1Yerkes Regional Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia 30322; 2Department of Anatomy and Neuroscience, University of Texas Medical Branch, Galveston, Texas 77555; and 3Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195
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ABSTRACT |
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Mustari, Michael J., Ronald J. Tusa, Andrew F. Burrows, Albert F. Fuchs, and Christine A. Livingston. Gaze-Stabilizing Deficits and Latent Nystagmus in Monkeys With Early-Onset Visual Deprivation: Role of the Pretectal NOT. J. Neurophysiol. 86: 662-675, 2001. We studied the role of the pretectal nucleus of the optic tract (NOT) in the development of monocular optokinetic nystagmus (OKN) asymmetries and latent nystagmus (LN) in two monkeys reared with binocular deprivation (BD) caused by binocular eyelid suture for either the first 25 or 55 days of life. Single-unit recordings were performed in the right and left NOT of both monkeys at 2-3 yr of age and compared with similar unit recordings in normally reared monkeys. We also examined ocular motor behavior during electrical stimulation of the NOT and during pharmacological inactivation and activation using GABAA agonists and antagonists. In BD animals a large proportion of NOT units was dominated by the contralateral eye, in striking contrast to normal animals where 100% of NOT units were sensitive to stimuli delivered to either eye. In the 55-day BD animal no binocularly sensitive neurons were found, while in the 25-day BD animal 60% of NOT units retained at least some binocular sensitivity. Differences in direction sensitivity were also observed in BD animals. We found that 56% of units in the 55-day BD monkey and 10% of units in the 25-day BD monkey responded preferentially to contraversive visual motion. In contrast, only 5% of the NOT units encountered in normally reared monkeys respond preferentially during contraversive visual motion, the rest were most sensitive to ipsiversive visual motion. NOT neurons of BD monkeys showed a wide range of speed sensitivities similar to that of normal monkeys. Unilateral electrical stimulation of the NOT in BD animals induced a conjugate nystagmus with slow phases directed toward the side of stimulation. When we blocked the activity of NOT units with muscimol, a potent GABAA agonist, LN was abolished. In contrast, LN was increased when spontaneous activity of the NOT was enhanced with bicuculline, a GABAA antagonist. Our results indicate that the NOT in BD monkeys plays an important role in the OKN deficits and LN generation during monocular viewing. We hypothesize that the large proportion of units dominated by the contralateral eye contribute to the development of monocular OKN asymmetries and LN.
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INTRODUCTION |
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In our previous paper
(Tusa et al. 2001), we described the eye movement
behavior of monkeys reared with brief periods of early binocular
deprivation of vision (BD). The presence of monocular optokinetic
nystagmus (OKN) asymmetry and latent nystagmus (LN) suggested to us
that there might be a problem in the neural properties of the nucleus
of the optic tract (NOT). The NOT contains neurons that are sensitive
to visual motion, typically, toward the side of recording
(Hoffmann et al. 1988
; Mustari and Fuchs
1990
). The visual sensitivity of units in the NOT is derived
from contralateral retinal (Hoffmann and Stone 1985
) and
ipsilateral striate and extrastriate visual cortical inputs
(Baleydier et al. 1990
; Hoffmann et al.
1992
; Mustari et al. 1994
). Many units in the
primate NOT have very large receptive fields appropriate for encoding
full-field visual motion to support optokinetic eye movements
(Hoffmann et al. 1988
; Mustari and Fuchs
1990
; see Fuchs and Mustari 1993
for review).
Lesions of the NOT of rabbits (Collewijn 1975b
),
cats (Precht and Strata 1980
), and primates
(Kato et al. 1988
; Schiff et al. 1990
)
eliminate the slow buildup in OKN eye velocity, toward the side of
lesion, during horizontal full-field visual motion. The slow buildup in
eye velocity during OKN is thought to be due to the charging of a
velocity storage mechanism (Raphan et al. 1977
). The NOT
could provide inputs to the velocity storage mechanism through
projections to the medial vestibular nucleus (MVN) and nucleus
prepositus hypoglossi (NPH) (Belknap and McCrea
1988
; Büttner-Ennever et al.
