Center for Neural Science, New York University, New York, New York 10003
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ABSTRACT |
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Handel, Ari and Paul W. Glimcher. Quantitative Analysis of Substantia Nigra Pars Reticulata Activity During a Visually Guided Saccade Task. J. Neurophysiol. 82: 3458-3475, 1999. Several lines of evidence suggest that the pars reticulata subdivision of the substantia nigra (SNr) plays a role in the generation of saccadic eye movements. However, the responses of SNr neurons during saccades have not been examined with the same level of quantitative detail as the responses of neurons in other key saccadic areas. For this report, we examined the firing rates of 72 SNr neurons while awake-behaving primates correctly performed an average of 136 trials of a visually guided delayed saccade task. On each trial, the location of the visual target was chosen randomly from a grid spanning 40° of horizontal and vertical visual angle. We measured the firing rates of each neuron during five intervals on every trial: a baseline interval, a fixation interval, a visual interval, a movement interval, and a reward interval. We found four distinct classes of SNr neurons. Two classes of neurons had firing rates that decreased during delayed saccade trials. The firing rates of discrete pausers decreased after the onset of a contralateral target and/or before the onset of a saccade that would align gaze with that target. The firing rates of universal pausers decreased after fixation on all trials and remained below baseline until the delivery of reinforcement. We also found two classes of SNr neurons with firing rates that increased during delayed saccade trials. The firing rates of bursters increased after the onset of a contralateral target and/or before the onset of a saccade aligning gaze with that target. The firing rates of pause-bursters increased after the onset of a contralateral target but decreased after the illumination of an ipsilateral target. Our quantification of the response profiles of SNr neurons yielded three novel findings. First, we found that some SNr neurons generate saccade-related increases in activity. Second, we found that, for nearly all SNr neurons, the relationship between firing rate and horizontal and vertical saccade amplitude could be well described by a planar surface within the range of movements we sampled. Finally we found that for most SNr neurons, saccade-related modulations in activity were highly variable on a trial-by-trial basis.
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INTRODUCTION |
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For most of the nearly 350 years since the basal
ganglia first were distinguished by Willis (1664, 1978),
their role in motor control has been the subject of much speculation
but little certainty (cf. Marsden 1980
). In the late
1970s and early 1980s, a possible oculomotor role for the basal ganglia
was raised by anatomic data demonstrating a dense, inhibitory,
GABAergic projection from a major output nucleus of the basal ganglia,
the substantia nigra pars reticulata (SNr), to the intermediate layers
of the superior colliculus (SC) (cf. Beckstead 1981
;
DiChiara et al. 1979
; Hopkins and Niessen
1976
; Huerta and Harting 1984
; Jayaraman
et al. 1977
; Ma 1989
; Vincent et al.
1978
; Wurtz and Albano 1980
), a major saccadic
control center (for reviews of the SC and saccadic control, see
Sparks 1986
; Sparks and Mays 1990
;
Wurtz and Albano 1980
). To demonstrate a physiological
role for this pathway and thereby link basal ganglia studies to one of
the simplest and best-studied motor systems, Hikosaka and Wurtz
recorded from hundreds of SNr neurons in monkeys trained to make
saccades in response to visual stimuli (Hikosaka and Wurtz
1983a
-d
).
Hikosaka and Wurtz found a population of neurons in the lateral portion
of the SNr that tonically generated action potentials at 50-100
spikes/s but decreased this rate of activity after the presentation of
saccadic targets or before the generation of saccades in oculomotor
tasks (Hikosaka and Wurtz 1983a; for similar results in
cat, see Joseph and Boussaoud 1985
). Closely related
pharmacological experiments indicated that GABAergic manipulations of
both the superior colliculus and the SNr profoundly affected the
properties of saccadic eye movements (Hikosaka and Wurtz
1985a
,b
; for cat, see Boussaoud and Joseph
1985
). Based on these data, Hikosaka and Wurtz proposed that
the SNr may be an important component of the oculomotor system that
functions by tonically inhibiting the superior colliculus and then
releasing that inhibition before saccades (Hikosaka and Wurtz
1989
).
This hypothesis has been extended by the observation that the central
region of the caudate, a principal afferent source of the SNr
(Hikosaka et al. 1993; Parent et al.
1984
; Szabo 1970
), also carries visual and
saccade-related signals (Hikosaka et al. 1989a
-c
). The
central region of the caudate is itself innervated by multiple cortical
areas, including the frontal eye fields (FEF) (Kunzle and Akert
1977
), an area that carries well-studied visual and
saccade-related signals (cf. Bruce and Goldberg 1985
;
Segraves and Goldberg 1987
). Although the FEF is only
one possible source of caudate visual and saccade-related signals (cf.
