to actions on somatosensory cortex,
although the possibility that drug actions at subcortical sites
contributed to those alterations cannot be ruled out.
The data obtained from the 38 SI neurons studied with intravenous PCP
and/or KET were used to construct the plots shown in the top
left and top middle panels of Fig.
11. These plots show the relationship
between magnitude of CV associated with the predrug response to the
repetitive brushing stimulus (CVpre; on the
x-axis) and the difference (on the y-axis)
between the pre- (CVpre) and postdrug (CVpost)
CV values obtained at the time the drug effect was maximal (30-60 min
after injection for PCP; 5-10 min after injection for KET).
Statistical evaluation (using linear regression analysis; see Fig. 11
legend) of the data points in the top left and middle
panels of Fig. 11 revealed that 1) the magnitude of the
reduction in SI neuron CV that followed either PCP or KET (estimated by
CVpost CVpre) is highly associated
(P < 0.001) with the magnitude of CV measured before
drug administration (that is, the higher the value of
CVpre, the larger the reduction in CV that accompanied NMDA
receptor block by PCP or KET); and 2) the effect of PCP or
KET on SI neuron CV was independent (P > 0.5) of the
effect on (Fig. 11, left and middle panels at
bottom).
|
In contrast, the effects of intravenous administration of PB on SI
neuron CV (top right panel in Fig. 11; determined for
another 12 SI neurons) and (bottom right
panel in Fig. 11) differ fundamentally from those of PCP or KET
(compare panels in right column with left and
middle columns of Fig. 11), whereas PCP and KET consistently decreased CV whenever SI neuron CV was high before drug administration, and had variable effects on
that were independent of
the effect on CV, PB administration consistently increased CV and
decreased
. The maximal effects of PB occurred within
5-20 min of the injection and, contrary to those of PCP and KET,
remained evident until data collection was terminated (in some cases as
long as 2-3 h after injection).
The high degree of similarity between the effects of PCP and KET on CV
and MFR, and the striking differences between the effects of PB and
those of PCP and KET on CV and MFR evident in Fig. 11 are viewed as
consistent with the idea that PCP and KET influence a common CNS
mechanism (NMDA receptors), whereas PB acts via other, entirely
different mechanisms. Linear regression analysis revealed that the
magnitude of intertrial response variation obtained before drug
administration (CVPRE) and the difference in mean firing rates obtained before and after PCP or KET administration
(MFRPRE MFRPOST) were unrelated (Fig.
12).
|
SI neuron discriminative capacity and intertrial response variability
It is infrequently acknowledged that for many SI neurons
directional discriminative capacity is greatest at stimulus conditions that do not elicit maximal mean firing rates (Essick and Whitsel 1985a,b
). An example of such a neuron is shown in Fig.
13. This SI neuron's response to
opposing directions of skin brushing stimulation to a path on the
contralateral forearm skin was recorded at five different velocities of
motion (1, 2.5, 5, 10, and 25 cm/s). Figure 13A, top plot
(solid line), reveals that, although the across-trial mean firing
rate (
) versus velocity plots (dotted lines) for the P
D and D
P stimuli diverge progressively with increasing velocity, this neuron's capacity to discriminate between the opposing directions of motion (as estimated by
'e) does not
increase progressively as velocity is increased; that is,
'e is maximal at 5 cm/s and declines at both lower and
higher velocities. The plots in Fig. 13B demonstrate the
high negative correlation between the magnitude of the
"velocity-tuned" directional sensitivity of this SI neuron and
magnitude of intertrial response variation (estimated by CV); i.e., at
the velocity (5 cm/s) at which directional sensitivity is maximal,
intertrial response variation is minimal, and directional sensitivity
declines and magnitude of intertrial response variation increases as
velocity is shifted away from the 5-cm/s optimal velocity.
|
In summary, Fig. 13 reveals that it is the velocity dependency of
intertrial response variation, not the differences in the mean firing rates evoked by the opposing directions of motion, which
makes the major contribution to the velocity dependency of this SI
neuron's directional sensitivity. Unlike other measures of SI neuron
directional sensitivity (e.g., the absolute difference between the
firing rates evoked by opposing directions of motion) that do not take
intertrial response variation into consideration, the 'e
measure correlates closely with measures of cutaneous directional
sensitivity obtained in human psychophysical studies (Essick and
Whitsel 1985a
,b
).
Effects of NMDA receptor block on SI neuron discriminative capacity
Figure 14 shows the effects of
NMDA receptor block produced by PCP (500 µg/kg iv) on a directionally
selective SI neuron studied in the same way as the neuron shown in Fig.