1996a
; Magnin et al. 1983
;
Mustari et al. 1994
). Earlier studies have shown that
NOT unit responses are affected by lesions of the visual cortex or
disruptions of binocular vision early in development (see Schor
1983
for review). For example, NOT units may lose their ability
to respond to high-velocity visual motion or small-sized stimuli after
lesions of the visual cortex (Hoffmann 1982
). NOT units
lose their binocularity when animals are reared with early onset
strabismus (Cynader and Hoffmann 1981
; Distler
and Hoffmann 1996
) or monocular deprivation (Hoffmann 1983
). Behaviorally, such animals exhibit an asymmetric OKN,
like that found in human infants (see Schor 1993
for review).
We hypothesize that monocular OKN deficits and LN in BD monkeys are due
to a defect in the NOT. To adequately test this hypothesis, we
conducted single-unit studies recording studies in the NOT of BD
monkeys. A preliminary report of this study has appeared previously
(Mustari et al. 1995).
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METHODS |
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We have described most of the methods used in this study in
detail elsewhere (Mustari and Fuchs 1990), so only a
brief description is provided here. All of the work described here was
approved by our respective Institutional Animal Care and Use Committees.
We prepared animals for single-unit recording experiments as described
below. Single-unit activity was recorded from the NOT in the two
deprived (25- and 55-day BD) and the three normal monkeys when they
were 2-3 yr old. Eye movements were measured with an implanted scleral
search coil (Judge et al. 1980) and an electromagnetic induction method (Fuchs and Robinson 1966
). All surgical
procedures were performed under aseptic conditions with the monkey
under deep anesthesia (halothane 1.5%).
During single-unit recording sessions, the monkeys sat in a sound-dampened and light-proof enclosure facing a tangent screen onto which the target spot and other visual stimuli were rear-projected. The monkeys were rewarded for fixating a stationary target spot while other visual test stimuli were moved on the tangent screen, for making accurate saccades to target steps and for smoothly tracking a sinusoidally oscillating target. Visual stimuli were either random dot patterns subtending a large portion of the visual field (70° × 50° or 100° × 100°) or a small-diameter target spot (0.1°). Visual test stimuli were moved in various directions at various speeds (1-200°/s) with either sinusoidal or constant velocity wave shapes.
Extracellular single-unit potentials were recorded with tungsten
microelectrodes by conventional methods (Mustari and Fuchs 1990). Target- and eye-position signals, unit discharge, and
other relevant signals were saved on analog or digital-audio tape for subsequent computer digitization and quantitative off-line data analysis. The eye and target positions were digitized at 1 kHz. We used
a window discriminator (Bak Electronics) to provide a transistor-transistor logic (TTL) acceptance pulse that accurately indicated the time of each action potential. The rising phase of the
acceptance pulse was recorded with an accuracy of 10 µs with an
interrupt driven process.
Single-unit recording experiments were performed in different ways in
the 25- and 55-day BD animals. The 55-day BD monkey had difficulty
suppressing nystagmus and holding good fixation, even during binocular
viewing. Therefore we immobilized the eye contralateral to the NOT
recording site. This immobilization was performed when the animal was 3 yr of age. We used a retrobulbar injection of 15 units of botulinum
toxin-A (BTX; provided by Dr. Alan Scott, Smith-Kettlewell Institute,
San Francisco and administered by Dr. Ray Gariano) to immobilize the
eye. The immobilization reduced eye velocities to less then a few
degrees per second and lasted for the entire time we performed
single-unit recording experiments in the 55-day BD monkey. This allowed
us to perform accurate visual receptive-field testing. Each eye was
tested for visual sensitivity during viewing of a stationary or moving
visual stimulus. We measured the eye movements in the mobile eye during single-unit recording and LN testing in this animal. When the animal
was returned to his cage, the eyelid over the immobilized eye was held
closed by a single mattress suture (8-0 nylon). This ensured that the
cornea stayed protected in the event that the Botulinum interfered with
blinking. We did not check for potential adaptation of LN during this
monocular viewing condition. However, extensive behavioral testing was
performed prior to retrobulbar injections (see Tusa et al.
