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. Contextual Modulation of Substantia Nigra Pars Reticulata Neurons. J. Neurophysiol. 83: 3042-3048, 2000. Neurons in the substantia nigra pars reticulata (SNr) are known to encode saccadic eye movements within some, but not all, behavioral contexts. However, the precise contextual factors that effect the modulations of nigral activity are still uncertain. To further examine the effect of behavioral context on the SNr, we recorded the activity of 72 neurons while monkeys made saccades during a delayed saccade task and during periods of free viewing. We quantified and compared the movement fields of each neuron for saccades made under three different conditions: 1) spontaneous saccades, which shifted gaze during periods of free viewing when no stimuli were presented and no reinforcements were delivered; 2) fixational saccades, which brought gaze into alignment with a fixation target at the start of a delayed saccade trial, were necessary for trial completion, but were not directly followed by reinforcement; and 3) terminal saccades, which brought gaze into alignment with a visual target at the end of a delayed saccade trial and were directly followed by reinforcement. For three of the four SNr neuron classes, saccade-related modulations were only present before terminal saccades. For the fourth class, discrete pausers, saccade-related modulations were substantially larger for terminal saccades than for fixational saccades, and modulations were absent for spontaneous saccades. These results and other recent work on the basal ganglia suggest that some saccade-related signals in the SNr may be influenced by the reinforcement associated with a particular saccadic eye movement.
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INTRODUCTION |
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By examining brain stem afferents to the
extraocular motoneurons, movement physiologists have demonstrated the
existence of neural signals tightly correlated with the rotational
position and velocity of the eye. Upstream from the neurons that carry these signals, neurons of the superior colliculus have been identified that topographically map saccades of all possible amplitudes and directions. A large body of evidence suggests that modulations of
collicular activity are also tightly correlated with the generation of
eye movements (for a review of these findings see Fuchs et al.
1985; Sparks and Mays 1990
).
It seems likely, however, that a nearly perfect correlation between
neural activity and movement generation cannot persist in areas that
lie even further upstream from the musculature than the colliculus.
Goldberg and his colleagues (Bushnell et al.
1981; Goldberg and Bushnell 1981
) were the first
physiologists to explicitly recognize this possibility in the
oculomotor system. In the early 1980s they demonstrated the existence
of neurons of the frontal eye fields and posterior parietal cortex that
carried saccade-related signals that were modulated by the behavioral
context within which a saccade occurred. Hikosaka and Wurtz
(1983a
-d
, 1985a
,b
, 1989
) extended this concept to studies of the basal ganglia when they demonstrated that the activity of saccade-related neurons in the substantia nigra pars reticulata (SNr), which project to the
colliculus, was also correlated with the behavioral context within
which a movement occurred.
Although Hikosaka and Wurtz's early studies clearly established that
saccade-related signals in the SNr could be modulated by the conditions
under which a saccade was produced, an identification of the precise
contextual variables that influence nigral modulation has remained a
subject of considerable investigation. Recent studies, for example,
have demonstrated that many closely related neurons in the basal
ganglia may carry information about the value of a movement to an
animal: Schultz and colleagues (cf. Hollerman and Schultz
1998; Mirenowicz and Schultz 1996
;
Schultz 1998
; Schultz et al. 1993
) have
identified signals in the pars compacta subdivision of the substantia
nigra (SNc), which receives afferents from the SNr, correlated with the
discrepancy between expected and received rewards. Hikosaka and his
colleagues (cf. Hikosaka 1991
; Hikosaka et al.
1993a
,b
; Kato et al. 1995
; Kawagoe et al.
1998
; Kori et al. 1995
) have found that neurons
in the caudate nucleus, an area that receives afferents from the SNc
and projects to the SNr, generate movement-related activity that is
correlated with the gain an animal should expect to receive for
performing a movement.
To begin to test the hypothesis that, like the caudate and the SNc, the SNr carries contextually modulated signals associated with the reward that an animal can expect to realize for producing a movement, we examined the responses of nigral neurons during saccades made in three contexts: 1) spontaneous saccades, which shifted gaze during periods of free viewing when no stimuli were presented and no reinforcements were delivered; 2) fixational saccades, which brought gaze into alignment with the fixation location at the start of a delayed saccade trial, were necessary for trial completion, but were not directly followed by reinforcement; and 3) terminal saccades, which brought gaze into alignment with a visual target at the end of a delayed saccade trial and were reinforced at short latency. We found that, although all saccade-related SNr neurons were modulated in association with the terminal movements made at the end of a delayed saccade trial, no nigral neurons were modulated for spontaneous movements and only one physiological subclass was weakly modulated for fixational movements.