13. Figure 13, A and B, shows the average mean
firing rates (s) evoked by stimuli applied in the
preferred (P;
) and nonpreferred (NP;
) directions of motion at
four different velocities (7.5, 12, 15, and 24 cm/s) before
("control" observations; A) and after injection of 500 µg/kg iv PCP (B). Figure 13, C and
D, shows the average ITV (
;
) exhibited by
the responses obtained in each direction of motion at each velocity, as
well as the pronounced velocity dependency of this SI neuron's
directional sensitivity (
'e;
).
|
Before drug administration the SI neuron that yielded the data shown in
Fig. 14 signaled direction of motion most unambiguously at 15 cm/s
(C, ), but less unambigously at the lower velocities and
also at the highest velocity, due to the higher levels of response
variation associated with those velocities (
,
).
Comparison of Fig. 14, B and D (the postdrug
observations) with A and C (the predrug
observations) reveals that, for this SI neuron, PCP administration led
to a substantial modification of the velocity dependency of both
and
'e. It also is evident that after PCP
the optimal velocity (the velocity at which directional sensitivity was
maximal) shifted to the highest velocity used (24 cm/s); an outcome
attributable principally to the reduction of the intertrial response
variation that followed PCP administration, because at both 15 and 24 cm/s the difference in the magnitude of the postdrug
s
evoked by opposing directions of motion is less than it was before drug administration.
The effects of PCP-induced NMDA receptor block on yet another
directionally selective SI neuron are shown in Fig.
15. In contrast to the neuron
illustrated in Fig. 14, this neuron's mean firing rate was increased
after PCP administration (300 µg/kg iv; the MFRs observed before PCP
administration and at a series of postinjection times are shown in Fig.
15, A and B). As was the case with the neuron
shown in Fig. 14, however, PCP again caused 1) a prominent decrease in intertrial response variation (flags in Fig. 15,
A and B, indicate ±1 SD in mean firing rate) and
2) substantially increased the neuron's capacity to
differentially signal both direction of motion in the RF (direction
'e, Fig. 15D) and velocity (velocity
'e, Fig. 15C) of brushing stimulation. The MFR
data in Fig. 15A show that the postdrug increase in this
neuron's capacity to signal direction of motion at velocity 5.6 cm/s
occurred in spite of a drug-induced reduction in the difference in the
MFRs evoked by two directions of motion. Once again, therefore, the change in SI neuron discriminative capacity (increase in
'e) after NMDA receptor block is attributable to the
drug-induced decrease in intertrial response variation, not to the
alterations in mean firing rate.
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DISCUSSION |
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Comparison of response variation of sMRAS and SI neurons
The initial series of experiments demonstrated that SI neurons
exhibit larger trial-by-trial response variation than do sMRAs at each
velocity of skin brushing stimulation studied (Fig. 3). This result is
fully consistent with the idea that the magnitude of the trial-by-trial
variations in sensory neuron response increases progressively with the
number of synapses in the projection from sensory receptor to primary
sensory cortex (Levine 1994; Petrovaara et al.
1986
; Tolhurst et al. 1983
). There is no
precedent, however, for the finding that the dependency of the
magnitude of SI neuron and sMRA response variation on velocity of skin
brushing stimulation is very different (Fig. 3);
sMRA increases monotonically over the entire
1- to 100-cm/s velocity range, but
SI
declines over the range 1-10 cm/s and then increases with velocity
over the range 10-100 cm/s. Similarly, the observation that for some
SI neurons CV is minimal over a relatively wide range of velocities, whereas for other SI neurons CV is minimal over only a very narrow range of velocities (Fig. 5) was not anticipated because previous studies have emphasized the neuron-to-neuron consistency of the effects
of changing a parameter of natural stimulation on neuronal variability.
For example, Tolhurst et al. (1981
,
1983
), Vogels et al. (1989)
, and
Zohary et al. (1994)
reported the variance in the mean
firing rate response of striate cortical neurons to increase
proportionately with increasing stimulus contrast, and Levine
(1994)
observed that the variance in the mean firing rate responses of retinal ganglion cells and lateral geniculate neurons increases monotonically with increasing stimulus luminance.