2001). Because the 25-day BD animal had little trouble fixating
or suppressing nystagmus during binocular viewing (see
RESULTS), a retrobulbar BTX block was unnecessary. Single-unit data from the NOT of normally reared monkeys, obtained in
previous and ongoing studies (Mustari and Fuchs 1990
),
were used for comparative purposes.
To pharmacologically activate or inactivate the NOT, we placed microinjections of a GABAA antagonist (bicuculline methiodide) or GABAA agonist (muscimol) into the NOT. Reversible activation or inactivation, through modulation of GABAA circuits, was achieved by delivering small (0.2 µl) injections of bicuculline (2%) or muscimol (2% in sterile physiological saline) at the center of the NOT. For control injections, we used similar volumes of sterile saline. For all injections, we replaced our standard tungsten single-unit recording electrode with a glass pipette of relatively small tip diameter (15 µm). Injections were delivered slowly over the course of about 2 min by applying short-duration (10-50 ms), low pressure pulses (20-50 psi) with a pico-pump (W.P.I. PV-830).
We marked the location of our recording sites by placing electrolytic lesions (10 µA D.C. for 10 s) on several electrode tracks in each animal. At the conclusion of the experimental series, the animal was given a lethal dose of barbiturate and perfused transcardially, with saline followed by 10% Formalin. Frozen sections were cut in a coronal stereotaxic plane every 50 µm, mounted on microscope slides, and stained with cresyl violet for histologic reconstruction of electrode tracks and unit locations.
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RESULTS |
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Location of recording
We were able to use well-established functional
landmarks (Mustari and Fuchs 1990) to verify that we
were recording in the NOT including localizing following-omnipause
neurons (FOPNs) immediately dorsal to the NOT (Mustari and Fuchs
1990
; Mustari et al. 1997
). At the end
of our recording experiments, histological sections were stained to
localize electrode tracks as described in METHODS. Figure
1 shows examples of lesions (arrows)
placed on two different rostral NOT tracks in the 55-day BD monkey.
These lesions were placed either at the depth where we recorded
direction-selective units (medial track) or 1 mm deep to these units
(lateral track).
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We recorded from the NOT on each side of the brain stem in both the 25- and 55-day BD monkeys. We tested units for ocular dominance, visual speed sensitivity, direction selectivity, receptive-field size, and spontaneous activity in the light and dark. Unfortunately, in some cases, we lost isolation before completing all testing.
Direction selectivity
NOT units of BD monkeys, like those of normally reared animals,
were differentially sensitive to the direction of visual motion. Figure
2 (left column) shows examples
of directional tuning curves obtained in normally reared and in BD
monkeys (25 or 55 day). We tested direction selectivity by presenting a
large-field random-dot pattern moving in eight different directions,
separated by 45°, either to a fixating monkey or immobilized eye. We
estimated the preferred direction of each unit by fitting a curve to
the average firing rate measured at each direction (Mustari and
Fuchs 1990; Wallman and Velez 1985
). The point
where the fitted curve reached a maximum was considered the preferred
direction. Figure 2 shows the preferred directions for our population
of NOT neurons in polar histogram form (Fig. 2, right
column). Included in the plot for the 55-day BD case are seven
neurons that we classified as purely ipsiversive. For these cells, we
used the results obtained during horizontal motion to assign them to
the ipsiversive group because isolation was lost before pure vertical
visual motion was tested. In normally reared monkeys, most (95%;
n = 44) NOT units prefer ipsiversive visual motion.
Ipsiversive units also were most common (90%; n = 38)
in the 25-day BD monkey. However, a striking difference in direction
preference was observed in the 55-day BD monkey where 56%
(n = 35) of NOT units responded preferentially during
contraversive visual motion.