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METHODS |
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Seventy-two neurons were recorded from four substantia nigra
pars reticulati in three awake-behaving rhesus macaques. During each
experiment, eye position was monitored at 500 Hz using the scleral
search coil technique (Fuchs and Robinson 1966;
Judge et al. 1980
). Standard behavioral, physiological,
and histological procedures were employed as described in detail
previously (Handel and Glimcher 1999a
). All procedures
and protocols were designed in association with the University
Veterinarian, approved by the New York University Animal care and use
committee, and were in compliance with the U.S. Public health
service's Guide for the care and use of animals.
We recorded neuronal activity while animals were free to shift gaze around a visually stationary, dimly illuminated room during free periods and while animals made gaze shifts during a delayed saccade task. Free periods were unsignaled, always 2.3 s in duration, and were inserted randomly between 5 and 10% of delayed saccade trials. Delayed saccade trials (Fig. 1) began with an audible beep. Three hundred milliseconds later a central light-emitting diode (LED) subtending 0.25° of visual angle, 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 later, a single yellow eccentric LED was illuminated for 200-1,200 ms, after which the fixation LED was extinguished and the subject was required to shift gaze into alignment with the eccentric LED (±3-5°) within 350 ms. If the subject's gaze remained in alignment with the eccentric LED for 350-450 ms, the trial was considered to be performed correctly. Each correctly executed trial was immediately followed by a 300-ms noise burst that served as a secondary reinforcer. In addition, a random 1/5 to 1/3 of correct trials were also followed by delivery of a 0.25-ml drop of fruit juice that served as a primary reinforcer. Eccentric LEDs were placed randomly within 20 horizontal and 20 vertical degrees of the central stimulus. An intertrial interval that ranged from 200 to 3,800 ms followed all free periods and delayed saccade trials.
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Terminal saccades were identified as movements produced after fixation
stimulus offset that brought gaze into alignment with the eccentric
target (±3-5°). Fixational saccades were identified from records of
each delayed saccade trial and were defined as the first movement
(2° in amplitude) after trial onset, which brought the point of
gaze into alignment with the fixation position (±4°). Because
fixational saccades were unconstrained in starting point, they were
often >20° in amplitude. The range of fixation saccade amplitudes
and directions we sampled thus exceeded the range sampled for terminal
saccades that were constrained to fall within the central 40° of the
oculomotor range. Finally, during each free period, from 0 to 4 spontaneous saccades (
2° in amplitude) were identified. Because
spontaneous saccades were not constrained either in starting point or
ending point, the range of spontaneous saccade amplitudes and
directions we sampled also exceeded the range of terminal saccades we sampled.
For each neuron, perievent time histograms were produced using all movements into the quadrant or hemifield (e.g., upper, upper right, lower left, etc.) that produced the largest modulations for the neuron under study (for untuned neurons, movements of all amplitudes and directions were included). Histograms were generated by aligning trials on movement onset and then averaging the data in 25-ms bins and nomalizing spike counts/bin to spikes/second. Normalized standard deviations and standard errors were then computed for each bin to assess both the variance in our samples and the confidence that could be placed in our estimates of mean rate.
The perimovement firing rates associated with all movements were defined as the mean spike rate during the 150-ms period beginning 100 ms before saccade onset. Movement fields were generated for data from all three conditions by plotting perimovement firing rate as function of vertical and horizontal movement amplitude. Plots of movement fields were generated by averaging all observed spike rates within 2° × 2° bins and plotting average rate as a function of horizontal and vertical movement amplitude. Linear regressions were performed on the unaveraged raw data for each of our three saccade types to identify best-fit planes that described the movement fields.
In a previous description of the terminal saccade data presented here
(Handel and Glimcher 1999a), we showed that these planes described nigral response fields at least as well as Gaussian functions
for terminal saccade movement fields. Those linear regressions accounted for, on average, 86% of the total variance in each movement field. To determine whether the linear regressions were equally effective at describing spontaneous and fixational movement fields, we
also computed variance accounted for by these regressions using the
same techniques that we have described for terminal saccades (Handel and Glimcher 1999a
).