Although prior studies did not systematically evaluate the effects of
skin stimulus parameters on central somatosensory neuron intertrial
response variation, Essick and Whitsel (1985a,b
)
observed that the directional sensitivity (as estimated by the
'e measure) of many SI neurons was maximal at velocities
not associated with the largest differences between the mean firing
rates evoked by opposing directions of motion, an observation that,
with the benefit of hindsight, can be attributed with near certainty to
the velocity dependency of the magnitude of SI neuron CV identified in
this study. The observations reported in this paper thus not only
extend those of Essick and Whitsel (1985a
,b
) but
establish, for the first time, that under most conditions of skin
brushing stimulation the directional sensitivity of many SI neurons is
attributable chiefly to the velocity dependency of intertrial response
variation and, to a lesser extent than has been assumed, to the
difference in the mean firing rates evoked at each velocity by opposing
directions of skin brushing stimulation. Neither the prominent and
systematic effect of position of the skin brushing stimulus in the RF
on SI neuron CV (Fig. 7), nor the trial-by-trial changes in the
distribution of sensitivity within the RF that accompany the
trial-by-trial fluctuations in SI neuron response magnitude (Fig. 8)
have been reported previously.
Mechanisms of SI neuron ITV
The experimental observations that invite mechanistic explanation
are as follows: 1) SI is much
greater than
sMRA (Fig. 3); 2)
CVSI varies with the position of the stimulus within the RF
(Fig. 7), being lowest at the RF center and increasing with distance
from the RF center; 3) KET and PCP consistently reduce CVSI (Figs. 9-11, also Fig. 13); 4) when
stimulus velocity is increased within the 1- to 10-cm/s range of
velocities, the values of CVsMRA and CVSI
change in opposite directions (Fig. 3); and 5) NMDA receptor block with either PCP or KET causes some SI neurons to increase their
mean firing rate (e.g., Fig. 11).
That CVSI consistently is greater than CVsMRA
has a ready explanation: i.e., each additional synapse in the
projection path from the skin receptor to SI neuron adds to the
magnitude of intertrial response variation. This explanation also is
relevant to the observation that CVSI is smaller at the RF
center than at off-center locations; in this situation our assumption
is that the activity reaching an SI neuron from the off-center regions
of its RF does so "indirectly" via long-range horizontal
connections it receives from the neurons in other cortical columns
(Armstrong-James 1995; Burton and Fabri 1995
; DeFelipe et al. 1986
), rather than
"directly" from somatosensory thalamus. Accordingly, the afferent
activity evoked by a stimulus to the RF periphery of an SI neuron
traverses a longer series of synaptic relays than does activity evoked
from the RF center, with each additional relay contributing to the
magnitude of response variation observed with repeated stimulation.
At the low dosages used in these experiments, both PCP and KET
are known to selectively block NMDA receptors (Collingridge and
Watkins 1994; Iversen et al. 1989
; Lodge
et al. 1989), and to selectively elevate the threshold
for evoking SI neuron activity at off-center locations in the RF
(Duncan et al. 1982
; McKenna et al.
1982
). These actions, together with the substantial evidence that somatosensory corticocortical influences are mediated
predominantly by NMDA receptors that occur at highest density in layers
II/III (Monaghan and Cotman 1985
), whereas direct
thalamocortical influences are mediated predominantly by
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
(Fukada et al. 1998
; Hagihara et al.
1988
; Hicks and Conti 1996
; Salt et al.
1995
; Weinberg and Kharazia 1996
; also
Armstrong-James 1995
; Armstrong-James et al.
1993
; Fox et al. 1989
, 1990
;
Nishigori et al. 1990
; Shirokawa et al. 1989
; Thomson et al. 1988
, 1996
)
raise the possibility that PCP and KET reduce CVSI by
selectively reducing the influences conveyed via corticocortical
connections. That is, PCP and KET may selectively eliminate the NMDA
receptor-mediated influences of the relatively more variable,
long-range corticocortical connections that convey activity evoked at
off-center locations in the RF, and at the same time spare the AMPA
receptor-mediated influences that are evoked from the RF center and
conveyed by thalamocortical afferents (by means of direct monosynaptic
connections, and also disynaptically via the spiny stellate cells of
the same column).