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The directional tuning for individual NOT units was relatively broad in
both normally reared and BD monkeys. We estimated the broadness of
directional tuning by computing a bandwidth that takes into account
average firing rate in both the excitatory and inhibitory directions
(Albright 1984). Bandwidth was estimated as the width at
half-maximum firing rate. Bandwidths ranged from relatively narrow as
shown for the unit illustrated in the middle left column of
Fig. 2 to broad (Fig. 2, top left column) in both normally
reared and BD monkeys. Figure 3 shows the
bandwidth data for normally reared and BD monkeys. The bandwidth
histograms showed considerable overlap with means of 126 ± 32° (mean ± SD), 140 ± 53°, and 110 ± 20° for normal, 25-day BD, and 55-day BD, respectively. We performed
a one-way ANOVA (Tukey test) and found no significant difference in the
bandwidth distributions of normal versus BD (either 25 day or 55 day)
NOT units.
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We used the vectors associated with maximum and minimum firing to
construct a directionality index for each unit. The degree of direction
selectivity for a given unit can be described by the ratio of activity
in the maximum and minimum directions (max min)/(max). Units
were judged as highly direction selective if the above ratio was
greater than 0.5 and direction biased if the value exceeded 0.25. If a
unit had appreciable spontaneous firing rate, this could be accounted
for by computing a second index (max
min)/max
spont). A
value greater than 1 with this index indicated strong directional
tuning (not illustrated). As illustrated in Fig.
4, the majority of units were highly
direction selective or biased. This remained the case when spontaneous
firing rate was taken into account (2nd index). Furthermore, the degree of direction selectivity was similar in normally reared and BD monkeys.
We performed a one-way ANOVA and found no significant difference in the
directionality indexes of normal versus BD NOT units.
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Ocular dominance
We tested the ocular dominance preference of NOT units in our BD
monkeys by presenting stimuli moving in the optimal direction, over a
similar range of velocities (see Visual speed sensitivity below) to those tested during binocular viewing. We measured
the average firing rate in the preferred direction, tested through each
eye, to assign units to one of five different ocular dominance groups.
Units driven exclusively by the contralateral (contra) or ipsilateral
(ipsi) eye were placed in group 1 or 5, respectively. Units biased
toward either the contralateral or ipsilateral eye were placed in
groups 2 or 4, respectively. NOT units driven equally by either eye
were placed assigned to group 3. To place a unit into one of these
groups, we calculated an ocular dominance index (OD) from the ratio
(contra ipsi)/(contra + ipsi). Units in OD group 1 (contra) had
OD indexes >0.95. Units with OD index near 0.0 ± 0.2 were
assigned to group 3. Other units were assigned to groups 2 or 4. Units
biased toward the ipsilateral eye had negative values using the above
index. We encountered no units driven exclusively from the ipsilateral
eye in our monkeys. In the normal monkey, all NOT units can be driven
from either eye (Hoffmann 1992
; Inoue et al.
2000
; Mustari and Fuchs 1990
). As shown in Fig.
5, NOT units in BD monkeys had a
strikingly abnormal distribution of ocular dominance. In the 55-day BD
monkey, all units (n = 31) were driven exclusively by
the contralateral eye. In the 25-day BD monkey, 62% of NOT units were
dominated by the contralateral eye with some responding only to
stimulation of the contralateral eye. However, binocular units were
present in this animal, and a few of these units even showed a bias in
favor of the ipsilateral eye (group 3). The pattern of ocular dominance in BD animals is clearly biased toward the contralateral eye. We
performed a one-way ANOVA (Tukey test) and found that the ocular dominance distributions of normal and BD units were significantly different (P < 0.001).