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RESULTS |
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In a previous examination of these nigral neurons (Handel
and Glimcher 1999a), we described the pattern of firing
associated with the terminal movement produced at the end of a delayed
saccade task. By analyzing those firing rates we found that
saccade-related nigral neurons could be divided into two broad
categories: neurons that showed a reduction in firing rate before
saccades (pausers) and neurons that showed an increase in firing rate
before saccades (bursters). Although saccade-related pausing neurons in
the SNr had been described previously (Hikosaka and Wurtz
1983a
-d
; Joseph and Boussaoud 1985
), bursting
neurons in the SNr had only been described among skeletomuscular
movement-related cells (Schultz 1986
). We also found
that each of these two categories could be divided into two subclasses.
One subclass of pausing cells showed a perimovement decrement in firing
rate for terminal movements of all the amplitudes and directions we
sampled (±20° from fixation; universal pausers), whereas others
paused more strongly for contraversive movements than for ipsiversive
movements (discrete pausers). Nearly all of the bursting neurons that
we encountered showed an increase in firing rate for contraversive
movements, but one subclass (pause-bursters) showed a decrease in
firing rate for ipsiversive movements, whereas the other subclass
(bursters) did not.
For this report, we examined the firing rates of these same neurons during spontaneous and fixational movements and compared those data with our previously published description of firing rates during terminal saccades. Figure 2A plots the firing rate of a universal pauser during three metrically similar upward saccades. Note that in the left and middle panels, which plot spontaneous and fixational movements, respectively, this universal pauser is unmodulated around the time of the upward saccade. In Fig. 2A, right, by contrast, the firing rate of the neuron is reduced immediately before the saccade and remains at a reduced level for >500 ms.
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To determine how characteristic this response was of all the trials we obtained for this cell, we generated perievent time histograms, centered on movement onset, that averaged firing rates in 25-ms bins (Fig. 2B; upward bars = standard deviations; downward bars = standard errors). Note that although the average firing rate of the neuron began to decrease ~150 ms before terminal saccade onset, no modulation was apparent at any time in association with either spontaneous or fixational movements.
To quantify this relationship and to account for the fact that most nigral neurons are spatially tuned with regard to movement amplitude and direction, we plotted the firing rate of each neuron immediately before and during spontaneous, fixational, and terminal saccades, as a function of horizontal and vertical movement amplitude. Figure 2C presents these movement fields that plot raw data for spontaneous movements, fixational movements, and terminal movements averaged into 2° bins with mean firing rate coded in color. Note that during all terminal movements the firing rate of the neuron dropped to nearly zero. In contrast, during all spontaneous and fixational movements the firing rate of the neuron remained at baseline levels, which are indicated by the gray arrow.
Like the neuron shown in Fig. 2, most nigral neurons were not modulated during either spontaneous or fixational movements. However, as shown in Fig. 3 for a discrete pauser, we did find that some neurons were weakly modulated during fixational saccades. Figure 3A plots neuronal activity during three metrically similar up-right movements. Note that the neuron appears weakly, if at all, modulated before a spontaneous saccade, clearly modulated before a fixational saccade, and profoundly modulated before a terminal saccade. The perievent time histograms indicate that for this neuron there was, in fact, a repeatable modulation associated with fixational movements that was about one-half the size of the modulation associated with terminal movements.
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The movement fields plotted for this neuron in Fig. 3C reveal that these modulations were spatially tuned: the neuron paused more strongly for rightward (contraversive) fixational movements than for leftward movements, just as it paused more strongly for rightward than for leftward terminal saccades.
To provide a statistical test of the hypothesis that some or all of the
population of nigral neurons are unmodulated during spontaneous and
fixational saccades, we fit each of the three movement fields, for all
neurons, with planar regressions and then analyzed the parameters that
described those regression planes for our nigral population. Figure
4 plots the total variance accounted for
by the planar regressions for all three types of movement fields. The
planar regressions accounted for, on average, 91% the variance
associated with spontaneous movements and 90% of the variance
associated with fixational movements. Thus the regressions did at least
as good a job describing spontaneous and fixational movement fields as
they did describing terminal movement fields (Handel and
Glimcher 1999a).