Alexander et al. 1986
; Hikosaka et al.
1989a
), a broadly accepted hypothesis has emerged (cf.
Alexander et al. 1986
; Hikosaka and Wurtz
1989
; Kandel et al. 1991
; Leigh and Zee
1991
; Wurtz and Hikosaka 1986
) that the SNr
specifically, and the oculomotor basal ganglia in general, lies
primarily within a FEF-SC circuit. However, a more detailed comparison
of the response properties of neurons in the FEF, SNr, and SC, which
would provide a more rigorous test of the hypothesis that the SNr
relays saccade-related signals from the FEF (via the caudate) to the
SC, is not possible until the SNr has been examined with the same
degree of quantitative detail as the FEF and SC (for detailed studies
of the FEF, see Bruce and Goldberg 1985
; Bruce et
al. 1985
; Segraves and Goldberg 1987
; Sommer and Wurtz 1998
; for the SC, see Ottes et
al. 1986
; Sparks 1978
; Sparks et al.
1976
).
There is also a more fundamental reason to provide a rigorous
quantification of the responses of SNr neurons during saccadic tasks.
Evidence from the work of Hikosaka and Wurtz suggests that the
saccade-related decreases in the firing rates of SNr neurons are
modulated by "contextual" factors, such as whether a target location is visible or remembered or whether a saccade is made inside
or outside of a behavioral task (Hikosaka and Wurtz
1983a,c
). Although the nature of this context dependence has
not been fully explored, it may provide an important clue to the role
played by the basal ganglia in movement generation (Evarts et
al. 1984
). To build on the work of Hikosaka and Wurtz and to
further explore the information carried by these neurons under a
variety of conditions, a rigorous quantification of nigral response
fields is necessary.
Therefore to build on earlier descriptions of SNr response properties, allow a comparison with other oculomotor areas, and facilitate further explorations of the role of the SNr in saccade generation, we attempted to provide a detailed quantitative description of the relationships between the firing rates of SNr neurons and the horizontal and vertical amplitude of upcoming saccades during a visually guided saccade task. For this purpose, we recorded the activity of 72 neurons from the primate SNr while monkeys performed a large number of trials of a delayed saccade task. To sample a wide range of movement amplitudes and directions, on each trial the target was chosen randomly from a wide range of possible locations. To examine changes in neuronal activity throughout the task, on each trial firing rate was measured during five distinct intervals.
Our quantitative analysis led to three novel physiological findings
about the SNr. First, we were able to segregate and characterize four
distinct classes of saccade-related SNr neurons. Neurons in two of
these classes had response properties similar to those described by
Hikosaka and Wurtz (1983a-d
), but neurons in the other
two classes were characterized by saccade-related increases in
activity. Second, for the SNr neurons we studied, the relationship between firing rate, in each of the five measured intervals, and horizontal and vertical saccade amplitude could be well described by a
planar surface. This planar relationship was qualitatively different
from the Gaussian-like relationship between firing rate and horizontal
and vertical saccade amplitude than has been found when FEF and SC
neurons have been examined in a similar manner (cf. Bruce and
Goldberg 1985
; Ottes et al. 1986
). Finally, our SNr neurons were found to have high trial-to-trial variance in firing
rate. In future work, use of planar regressions to quantify the
response profile of SNr neurons should prove useful for explorations of
the effects of memory, and other behavioral contexts, on the saccade-related activity of SNr neurons.
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METHODS |
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Four male rhesus macaques (Macaca mulatta) were used as subjects. All animal procedures were developed in association with the University Veterinarian, approved by the New York University Institutional Care and Use Committee, and designed and conducted in compliance with the Public Health Service's Guide for the Care and Use of Animals.
Surgical and training procedures
All surgical and training procedures were performed using
standard protocols that have been described in detail elsewhere (Handel and Glimcher 1997). Briefly, in an initial
sterile surgery performed under isoflurane inhalant anesthesia, a
prosthesis for restraining the head and a scleral search coil
(Fuchs and Robinson 1966
; Judge et al.
1980
) for monitoring eye position were implanted. After this,
and all other surgical procedures, animals received analgesics and
antibiotics for a minimum of 3 days. After a 6-wk delay, access to
water was controlled and subjects were trained to perform oculomotor
tasks for juice rewards.
During training and subsequent recording sessions, monkeys were seated, with their heads immobilized, in a primate chair placed 57 in from a tangent screen containing a grid of light emitting diodes (LEDs). These LEDs (441) formed a grid of points, separated by 2° of visual angle, spanning 40° horizontally and 40° vertically.