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Visual speed sensitivity
We tested the speed sensitivity of NOT units in BD monkeys by moving a large-field visual stimulus in the unit's preferred direction over a series of speeds from 1 to 200°/s while the monkey fixated a stationary target spot. In Fig. 6, we illustrate representative speed tuning curves from each of our monkeys. We tested the speed sensitivity of 50 neurons in 3 normal monkeys, and 35 neurons in BD monkeys (n = 15, 55 day BD; n = 20, 25 day BD). As in normally reared monkeys, NOT units of BD monkeys responded over a wide range of stimulus speeds (Fig. 6). Some units showed firing rates that increased with stimulus speed over most of the range tested; others preferred or were tuned to a specific speed. In all animals, we found clear examples of NOT units that were most sensitive to either high (>50°/s) or low visual speeds (Fig. 6). We conclude that BD monkey NOT units retain sensitivity to high-speed visual motion (i.e., >50°/s). However, the peak firing rate at the optimal speed tended to be lower in the 55-day BD animal compared with normal animals.
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Initiation of LN
To measure the onset time of LN accurately, we placed ferro-electric liquid crystal shutters that close within 35 µs (Display Tech) in front of both eyes of the 25-day animal. We performed this testing when the animal was 3 yr old. Sample data from this testing are shown in Fig. 7. After the animal fixated a 0.1° stationary red target spot on a stationary 100° by 100° random dot field, the shutter in front of one eye was closed. Neither the fixation target nor random dot pattern were moved during this testing. To estimate the latency of LN initiation, we used the point where eye velocity exceeded baseline by 3°/s. LN was initiated at relatively short latency averaging 82.2 ± 9.0 ms (11 trials). Unfortunately, for our earlier experiments with the 55-day BD animal, we did not have the liquid crystal shutters, so data regarding the latency of LN are not available for that animal.
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Unit response during LN
If the NOT plays a role in LN, we would expect units there to be modulated during LN. Figure 8 illustrates the response of a unit recorded in the right NOT during LN. This unit had a large receptive field and preferred contraversive visual motion. For this testing, the monkey (25-day BD) viewed a 100° × 100° stationary random dot pattern and a stationary fixation spot rear-projected on a tangent screen. The unit illustrated in Fig. 8 discharged during each LN slow phase to the right (Fig. 8A), when visual motion was contraversive (leftward). Like all NOT units tested (n = 25), this one showed no response in association with the quick phases of nystagmus, whether ipsiversive (as here) or contraversive. Furthermore, units with ipsiversive direction preference were inhibited during LN. To verify that unit response during LN was visually contingent and not related to the eye movement per se, we blinked off the stationary visual stimulus during LN (Fig. 8A). Following the blink, unit discharge ceased, even though slow-phase eye movement continued. Furthermore, when the next slow phase started, NOT unit discharge did not resume at the expected latency (Fig. 8A, arrow). Finally, when the stationary visual scene was turned back on during a slow phase, the unit response resumed at its characteristic visual latency (55 ms). In Fig. 8B, NOT unit responses for 21 successive LN slow phases have been aligned on the start of each slow phase. Because slow phases vary in duration, the response duration in some rasters is shorter than in others. The peristimulus time histogram (Fig. 8B) for times later then 200 ms after slow-phase start decrements due to variable duration slow-phase events. The latency between slow-phase start time and the onset of unit discharge illustrated in Fig. 8 averages 55 ± 12 ms.
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Spontaneous firing rate
Because LN can be initiated during viewing of a featureless scene
or ganzfeld (Tusa et al. 2001), we checked whether NOT
unit discharge was associated with luminance level. For this testing, we measured the resting firing rate during binocular viewing of a
ganzfeld and compared this activity to that recorded in complete darkness. We restricted this testing to pretectal units that were direction selective (n = 15). In the absence of visual
motion, some NOT units had higher firing rates in the light then in
darkness; other units showed little difference in firing rate in these
two conditions. However, we did not test the effects of luminance on
NOT unit response during stimulation with moving visual stimuli.
Electrical stimulation of NOT
In earlier studies of normally reared monkeys, we found that
stimulus trains (50-250 Hz) of low current (10-80 µA) biphasic pulses (200 µs duration) delivered at the recording site of
direction-selective units elicited an optokinetic-like nystagmus with
ipsiversive slow phases (Mustari and Fuchs 1990).