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We therefore used the average modulation and spatial tuning estimates derived from the planar fits to the three movement fields measured for each neuron to compare the degree to which SNr neurons encoded spontaneous, fixational, and terminal saccades. The results of this comparison for universal pausers, bursters, and pause-bursters are shown in Fig. 5. The left panel of Fig. 5A plots the average modulation for spontaneous saccades as a function of the average modulation for terminal saccades, for each neuron. Note that, for terminal saccades, the average modulations in firing rate across this population, which included both bursters and pausers, spanned a range of >200%. In contrast, for spontaneous saccades, the average modulation for all of these neurons was very close to 0%. Similarly, the right panel of Fig. 5A shows that the tuning strength for spontaneous saccades rarely exceeded 1 spike/s/deg, whereas the tuning strength for terminal saccades ranged up to 3 spike/s/deg. A similar pattern is apparent in the comparison between fixational saccades and terminal saccades (Fig. 5B). Although there were a few neurons that were very weakly tuned for terminal saccades but showed some tuning for fixational saccades (Fig. 5B, right panel), across this population the average modulation and tuning strength were small for fixational saccades even when they were large for terminal saccades.
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We tested, for each of these three types of neurons, the hypothesis that the modulations for spontaneous or fixational saccades were statistically indistinguishable from the modulations of these neurons for terminal saccades. For all three groups of neurons were able to reject the null hypothesis (by t-test) for either the slope of the movement fields, their mean rates, or both, leading us to conclude that the modulations of these neurons during spontaneous and fixational saccades are different than during terminal saccades (see Fig. 5 legend). In fact, for all three classes the linear correlations between the movement field parameters for spontaneous and terminal movements were insignificant. Other than a weak effect for the spatial tuning in pause-bursters, there were also no significant correlations between fixational and terminal saccades movement field parameters for these classes.
A different pattern was seen for discrete pausers (Fig. 6). Like the other cell classes, there was very little average modulation in firing rate for either spontaneous (Fig. 6A, left panel) or fixational saccades (Fig. 6B, left panel) even in neurons with large average modulations in activity for terminal saccades. However, unlike other SNr cell classes, many discrete pausers did show spatially tuned decreases in activity before fixational saccades. On average, however, the responses of discrete pausers for fixational saccades tended to be only half as large as the responses of these neurons for terminal saccades (Fig. 6B, right panel: slope = 0.46; correlation, P < 0.0005). A statistical analysis of these modulations, however, did permit us to reject the null hypothesis (by t-test) that these neurons behaved in the same manner during fixational and terminal saccades (see Fig. 6 legend). Some discrete pausers also showed spatially tuned decreases in activity before spontaneous saccades, although these responses tended to be even weaker (Fig. 6A, right panel: slope = 0.27; correlation, P < 0.05). Thus discrete pausers appear to encode all three types of saccades, but in a manner that appears to be correlated with the reinforcement that can be expected to result from each type of movement.
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DISCUSSION |
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In summary, we replicated the original finding by Hikosaka
and Wurtz (1983a) that saccade-related neurons of the SNr are
modulated during terminal saccades produced in a delayed saccade task
but largely unmodulated during spontaneous saccades produced while the
animal is seated in a dimly illuminated stationary environment. We also
examined fixational saccades, which, like terminal saccades, shifted
gaze into alignment with an experimenter defined location within the
context of an operant task. Unlike terminal saccades, however, these
fixational saccades were not followed by a reinforcement at short
latency. We found that nigral universal pausers, pause-bursters, and
bursters were unmodulated during these fixational movements. Nigral
discrete pausers were relatively weakly, but significantly, modulated
during these fixational movements. These data may suggest that at least
some neurons in the SNr carry a signal related to the reinforcement
associated with an eye movement.
This conclusion should be tempered by the observation that, of
the saccades we studied, only the terminal saccades always shifted gaze
from a central starting position to an eccentric ending position. Both
the spontaneous and fixational saccades began with the eye at a
variable starting position within the orbit. This observation, however,
is unlikely to account for our findings for two reasons. First, the
initial eye position for many spontaneous saccades were similar to the
initial eye position for terminal saccades, and yet we found no
evidence that any of the spontaneous saccades we examined were
associated with rate modulations in universal pausers, pause-bursters,
or bursters. Second, when SNr activity has been previously examined
while subjects made saccades from different starting positions, no
effect of orbital position on neuronal activity has been reported
(Bayer and Glimcher 1999; Hikosaka and Wurtz
1983a
).