To gather the data presented in this report, each monkey was trained to produce saccadic eye movements in response to visual stimuli in a delayed saccade task. Each delayed saccade trial (Fig. 1) began with an audible beep. Three hundred milliseconds later a central fixation LED, which appeared yellow to normal human observers, was illuminated and the subject was required to align gaze with this stimulus (±3°) within 1,000 ms. Two hundred to 800 ms after gaze was aligned with this fixation LED, a single yellow eccentric LED was illuminated. After a further 200- to 1,200-ms delay the fixation LED was extinguished (the GO cue), and the subject was required to shift gaze into alignment with the eccentric target LED (±3-5°) within 350 ms. If the subject's gaze remained in alignment with the target for 350-450 ms, the trial was considered to be performed correctly. Each correct trial was reinforced with a 300-ms noise burst which was supplemented randomly with fruit juice on one-third to one-fifth of trials. On each trial, the location of the target was chosen pseudorandomly, with replacement, from the grid of LEDs. All trials were performed under dim illumination. Subjects performed the delayed saccade task with an intertrial interval of 200-800 ms.
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After a monkey was trained to perform the delayed saccade task, a second sterile surgery was performed to implant a recording chamber allowing vertical electrode penetrations into the SNr. We stereotaxically positioned a stainless-steel receptacle (Crist Instruments) over a 15-mm-diam craniotomy centered 4.5 mm anterior and 7.5 mm lateral to the intersection of the interaural line and the midsaggital plane (on the left side in 3 monkeys and the right side in 1), oriented the receptacle perpendicular to the stereotaxic horizontal plane, and fastened it to the skull with orthopedic bone screws and cement.
Microelectrode recording techniques
After the monkeys were trained to perform the delayed saccade
task and had been implanted with a recording chamber,
electrophysiological recording sessions were initiated. During each
recording session a 23-gauge guide cannula was fixed to an
x-y micropositioner and used to pierce the dura. A
paralyne-coated tungsten microelectrode (Microprobe: 0.5-2.0 M) or
a glass-coated platinum-tipped tungsten microelectrode (Ainsworth: 10- to 15-mm exposed tip) was then advanced. Individual action potentials
were identified by time and amplitude criteria and the times of
occurrence of these action potentials were recorded.
Recording protocol
Following the method of Schultz (Wolfram Schultz, personal
communication), we located the SNr in each subject by first recording from neurons of the ventroposterior complex of the somatosensory thalamus. By systematically recording from many locations in the lateral and medial divisions of this complex and determining the location on the animal's body surface that activated each neuron, we
were able to construct a topographic map of somatosensory receptive fields of ventroposterior thalamus. Once the region containing neurons
with somatosensory receptive fields centered on the lips and mouth was
located, we searched for the SNr by vertically advancing electrodes
past these neurons and into the underlying tissue. Putative SNr
neurons, with 50-125 spikes/s tonic firing rates and oculomotor
task-related modulations in activity, typically were first encountered
~2-5 mm ventral to the deepest orofacial somatosensory responses.
These neurons were typically encountered while the electrode was
advanced for 1-2 mm, after which no further cellular activity was
apparent, presumably because the electrode had entered the cerebral
peduncle. In some of our more anterior penetrations, when the electrode
was extended ventral to neurons with orofacial somatosensory responses,
we encountered neurons that were characterized by lower, more variable
tonic rates (usually <25 spikes/s) punctuated by saccade-related
bursts of activity; the background activity in the neighborhood of
these neurons was often more irregular and less vigorous than the
background activity in the neighborhood of putative SNr neurons. These
low tonic firing rates were inconsistent with Hikosaka and
Wurtz's (1983a) descriptions of SNr neurons, as well as our
putative SNr neurons, but consistent with Matsumura et al.'s
(1992)
descriptions of subthalamic neurons. Indeed, marking
lesions made at the sites of these neurons were later recovered in the
subthalamic nucleus. Thus when we encountered neurons with these
physiological properties we tentatively classified them as subthalamic
neurons and did not include them in this report.
Data analysis
SINGLE-TRIAL MEASUREMENTS. Data analysis was a three-step process. In the first step, for each correctly executed trial, we measured the horizontal and vertical amplitude of the saccade that aligned gaze with the target as well as the firing rate of the neuron during 5 intervals (Fig. 1): a 200-ms pre-trial interval ending at the onset of the beep that initiated the trial; a 200-ms fixation interval ending at the onset of the target LED; a 200-ms visual interval beginning 50 ms after the onset of the target; a 150-ms movement interval beginning 50 ms before the onset of the saccade; and a 200-ms reward interval ending at the delivery of reinforcement.