Similarly, when we delivered comparable stimulation in BD monkeys, we
also generated an optokinetic-like nystagmus with slow phases directed
toward the side of stimulation. For example, electrical stimulation
applied for 10 s in the 25-day BD monkey produced an ipsiversive
slow-phase nystagmus with slow-phase velocities reaching well over
100°/s (Fig. 9). Because this
stimulation was delivered during binocular viewing in the light, the
animal may have been able to suppress some of his nystagmus by fixating on stationary contours in the large-field random dot pattern. This is
indicated by the fall-off in eye velocity during the electrical stimulation. We found the same type of ipsiversive (slow-phase) response during electrical stimulation in the 55-day BD monkey (not
illustrated). Therefore, despite the increased percentage of
contraversive units in the NOT of BD monkeys, stimulation of their NOTs
still produced nystagmus with ipsiversive slow phases.
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Effect of NOT inactivation on LN
If the NOT plays an important role in LN, silencing its output should produce an effect opposite to that of electrical stimulation, i.e., LN should be reduced or abolished. Rather then use permanent lesions to test this hypothesis, we injected muscimol (a potent GABAA agonist) into the NOT to reversibly block this area. For this testing, the monkey viewed a stationary small target spot centered on a stationary large-field (100° × 100°) random dot pattern.
Covering the left eye of the 55-day BD monkey produced a strong LN with leftward slow phases (Fig. 10A). The left eye was the mobile eye in these experiments. The right eye had been previously immobilized with botulinum injections (see METHODS). After we blocked the left NOT with a small (0.2 µl) injection of 2% muscimol, the direction of nystagmus reversed (Fig. 10B). This reversal in the direction of nystagmus took about 3 min to reach a maximum velocity and lasted for over 1 h. When we tested the animal the following day during right eye viewing, the usual pattern of leftward slow-phase nystagmus was observed. When we performed a bilateral muscimol blockade of the NOTs in the 55-day BD animal, LN was virtually eliminated (Fig. 10C).
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Figure 11 shows examples of our muscimol experiments in the 25-day BD monkey. In the 25-day BD day animal, LN was strongest during left eye viewing conditions (e.g., Fig. 11A). Prior to injection, a brisk LN with typical nonconstant velocity slow phases was produced (Fig. 11A). During binocular viewing (Fig. 11B), gaze was stable because the monkey could fixate on components in the stationary scene. During right eye viewing, only a modest LN was present with slow phases toward the left (Fig. 11C). After muscimol injection of the right NOT, LN during left eye viewing was abolished (Fig. 11D). Furthermore, OKN could not be elicited toward the side of muscimol injection (not illustrated). The normally weak LN associated with right eye viewing became much stronger following muscimol injections in the right NOT (Fig. 11F). So we conclude that the muscimol produced a functional inactivation of the NOT.
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After bilateral muscimol blockade in the 25-day BD monkey (Fig. 12B), LN was virtually abolished. Here we show the initiation of LN by including the shutter trace representing closure of a liquid-crystal shutter (upward deflection), placed in front of the right eye (Fig. 12, bottom trace). In the preinjection condition (Fig. 12, top panel), the monkey is able to hold a steady fixation during binocular viewing. When the shutter in front of the right eye was closed, a brisk LN was present. However, after simultaneous muscimol injection into both the right and left NOTs, LN does not occur during monocular viewing (Fig. 12, bottom panel). Instead, there is a series of saccades either to the left or right with drifts back to the center of the screen. The time constant of decay in velocity of these drifts averages 300 ms, a value close to that reported for the oculomotor plant. In summary, we found that muscimol blockade of the NOT virtually eliminated LN in both the 55-day BD animal (Fig. 10C) and 25-day BD monkey (Fig. 12B), supporting the hypothesis that the NOT is necessary for LN.