When Hikosaka and Wurtz (1983a-d
,
1985a
,b
) first examined the saccade-related SNr
nearly 20 yr ago, they concluded that unlike many brain stem and
cortical areas, the SNr encoded saccade-related signals in a
contextually dependent manner. Many nigral neurons were inhibited
before saccades under some environmental contexts but not under others.
In their preliminary examination of these saccadic contexts, they noted
that some neurons were more strongly inhibited during tasks which
1) imposed a memory requirement on the subject,
2) required that saccades be produced at a very precise time, and 3) imposed very specific constraints for
reinforcement. In light of existing data suggesting that the basal
ganglia were preferentially involved in the generation of movements
guided by remembered stimuli (cf. Divac et al. 1967
;
Leigh et al. 1983
; Rosvold et al. 1958
),
they interpreted their data to suggest that the SNr might be
specialized to disinhibit brain stem saccadic circuitry before memory
saccades (cf. Hikosaka and Wurtz 1989
). Further, because
the flow of signals through the oculomotor SNr was then believed to
originate largely in the saccade-associated frontal eye fields and to
reach the SNr via the caudate, they proposed a general frontal eye
fields-caudate-SNr circuit for the gated activation of the
topographically mapped superior colliculus during memory saccades.
Many of the assumptions on which that original theory was based have
been refined over the past 20 yr. First, the work of Schultz (cf.
Hollerman and Schultz 1998; Mirenowicz and
Schultz 1996
; Schultz 1998
; Schultz et
al. 1993
) and Hikosaka (Hikosaka 1991
;
Hikosaka et al. 1993a
,b
; Kato et al.
1995
; Kawagoe et al. 1998
; Kori et al.
1995
) has suggested that the responses of neurons in the basal
ganglia may be more tightly tied to the reinforcement or gain that an
animal can expect to receive than to simple properties of the sensory
stimulus guiding the movement. Second, new anatomic evidence
(Middleton and Strick 1996
) suggests that afferents and efferents of the SNr outside the basal ganglia include not only the
frontal eye fields and the superior colliculus but also a number of
other cortical areas believed to play a role in visual perception and
saccade planning. Third, our own work (Handel and Glimcher
1999a
,b
) has shown that not only does the SNr also contain saccade-related bursting neurons undescribed by Hikosaka and Wurtz but
that when saccade-related nigral neurons are examined with identically
reinforced memory and nonmemory tasks, the nigral population is not
preferentially modulated before memory saccades.
At least some of these observations have been interpreted to
suggest that a principal function of the basal ganglia is to predict
the magnitude and timing of future reinforcements and to identify
errors in those predictions (cf. Schultz et al. 1997). Both theoretical and experimental work conducted over the past several
years has identified signals of these types as critical for response
selection and generation (cf. Hikosaka 1991
;
Hollerman and Schultz 1998
; Kawagoe et al.
1998
; Platt and Glimcher 1999
). If, as these
observations suggest, the basal ganglia serves as a source for signals
of this type and these signals are critical for behavioral control,
then output nuclei like the SNr might be expected to carry signals of
this type beyond the basal ganglia. Our data begin to suggest that the
SNr, a principal motor-related output nucleus of the basal ganglia,
carries a signal related to the reinforcement an animal can expect to
receive for producing an eye movement in an operant task.
To more fully test this hypothesis, it will be necessary to design experiments in which animal subjects specifically communicate an estimate of the gain that they expect to receive for a behavioral response. These behaviorally measured estimates, or psychometric functions, could then be correlated with physiologically derived neurometric functions for neurons in the SNr.
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ACKNOWLEDGMENTS |
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We are grateful to M. Platt, V. Ciaramitaro, M. Brown, and H. Bayer for assistance with the experiments and comments on the manuscript. We also thank B. Miller, S. Corathers, J. Mones, and H. Tamm for technical support.
This work was supported by National Institutes of Health Grants EY-10536 and MH-11359 to A. Handel.
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FOOTNOTES |
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Address for reprint requests: P. W. Glimcher, Center for Neural Science, 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 27 September 1999; accepted in final form 2 February 2000.
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REFERENCES |
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