DESCRIPTION OF INDIVIDUAL NEURONS. In the second step of data analysis, for each neuron we examined the relationship between the firing rate during a trial and the horizontal and vertical amplitude of the movement made at the end of the trial. To do this, we generated five response fields for each neuron: one response field for each measured interval. Each response field plotted the firing rate of the neuron during the interval as a function of the horizontal and vertical amplitude of the saccade made at the end of each trial.
To quantify the relationship between the firing rate during an interval and the horizontal and vertical amplitude of the saccade made at the end of each trial, we fit each response field with both a planar model (2-dimensional least-squares regression) and a two-dimensional Gaussian model. To compare the efficiencies with which these two models described the data, the proportion of total variance accounted for (VAF) by both the planar and Gaussian fits was computed as (total varianceCLASSIFICATION OF NEURONS. By informally examining single trials and response fields for each neuron, we found that nigral neurons exhibited one of four basic response profiles during the delayed saccade task: a decrease in firing rate after target onset and/or before saccade onset on trials ending with contraversive movements, a decrease in firing rate that began after fixation and continued until the delivery of reinforcement on all trials, an increase in firing rate after target onset and/or before saccade onset on trials ending with contraversive movements, and an increase in firing rate after target onset and/or before saccade onset on trials ending with contraversive saccades and a decrease in firing rate on trials ending with ipsiversive saccades.
These four response profiles could be distinguished by whether firing rate increased or decreased during each interval, and we used this property to systematize our classification scheme. First, we computed a measure of the tonic baseline firing rate of each neuron by calculating the mean and standard deviation of the firing rate during the pre-trial interval across all trials. Then for each of the other four measured intervals, we calculated the percentage of trials in which the firing rate during the interval wasPOPULATION ANALYSES. The third step of data analysis was a population level description of SNr neurons. We described the characteristics of the neurons assigned to each cell class by extracting the relative z intercepts, the slope magnitudes, and slope directions from the regression planes fit to the response fields generated for each neuron. These parameters provided estimates of the intervals during which the average firing rates of the neurons were modulated up or down, the degree to which these modulations were linearly related to horizontal and vertical saccade amplitude, and the movement directions associated with the largest modulations. Histograms and polar plots of these values were then prepared and these data were tested for statistical significance.
Histology
The locations of recording sites were identified histologically in two monkeys. During the 2 wk before the animals were killed, electrolytic marking lesions were made at the sites where the activity of single neurons was recorded. Lesions were made by passing a 5 µA anodal current through the tip of the recording electrode for 5-10 s. At the end of this 2-wk period, the animals were premedicated with ketamine and then killed with an overdose of thiopental sodium. They were perfused intracardially with a saline solution followed by 4% paraformaldehyde in phosphate buffered saline and finally by 30% sucrose in phosphate buffered saline. The brains were removed from the skulls, submerged in 30% sucrose for 3 days, blocked and cut into 40-µm frozen sections. The sections then were mounted and stained with thionine, and the anatomic locations of the lesions were identified, photographed, and recorded on camera lucida reconstructions of the sections.
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RESULTS |
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We examined 72 saccade-related neurons in this study. Each neuron was examined while subjects correctly executed 50-500 delayed saccade trials (136 ± 80; mean ± SD). After all the neuronal data were collected, each neuron was classified as described in METHODS. For each cell class, we present data for a single neuron having near modal response properties. We then present a population level analysis of all the neurons in the class.
Discrete pausers
SINGLE NEURON DATA. Thirty-five percent of the SNr neurons we studied (n = 25) were classified as discrete pausers. Figure 2 plots the activity of a typical discrete pauser during two delayed saccade trials. Horizontal and vertical eye position is plotted as a function of time above the instantaneous firing rate of the neuron. At the end of one trial (left), the monkey made a downward and contraversive saccade. Note that shortly after the onset of this target, firing rate decreased to nearly zero and continued at this lower level until the saccade. During another trial (right), at the end of which the monkey made an upward and ipsiversive saccade, the firing rate of the neuron remained near baseline throughout the trial.