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Figure 13 shows the results of delivering bicuculline methiodide (0.2 µl) into the center of the right NOT in the 25-day BD monkey. Bicuculline injections were not performed in the 55-day BD animal. During this testing, the monkey faced a tangent screen with stationary visual stimuli including a centrally located target spot and large-field random dot pattern. Prior to the injection, viewing by the left eye produced LN with slow phases to the right, whereas viewing through the right eye produced LN with slow phases to the left (Fig. 13, A and C). During binocular viewing, gaze was stable (Fig. 13B). After bicuculline injection in the right NOT, slow phases were always ipsiversive (rightward) regardless of the viewing condition (Fig. 13, D-F). Furthermore, slow phases of the pharmacologically evoked nystagmus were virtually constant velocity (e.g., Fig. 13D), unlike the decreasing velocity slow phases of preinjection LN (see Fig. 13A). Therefore bicuculline-evoked nystagmus resembled normal OKN. This result compliments that obtained with electrical stimulation (described above), showing that unilateral NOT activation in the BD monkey produces a nystagmus with ipsiversive slow phases as in normally reared monkeys. During binocular viewing postinjection, there was some decrease in the slow-phase eye velocity, perhaps due to attempted fixation. Control injections of sterile saline of the same volumes used in bicuculline or muscimol experiments produced no change in LN or OKN.
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DISCUSSION |
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In this study, we have tested the hypothesis raised in
our previous paper that monocular OKN (MOKN) asymmetry in BD monkeys may be due to a loss of binocular cells in the NOT (Fig. 11,
Tusa et al. 2001). We also made several observations in
different experiments, which support our hypothesis that the NOT is
involved in the production of LN. These observations include the
alteration of response properties of NOT neurons in BD monkeys during
LN and the amelioration or enhancement of LN with different
pharmacological manipulations of the NOT.
Unit discharge in BD monkeys
BINOCULARITY.
In normally reared monkeys, all NOT neurons are binocularly driven with
approximately equal influence from either eye (Hoffmann et al.
1988; Mustari and Fuchs 1990
). In our BD
monkeys, however, units were either driven exclusively from the
contralateral eye (55-day BD) or biased toward the contralateral eye
(25-day BD). Indeed, loss of NOT binocularity in cats is commonly
associated with monocular deprivation or strabismus, and in such
animals, monocular OKN is asymmetric with weak or absent temporalward
responses (see Hoffmann et al. 1996
). Our results
indicate that the degree of monocular OKN asymmetry could be associated
with the degree of binocularity of the NOT. This is because monocular
OKN asymmetry was more prominent in our 55-day BD animal compared with
the 25-day BD animal. This was coincident with a complete shift in
ocular dominance to the contralateral eye in the 55-day BD animal and only a partial shift in the 25-day BD animal.
DIRECTION SELECTIVITY. In the normal monkey, the majority of NOT units are direction selective with over 95% preferring ipsiversive visual motion (Fig. 2). However, in the BD monkeys, units with a preference for contraversive visual motion were more frequently encountered. This was most obvious in the 55-day BD monkey, where 56% of the NOT units preferred contraversive visual motion. It seems unlikely that the directionality of NOT units changed as a result of BD. It is more likely that there was a dropout of normal ipsiversive cells, which raised the proportion of contraversive cells.
Contraversive units do not seem to contribute to the OKN because there is no temporalward response during monocular stimulation. It is possible that these contraversive units could maintain LN for as long as monocular viewing continues. Such contraversive visual units are robustly activated during LN (Fig. 8). For example, a slow phase that moves the eye to the right over a stationary visual scene produces net leftward visual motion. For units recorded in the right NOT, during LN associated with left eye viewing (rightward slow phases), net visual motion is to the left. This is analogous to the situation seen during smooth pursuit of a small target spot moving across a stationary large-field visual pattern. For example, an ipsiversive NOT unit will respond during the contraversive direction of smooth pursuit over a stationary background because the net direction of large-field visual motion remains ipsiversive (Mustari and Fuchs 1990OCULAR FOLLOWING, OPTOKINETIC AND LATENT NYSTAGMUS INITIATION.