In addition to reducing intertrial response variation, administration of PCP or KET frequently modified mean firing rate. Specifically, PCP increased MFR in the majority of SI neurons studied (Fig. 11, bottom left plot), and KET increased MFR in approximately half of the neurons studied (Fig. 11, bottom middle plot). This observation seems, at least at first glance, difficult to attribute to drug-induced block of NMDA receptors if one accepts the ideas that excitatory influences evoked at the RF periphery are conveyed indirectly to pyramidal neurons via corticocortical connections, and that those influences are expressed through NMDA receptor activity (see preceding paragraph). This apparent conflict is resolved, however, if one takes into account the stimulus condition used in the drug studies reported in this paper. Because the skin brushing stimulus always was positioned so that it traversed the region corresponding to the neuron's RF center (see METHODS), it is presumed that for each SI neuron studied the predominant afferent drive was conveyed by direct thalamocortical connections acting via AMPA receptors. As a result, there is no reason to expect that PCP- or KET-induced NMDA receptor block would cause a decrease in SI neuron MFR; because the stimulus condition that was used (RF center stimulation) evoked little or no afferent drive from the RF periphery, it is presumed that the great majority of the neurons' response was mediated by AMPA receptor activation.
How then does one explain the increases in SI neuron MFR that were
observed after PCP or KET? Although our experiments provided no direct
information about the nature of the mechanism(s) by which systemically
administered PCP and KET increased SI neuron mean firing rate, or about
the CNS locus (loci) at which these drugs would cause this effect, the
explanation we favor is that the NMDA receptor block caused by these
agents disrupts pericolumnar interactions within cortical networks.
Pericolumnar interactions are both excitatory and inhibitory
(Stemmler et al. 1995), with surrounding cortex exerting
a net inhibitory action on a column (Gardner and Costanzo
1980
; Goldreich et al. 1998
; Grinvald et al. 1994
; Knierim and Van Essen 1992
;
Laskin and Spencer 1979
; Levitt and Lund
1997
) when the neurons in that column are strongly and directly
activated by a stimulus to the RF center. When a SI column is under
direct and strong sensory afferent drive, its response to that direct
drive thus will not be maximal, but will be partially suppressed by
lateral inhibitory influences deriving from the co-active columns that
surround it. Therefore, under this condition (one presumed to
approximate the condition of afferent drive evoked by application of a
skin brushing stimulus to a neuron's RF center), systemic
administration of an NMDA receptor antagonist is expected to reduce
lateral inhibitory influences (because these are attributable to
glutaminergic corticocortical influences, and are mediated via NMDA
receptors on local GABAergic interneurons that terminate synaptically
on pyramidal neurons) on the pyramidal neurons of the directly
activated column. In this way, systemic administration of either PCP or
KET would permit full expression of the direct thalamocortical (AMPA
receptor mediated) excitatory drive that reaches those pyramidal
neurons during skin stimulation. The frequent, but usually relatively
small, increases in MFR obtained with the relatively low doses of PCP
and KET used in our experiments are regarded as consistent with this explanation.
Why is it that over the 1- to 10-cm/s range of stimulus velocities,
CVSI behaves differently than CVsMRA
(sMRA increases monotonically with increasing
stimulus velocity over the range 1-10 cm/s, but
SI declines over the same range; see Fig. 3)? The explanation we favor is that the negative slope of the
SI versus velocity relationship over the
velocity range 1-10 cm/s is achieved by an action mediated by a
particular set of intrinsic connections known to exist within SI
cortex. More specifically, our view is that the influence on SI
pyramidal neurons of corticocortical input is selectively attenuated by
an intrinsic cortical inhibitory mechanism that leaves the direct input
conveyed to pyramidal neurons from somatosensory thalamus (and
expressed by AMPA receptors) unimpaired.
How might this intrinsic inhibitory mechanism be achieved? A selective
decrease in the influence of corticocortical input on SI pyramidal
neurons (expressed by postsynaptic NMDA receptors) could be achieved
via the double bouquet (DB) cells located within the same cortical
column as the pyramidal cells. DB cells are very numerous in the upper
cortical layers, and their axons descend radially through both the
upper and middle cortical layers, making numerous GABAergic inhibitory
synaptic contacts along the way (Jones 1975). The
feature of DB cells that makes them especially interesting insofar as
this mechanism is concerned is that, although their radially oriented
axons make many synapses on the basal dendrites and also on the oblique
side branches of apical dendrites of pyramidal neurons in the same
column, the synapses made by DB axon terminals completely avoid the
main shaft of the apical dendrites (DeFelipe et al.
1989
; DeFelipe and Farinas 1992
). As a result,
DB cells may be able to powerfully and selectively attenuate (by
membrane hyperpolarization and by electrotonic shunting) the contributions of synapses at distal locations on the basal and oblique
dendrites to a pyramidal neuron's spike discharge response to skin
stimulation, while permitting synapses on the apical dendrite to remain
fully competent in terms of their ability to influence the neuron's
spike discharge response to skin stimulation.