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POPULATION ANALYSES. As shown in Table 1, planar linear regressions were good descriptors of the relationship between neuronal firing rate and horizontal and vertical saccade amplitude for all 25 neurons we classified as discrete pausers. For each neuron we compared the average firing rate (the z intercept from each planar fit) during the fixation, visual, movement, and reward intervals with the average firing rate during the pre-trial interval to determine the degree to which the firing rates of each discrete pauser were modulated in each interval (a property that could not be predicted from our classification criteria). Figure 5A plots histograms of average firing rate as a percentage of baseline for all 25 discrete pausers. During the fixation interval, the firing rate of the neurons remained close to baseline. Not surprisingly, average firing rate did drop below baseline during the visual and movement intervals, though it is noteworthy that the decreases were of similar magnitude in both intervals. Finally, in the reward interval, the firing rates of discrete pausers tended to return to, or slightly exceed, baseline levels.
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Universal pausers
SINGLE NEURON DATA. Twenty-four percent of the SNr neurons we studied (n = 17) were classified as universal pausers. Figure 6 plots the activity of a typical universal pauser during two delayed saccade trials; one ending with a contraversive saccade and the other with an ipsiversive saccade. During both trials, the neuron fired action potentials at a high rate until the monkey aligned gaze with the central LED. After this fixation, the firing rate of the neuron decreased and remained below baseline until the trials ended. Note that the instantaneous firing frequency of the neuron did not decrease smoothly after fixation but became highly variable, although in both trials the neuron was practically inactive just before the movement and around the time reinforcement was delivered.
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POPULATION ANALYSES. Although our definition of universal pausers ensures that the average firing rates of these neurons decrease below baseline during all intervals, the magnitude of these decreases cannot be predicted by our classification criteria. The average depths of the decreases we did observe can be seen in the histograms in Fig. 9A that plot mean firing rates as a percentage of baseline for all 17 universal pausers. Although the firing rates of all universal pausers decreased from baseline during all postbaseline intervals, these decreases tended to be smallest during the fixation interval. In the visual, movement, and reward intervals, the decreases in activity tended to be more substantial; in all three of these intervals, the mean firing rate of universal pausers dropped to half of the baseline value.
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Bursters
SINGLE NEURON DATA. Thirty percent of the neurons we studied (n = 22) were classified as bursters. Figure 10 shows the activity of a typical burster during two delayed saccade trials. At the end of one trial (left), the monkey made an upward saccade. Before the saccade, neuronal firing rate increased and remained at an elevated level until reinforcement was delivered. During another trial (right), at the end of which the monkey made a downward saccade, the firing rate of the neuron remained constant.
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POPULATION ANALYSES.
Figure 13A plots
histograms of average firing rates, as a percentage of baseline, for
all 22 bursters. There was a slight tendency for the firing rate of
bursters to increase after fixation. During the visual and movement
intervals, the average firing rates of bursters tended to increase by
about one-third. These increases in activity usually grew larger by the
time reinforcement was delivered, although our population of bursters
varied widely in this respect. During the fixation interval, the tilt
of the best fit plane was significant for only 9% of the bursters.
However, during each of the visual, movement, and reward intervals, the planes for 64% of our bursters were significantly tilted. Figure 13B plots the directions and magnitudes of the slopes of the
regression planes from each interval. During the fixation interval, the
regression planes had relatively shallow tilts and were not
consistently oriented in any direction (Rayleigh P 0.42). However, during the visual, movement, and reward intervals, the
tilts of the regression planes were steeper. Moreover, during these
intervals the planes tended to be oriented so that the uphill slopes
pointed into the contraversive hemifield, although the slope directions
comprised a significant unimodal distribution only in the visual
interval (Rayleigh P
0.01, 0.12, 0.81). Thus the planar
fits indicated that, during the visual, movement, and reward intervals,
on average bursters tended to fire action potentials at a rate 25-35
spikes/s higher on trials ending with large-amplitude contraversive
saccades than on trials ending with large-amplitude ipsiversive
saccades. Note that although the regression planes tended to be
oriented in the opposite direction for bursters and discrete pausers,
this is only because the regression slopes point uphill,
toward the movements associated with the smallest decreases in the
firing rates of discrete pausers and the movements with the largest
increases in the firing rates of bursters. Both classes of neurons
tended to generate the largest modulations on trials terminating with large-amplitude movements into the contraversive hemifield.
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Pause-bursters
SINGLE NEURON DATA. Eleven percent of the SNr neurons we studied (n = 8) were classified as pause-bursters (see METHODS). Figure 14 plots the activity of a typical pause-burster during two delayed saccade trials. At the end of one trial (left), the monkey made a small amplitude downward saccade. Shortly after target onset the firing rate of the neuron increased abruptly, reached a peak of activity just before the movement, and continued to fire at an elevated rate until the end of the trial. During another trial (right), at the end of which the monkey made an ipsiversive saccade, the neuron ceased firing action potentials shortly after the target was illuminated and did not resume firing at the baseline rate until just before the onset of the saccade.