Our studies of LN onset latency provide an important perspective on
potential contributing neural pathways. When monocular viewing was
initiated by closing a shutter placed in front of the eye, LN occurred
with a latency as short as 70 ms. Considering that there was little
visual motion while the monkey was actively fixating, such a short LN
onset latency suggests the involvement of rather direct visual-motor
connections. The shortest latency, visually elicited, eye movement is
known as the "short latency ocular following response" (OFR). The
OFR has a latency of about 50 ms and is enhanced by triggering a step
of large-field visual motion 20-50 ms after a saccade. The OFR uses at
least some of the same circuits as OKN (Inoue et al.
2000). The initial rapid jump in eye velocity of OKN has a
latency of 95 ms. The difference in OFR and OKN latencies can be
accounted for by the way in which visual stimuli are typically
presented in these paradigms. OKN is normally elicited by suddenly
illuminating a moving stripped drum (see Fuchs and Mustari
1993
for review). In contrast, the OFR is elicited with a step
of visual motion of an already illuminated but stationary pattern.
Kawano and colleagues (1994)
have shown that the OFR is
delayed when a moving pattern is suddenly illuminated, resulting in
OKN-like latencies (i.e., 95 ms). Therefore we suggest that the LN
onset times we observed indicate that LN employs visual afferent
pathways very similar to those of the OFR and OKN. These pathways could
involve direct retinal projections to the contralateral NOT or
cortical-NOT circuits (see Mustari et al. 1994
for
review). We know from our work and others (Mustari and Fuchs
1990
; Schiff et al. 1988
) that electrical
stimulation of one NOT produces a nystagmus with slow phases directed
toward the side of stimulation. The onset of slow-phase eye velocity
produced by electrical stimulation is comparable to that produced by
the sudden onset of visual motion (Inoue et al. 2000
;
Kawano et al. 1992
; Mustari and Fuchs
1990
) or closing a shutter in front of one eye in our BD
monkeys (see Figs. 9 and 12A).
PHARMACOLOGICAL EXPERIMENTS. We found complimentary results in our reversible activation and inactivation studies in BD monkeys. When we placed unilateral injections of bicuculline into the NOT of the 25-day BD animal, a nystagmus with ipsilaterally directed slow phases was produced. Possibly, this occurred because we disinhibited the NOT, producing a net increase in firing rate of the injected NOT and an imbalance between the output of the two NOTs. In contrast, if one NOT is inactivated, a nystagmus with slow phases directed away from the side of injection develops. This nystagmus occurs possibly because the injected NOT is silenced, thus leaving the opposite NOT with a relatively increased net firing rate. Finally, if we block both NOTs simultaneously, LN is virtually abolished for the duration of the blockade.
We have not yet tested other oculomotor sites for their potential roles in LN. For example, the dorsolateral pontine nucleus (DLPN) might be expected to play a role in LN. This is because the DLPN has been shown in single-unit recording and lesion studies to play a role in smooth pursuit (Mustari et al. 1988 ![]() |
ACKNOWLEDGMENTS |
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The authors acknowledge the expert technical assistance offered by S. Usher and H. McMullen. We also acknowledge the contribution of Dr. Ray Gariano for placing the retrobulbar injections of botulinum toxin to immobilize the eye. We express our appreciation to J. R. Economides for help in preparing figures for the manuscript.
This work was supported by National Institutes of Health Grants EY-06069, EY-00745, RR-00165, and RR-00166.
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FOOTNOTES |
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Address for reprint requests: M. J. Mustari, Yerkes Regional Primate Research Center, Dept. of Neurology, 954 Gatewood Rd. NE, Emory University, Atlanta, GA 30322 (E-mail: mjmustar{at}rmy.emory.edu).
Received 6 November 2000; accepted in final form 10 April 2001.
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REFERENCES |
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