The idea that thalamocortical afferents appear to provide direct input
to pyramidal neurons that is less variable than the input provided via
corticocortical afferents, together with the above-described
distinctive pattern of DB cell axonal arborization, led us to ask
whether direct thalamocortical input might preferentially influence a
pyramidal neuron via its apical dendrite, while corticocortical input
preferentially influences the cell via the basal/oblique dendrites.
Because the neuroanatomic literature offers clear examples of
thalamocortical and corticocortical axons terminating on pyramidal neuron basal dendrites and also on apical dendrites (Deuchars et
al. 1994; Gabbott et al. 1987
; Hornung
and Garey 1981
; McGuire et al. 1991
), it seems
very unlikely that the two types of inputs to SI pyramidal neurons
terminate exclusively on either type of dendrite (see also
Thomson et al. 1989
). However, the existing evidence
does not rule out the possibility that there might be quantitative
differences in the termination of thalamocortical and corticocortical
axons on the apical and basal/oblique dendrites of pyramidal neurons.
Another aspect of cortical intrinsic connectivity that may be highly
relevant to the possibility that the contributions of NMDA
receptor-mediated corticocortical input to the stimulus-evoked response of SI neurons may be dynamically regulated is the pattern of
termination of spiny stellate cell (SS) axons on pyramidal neurons. SS
cells are located in layer 4 (Jones 1975
; Lund
1984
), are the major recipients of thalamocortical connections,
and distribute their axons radially to pyramidal cells in the same
cortical column. Because the axons of SS cells run parallel and in
close apposition to the apical dendrites of pyramidal cells, they have
the opportunity (and are widely believed) to form multiple,
high-density excitatory synapses on the apical dendrites (Jones
1981
; Lund 1984
). The intrinsic connectivity
described in this and the preceding paragraph is summarized
schematically in Fig. 16. Although the
pattern of synaptic termination of SS cell axons on SI pyramidal neuron
apical dendrites described above and shown in Fig. 16 is consistent
with the available evidence, it remains to be directly demonstrated.
|
The scheme of intrinsic connectivity shown in Fig. 16 would allow DB cells to selectively control the effectiveness of corticocortical inputs to pyramidal cells. To explain, consider the neural events set into motion on the delivery of a 10-cm/s stimulus to a discrete region on the skin. As detected in our recording experiments, a 10-cm/s stimulus evokes a vigorous (but submaximal) response in the sMRAs with an RF that falls within the stimulated skin region (Fig. 2), and the central projections of these sMRAs, in turn, provide strong drive to SI neurons (presumably both pyramidal and DB cells) that have an RF center that includes the stimulated skin site. The action essential for achievement of the minimal SI neuron response variation observed in our experiments under this stimulus condition is that with relatively little delay, the activated DB cells in a strongly activated cortical cell column(s) trigger postsynaptic inhibitory currents in the pyramidal cells that reduce (by membrane hyperpolarization and via electrotonic shunting) the synaptic currents set up by active excitatory synapses located more distally on the basal and oblique dendrites. If this actually occurs, the result would be a substantial reduction of the contributions to the pyramidal neuron response of the glutaminergic corticocortical inputs coming from other less-activated ("off-focus") cortical columns, because the major fraction of these inputs is targeted to distal sites on the basal and oblique dendrites. In contrast, the glutaminergic inputs from SS cells (because these inputs are relatively direct and exert a larger synaptic response than the corticocortical inputs, they should exhibit lower intertrial response variation) terminate principally on the main shaft of the neuron's apical dendrite, and thus they, unlike the corticocortical inputs, should be unaffected by the dendritic inhibitory/synaptic current shunting actions associated with DB cell activity. By means of this mechanism, therefore, DB cell activation would reduce the strength of corticocortical input relative to the input arriving via direct thalamocortical afferents, and, as a result, the response variation of the pyramidal cells in the column(s) that receive direct stimulus-evoked thalamocortical input would be less than that observed under stimulus conditions when both corticocortical and thalamocortical connections contributed to the response.
A quite different outcome is anticipated when the brushing stimulus moves more slowly (e.g., at 1 cm/s); in this case the stimulus evokes much weaker activity in sMRAs and, as a result, only weak spike discharge activity in SI pyramidal and DB cells. The DB cells, because they are only weakly activated under this stimulus condition, exert a weak shunting effect on the basal/oblique dendrites of pyramidal neurons with the result that the glutaminergic activity conveyed by corticocortical axons (and expressed mainly by NMDA receptors) contributes significantly (relative to the contribution of corticocortical influences to the response to a 10-cm/s stimulus) to the spike discharge response of pyramidal cells. Moreover, because the corticocortical input to pyramidal cells is more variable than that provided by SS cell axons, the response of pyramidal neurons to a 1-cm/s stimulus is more variable from one stimulus trial to the next.