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POPULATION ANALYSES.
Figure 17A plots histograms
of average firing rate as a percentage of baseline for all eight
pause-bursters. During the fixation interval, the average firing rate
of the neurons remained close to baseline. Interestingly, during the
visual interval, the average firing rate was still close to the average
baseline rate, even though the firing rates of most pause-bursters were
modulated during this interval in opposite directions for ipsiversive
and contraversive movements. However, during the movement and reward intervals, the average firing rate increased. During the fixation interval, the tilts of the regression planes were not significant for
any of the eight pause-bursters. However, 75% of the regression planes
were significantly tilted during the visual interval, 75% during the
movement interval, and 63% during the reward interval. During the
fixation interval, the regression planes (Fig. 17B) had
relatively shallow tilts and were not consistently oriented in any
direction (Rayleigh P 0.19). In the visual and movement intervals, the regression planes were tilted much more steeply. The
planes tended to be oriented so that the uphill direction was
contraversive and downward although, perhaps due to the small number of
pause-bursters in our sample, the slope directions did not form a
significant unimodal distribution (Rayleigh P
0.14 and
0.78 for the visual and movement intervals, respectively). Finally,
during the reward interval, although the average firing rate of
pause-bursters still was elevated, the firing rate of pause-bursters
did not vary as strongly with the horizontal and vertical amplitude of
the saccade at the end of the trial. Moreover, when there was a
relationship, the orientation of the planar fits did not appear to be
consistently biased in any particular direction (Rayleigh P
0.50).
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Histology
Figure 18 contains camera lucida reconstructions of six coronal sections from two monkeys showing the locations of 22 of the neurons included in this report. Also shown are the locations of seven additional neurons which were classified but were not studied with enough trials to be included in this report. Of these 29 neurons, 9 (2 discrete pausers, 4 universal pausers, 1 burster, and 2 pause-bursters) were recorded at the sites of electrolytic lesions. Three neurons were recorded on the same penetrations as lesions were made but at different depths. The remaining 17 neurons were recorded on electrode penetrations made at the same angle and from the same starting positions as penetrations on which lesions were made. The approximate depths of neurons in this third group were estimated by using the last thalamic somatosensory neurons encountered (presumably the ventral edge of ventroposterior thalamus) as a point of comparison between the penetration on which the lesion was made and the penetration on which the neuron of interest was recorded.
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In all, 12 discrete pausers, 7 universal pausers, 6 bursters, and 4 pause-bursters were localized. All but two of these neurons were localized in the lateral portion of the SNr, just medial and ventral to the lateral geniculate nucleus (LGN) and lateral to the substantia nigra pars compacta (SNc). The anatomy of this region is shown in more detail in Fig. 19, which presents one photomicrograph from each monkey along with three SNr lesions recovered in those sections. The remaining two neurons were both identified as universal pausers and were localized above the subthalamic nucleus in the zona incerta. This indicates that neurons with the properties we describe as typical of universal pausers are distributed both inside and outside the architectural boundaries of the SNr. Whether these neurons form two functionally distinct groups based on their precise response properties cannot be concluded from our data. However, it is clear that the majority of the universal pausers we localized anatomically (5 of 7) were within the lateral SNr. It is worth noting that, although six bursters and four pause-bursters were localized to the SNr, no bursters or pause-bursters were localized to the subthalamic nucleus, suggesting that our physiological criteria for discriminating subthalamic neurons from SNr neurons were effective.
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DISCUSSION |
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Description of the population of SNr neurons
CELL CLASSES. We recorded the activity of single SNr neurons while monkeys performed a delayed saccade task. The firing rate on each trial was measured during five intervals. For each of these five intervals, for each neuron, we constructed a response field which plotted firing rate as a function of horizontal and vertical saccade amplitude. We found that, for nearly all neurons, these response fields were planar.