The situation is most straight-forward at high stimulus velocities (velocities >10 cm/s), for at these velocities the period of time the stimulus remains in contact with the skin becomes the dominant factor. As was demonstrated in Fig. 1, the number of spikes evoked in both sMRAs and SI neurons by a moving stimulus decreases rapidly with increasing velocity because of the very brief time the stimulus remains in contact with the skin. As a result, the contribution of dendritic inhibition/shunting by DB cell axons to the SI magnitude of SI neuron intertrial response variation decreases progressively as velocity is increased over the range 10-100 cm/s.
To summarize, the observed decline of SI neuron response variation in
the 1- to 10-cm/s velocity range is hypothesized to be attributable to
a suppressive/inhibitory effect that the direct thalamic input to a
cortical column exerts (via the GABAergic synapses of DB cells on the
proximal basilar dendrites of pyramidal neurons; Fig. 16) on the
corticocortical input to the basilar and oblique dendrites of pyramidal
cells in that same column. Although the organization of cortical
intrinsic connections suggests that this effect may be attributable to
DB cell-mediated synaptic currents set up in the proximal basilar
dendrites, the same or at least a similar effect might also be achieved
by other means. For example, direct thalamocortical excitatory drive
could also suppress the contributions of corticocortical input to
pyramidal neurons by increasing dendritic membrane length constant
(Bernander et al. 1991; Holmes and Woody
1989
).
Contributions to somatosensory discriminative capacity
The velocity- and NMDA receptor dependency of SI neuron intertrial
response variation demonstrated by the experiments of this study may
account for what has been regarded as a discrepancy between human
somatosensory perception and SI neuron behavior; that is, although
human directional sensitivity on forearm hairy skin is optimal at
velocities in the vicinity of 10 cm/s, and falls off progressively as
velocity is increased or decreased (Essick and Whitsel
1985a,b
), for most SI neurons the differences between the mean
firing rates evoked by opposing directions of motion increases
progressively over the entire velocity range (1-100 cm/s) used in the
present study. The findings lead us to propose that the velocity tuning
of cutaneous directional sensitivity principally is attributable not to
the difference in SI neuron MFRs evoked by opposing directions of
stimulus motion, but to the fact that SI neuron response variation is
minimal at intermediate velocities (i.e., at velocities in the vicinity
of 10 cm/s for neurons with RFs on forearm hairy skin). Furthermore,
the evidence is consistent with the idea that the lowest SI neuron
intertrial response variation (and the highest capacity for
discrimination) occurs with stimulation of the RF center at velocities
in the vicinity of 10 cm/s because this condition of skin brushing
stimulation evokes a response to which NMDA receptor-mediated synaptic
currents (and corticocortical inputs) contribute minimally.
In general, the findings are regarded as consistent with the emerging
view that even at the earliest stages of cortical sensory information
processing cells are highly mutable in their functional properties and
process a much greater diversity of information than is conveyed via
direct, short-latency thalamocortical connections (Armstrong-James 1995; Gilbert 1998
;
Lee and Whitsel 1992
; Whitsel et al.
1989
, 1991
).
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ACKNOWLEDGMENTS |
---|
The authors gratefully acknowledge the technical assistance of C. Metz and C. Wong. The authors also thank Dr. E. Kelly for a helpful critique of an earlier version of the paper. T. Hester assisted with preparation of the illustrations.
The experiments were supported, in part, by National Institutes of Health Grants RO1 NS-35222 and RO1 NS-34979. M. Tommerdahl was supported by First Investigator (R29) Award MH-48654. K. A. Delemos and G. K. Essick were supported by NIH Grant PO1 DE-07509; O. Favorov was supported, in part, by Office of Naval Research Grant N00014-95-1-0113 and by a Whitaker Foundation Special Opportunity Award.
Present address of C.-J. Lee: Dept. of Biology, College of Science, Inha University, Incheon, Korea.
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FOOTNOTES |
---|
Address for reprint requests: B. L. Whitsel, 155 Medical Research, CB# 7545, Dept. of Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 April 1998; accepted in final form 5 March 1999.
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REFERENCES |
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