From these data, we were also able to observe that the firing rates of some SNr neurons decreased during the delayed saccade task but the firing rates of other SNr neurons increased. By statistically determining the intervals in which the firing rate of each SNr neuron was modulated from baseline on a significant fraction of trials and whether those modulations were increases in activity or decreases in activity, we were able to sort SNr neurons into four distinct classes. Discrete pausers. Thirty-five percent of the neurons in our sample were classified as discrete pausers. For the modal discrete pauser, the average firing rate across all trials remained near baseline during the fixation and reward intervals but fell below baseline during the visual and movement intervals, particularly on trials in which large-amplitude contraversive saccades were produced. The response profiles of discrete pausers were relatively homogenous; the depths of the average decreases in activity and the movement directions associated with the deepest decreases were similar in most neurons. Overall, the responses of discrete pausers were qualitatively similar to the responses of many SNr neurons described by Hikosaka and Wurtz (e.g., Hikosaka and Wurtz 1983cRESILIENCY AND RELIABILITY OF CELL CLASSES. For this report we sorted SNr neurons into classes by determining whether, and in which intervals, the firing rate of each neuron increased or decreased relative to baseline. We also examined other classification schemes, including a hierarchical cluster analysis, which took the relationship between firing rate and horizontal and vertical saccade amplitude into account as a classification tool. Under all the classification schemes we considered, we found that these four classes emerged with essentially the same modal characteristics as those produced by the analysis presented here. However, some neurons switched classes when we sorted our data using these different schemes. In particular, several neurons shifted between the discrete pauser and universal pauser classes or between the burster and pause-burster classes. This raises the possibility that the precise boundary between discrete pausers and universal pausers and the precise boundary between bursters and pause-bursters may not be absolute and that these two pairs of classes may actually form two continua of neuronal response properties. In general, however, we found our four basic response patterns to be a robust characterization of the SNr population.
COMPARISON OF CELL CLASSES WITH PREVIOUS REPORTS.
Hikosaka and Wurtz observed that SNr neurons had high tonic firing
rates (~75 spikes/s) (see Hikosaka and Wurtz 1983a,
Fig. 4) punctuated by decreases in activity during saccadic
tasks (Hikosaka and Wurtz 1983a
-d
). The neurons we
classified as discrete pausers and universal pausers behaved in exactly
this manner, showing high tonic firing rates [77 ± 19 (SD)
spikes/s] and task-related decreases in activity. Unlike Hikosaka and
Wurtz, we also encountered bursters and pause-bursters in the SNr that
had high tonic firing rates (65 ± 23 spikes/s) and task-related
increases in activity. Although saccade-related
increases in the activity of SNr neurons have not been reported
previously, this is consistent with the observations of physiologists
who have studied SNr neurons that are responsive during skeletomuscular
movement tasks. These researchers have reported that the firing rates
of SNr neurons either increase or decrease from baseline in association
with arm and mouth movements (DeLong and Georgopoulos
1981
; Joseph and Boussaoud 1985
; Joseph et al. 1985
; Magarinos-Ascone et al. 1992
, 1994
;
Schultz 1986
).
Comparison of SNr with SC and FEF
The hypothesis that the SNr participates in the generation of saccades as part of a FEF-SC circuit implies that, like collicular and frontal eye field neurons, neurons in the SNr may carry signals appropriate for specifying the metrics of upcoming saccades and/or signals appropriate for initiating saccades. Both specification and initiation signals have been examined in detail in the FEF and the SC. Our quantitative analysis of the response profiles of SNr neurons allows us to perform similar analyses of SNr spike trains and thus permits a more detailed comparison of specification and initiation-related signals in the FEF, SNr, and SC.
SIGNALS APPROPRIATE FOR SPECIFYING SACCADE METRICS.
Both SC and FEF neuronal populations have been reported to carry
topographically coded signals appropriate for specifying the metrics of
upcoming saccades (cf. Schlag and Schlag-Rey 1990; Sparks and Mays 1983
, 1990
). An essential element of
this code is that, in both nuclei, the firing rates of saccade-related
neurons vary systematically with horizontal and vertical saccade
amplitude. Like Hikosaka and Wurtz, we found that the firing rates of
most SNr neurons also vary with horizontal and vertical saccade
amplitude, indicating that populations of these neurons in principle
could carry signals appropriate for specifying the metrics of upcoming movements. However, unlike Hikosaka and Wurtz, we found that the relationship between SNr neuronal firing rate and horizontal and vertical amplitude can be described as well by planar regressions as by
Gaussian fits. Thus the SNr neurons in our sample encode horizontal and
vertical saccade amplitude using either an essentially planar
representation or an essentially Gaussian representation, but Gaussians
centered well beyond the 40 × 40° range of amplitudes we
studied. In contrast, when neurons in the FEF and SC have been studied
over a similar range of movement amplitudes and directions, the relationships between firing rate and horizontal and vertical saccade amplitude have been observed to more closely resemble Gaussian-like functions (Bruce and Goldberg 1985
;
Ottes et al. 1986
). This difference suggests that
specification signals in the SNr are carried in a qualitatively
different form than they are in the FEF and the SC.
SIGNALS APPROPRIATE FOR INITIATING SACCADES.
Both SC and FEF neurons also have been reported to carry signals
appropriate for the initiation of saccades because, in both nuclei, the
firing rates of saccade-related neurons have been shown to be modulated
in tight temporal correlation with movement onset (cf. Hanes et
al. 1995; Sparks 1978
). Like Hikosaka and Wurtz,
we found a temporal correlation between modulations in firing rate and
saccade onset in some SNr neurons when we averaged across many trials
(see Figs. 4, 8, 12, and 16). However, the high inter- and intratrial
variance in firing rate made initiation-related signals, particularly
initiation-related pauses, difficult for us to detect reliably on
single trials using the standard thresholding-type techniques that have
been applied successfully to the detection of initiation-related
signals in the FEF (Hanes et al. 1995
) and SC
(Sparks 1978
). Thus like specification signals,
initiation signals seem to be carried in a qualitatively different form
in the SNr than in the SC and FEF.
IMPLICATIONS FOR A POSITION OF SNr IN AN FEF-SC
CIRCUIT.
The diverse anatomic, physiological, and pharmacological evidence
presented by Hikosaka and Wurtz are compelling arguments for a
functional connection between the SNr and the SC, and our data are
consistent with the hypothesis that at least some SNr neurons take part
in saccade generation by disinhibiting collicular neurons. However,
there is also evidence that the SNr may play a role outside of this
circuit. Strick and his colleagues, for example, have used retrograde
trans-neuronal transport of herpes simplex virus to
demonstrate that the pathway from the SNr to the ventral anterior and
mediodorsal thalamic nuclei (Carpenter et al. 1976;
Ilinsky et al. 1985
) links SNr neurons to visual area
TE, area 9, area 12, and area 46 of cortex in addition to the FEF
(Middleton and Strick 1996
). Furthermore, Juraska and colleagues have gathered data showing that the apical dendrites of
neurons in the SNc extend into the SNr, which implies that signals from
the SNr may reach the pars compacta (Juraska et al. 1987
). Furthermore, our physiological data indicate that the
firing rates of some SNr neurons increased above baseline before some saccades in a delayed saccade task, that SNr neurons may carry information about saccadic metrics in a qualitatively different form
than FEF and SC neurons, and that SNr neurons may carry information about saccadic initiation in a qualitatively different form than FEF
and SC neurons. These anatomic and physiological data suggest that
gating collicular discharge as part of an FEF-SC circuit may not be the
only role of the SNr in the generation of saccades.
Future Directions
By developing a quantitative method for describing the
spatiotemporal response profiles of SNr neurons, we were able to
compare saccade-related neurons in the SNr, FEF, and SC. This same
quantitative method should allow us to further explore the influence of
context on SNr neurons, as originally described by Hikosaka and
Wurtz (1983a-d
). For example, it should be possible to
quantitatively describe the response profiles of SNr neurons during
both visually guided saccade tasks and memory-guided saccade tasks and
to thus quantitatively assess the effect of a memory requirement on the activity of SNr neurons. A similar approach could be used to explore the effects of other forms of behavioral context on SNr activity.
In the on-going theoretical discussion of basal ganglia function, it
has been suggested that the basal ganglia are activated by both
goal-directed movements (cf. Kandel et al. 1991;
Zigmond et al. 1999
) and movements that will yield
reinforcement (cf. Hollerman et al. 1998
). Either
explanation is consistent with Hikosaka and Wurtz' observation that
SNr neurons were modulated during task-related saccades but were
unmodulated during spontaneous saccades. Saccades aligning gaze with
the fixation LED at the beginning of the delayed saccade task, however,
are goal-directed but are not directly reinforced. By quantifying the
response profile of SNr neurons during these fixational movements and
comparing them to both the response profile of SNr neurons during
spontaneous saccades and to the response profile of SNr neurons during
saccades at the end of a delayed saccade trial, it may be possible to
improve our understanding of the role of the SNr in movement generation.
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ACKNOWLEDGMENTS |
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We thank M. Platt, V. Ciaramitaro, M. Brown, and H. Bayer for assistance with the experiments and comments on the manuscript. We also thank J. Zhang, L. Brooks, S. Corathers, J. Mones, and H. Tamm for technical support.
This work was supported by National Eye Institute Grant EY-10536 and National Research Service Award MH11359-2 to A. Handel.
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FOOTNOTES |
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Address for reprint requests: A. Handel, Center for Neural Science, New York University, 4 Washington Place, 809, New York, NY 10003.
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 26 March 1999; accepted in final form 29 June 1999.
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