Robijanto Soetedjo

Complex Spike Activity of Purkinje Cells in the Oculomotor Vermis during Behavioral Adaptation of Monkey Saccades

Throughout life, the oculomotor system can correct itself when saccadic eye movements become inaccurate. This adaptation mechanism can be engaged in the laboratory by displacing the target when the saccade toward it is in flight. Forward and backward target displacements cause gradual increases and decreases in saccade amplitude, respectively. Equipped with this paradigm, we asked whether Purkinje cells (P-cells) in the vermis of the oculomotor cerebellum, lobules VIc and VII, changed their complex spike (CS) discharge during the behavioral adaptation of horizontal saccades. We tested the hypothesis that CS activity would change only when a targeting saccade caused an error in eye position relative to the target, i.e., during the error interval between the primary and corrective saccades. We examined only those P-cells whose simple spike activity exhibited either a burst or pause with saccades in several directions. Approximately 80% of such P-cells exhibited an increase in CS activity during the error interval when the adaptation paradigm imposed horizontal eye-position errors in one direction and a decrease in activity for errors in the other. As adaptation progressed and errors were reduced, there was no consistent change in the CS activity. These data suggest that the CS activity of P-cells in the oculomotor vermis signals the direction but not the magnitude of eye-position error during saccade adaptation. Our results are consistent with cerebellar learning models that have been proposed to explain adaptation of the vestibulo-ocular reflex so similar mechanisms may also underlie plasticity of this precision voluntary oculomotor behavior.

Complex spike activity in the oculomotor vermis of the cerebellum: a vectorial error signal for saccade motor learning?

Brain stem signals that generate saccadic eye movements originate in the superior colliculus. They reach the pontine burst generator for horizontal saccades via short-latency pathways and a longer pathway through the oculomotor vermis (OMV) of the cerebellum. Lesion studies implicate the OMV in the adaptation of saccade amplitude that occurs when saccades become inaccurate because of extraocular muscle weakness or behavioral manipulations. We studied the nature of the possible error signal that might drive adaptation by examining the complex spike (CS) activity of vermis Purkinje (P-) cells in monkeys. We produced a saccade error by displacing the target as a saccade was made toward it; a corrective saccade approximately 200 ms later eliminated the resulting error. In most P-cells, the probability of CS firing changed, but only in the error interval between the primary and corrective saccade. For most P-cells, CSs occurred in a tight cluster approximately 100 ms after error onset. The probability of CS occurrence depended on both error direction and size. Across our sample, all error directions were represented; most had a horizontal component. In more than one half of our P-cells, the probability of CS occurrence was greatest for error sizes<5 degrees and less for larger errors. In the remaining cells, there was a uniform increased probability of CS occurrence for all errors<or=7-9 degrees. CS responses disappeared when the target was extinguished during a saccade. We discuss the properties of this putative CS error signal in the context of the characteristics of saccade adaptation produced by the target displacement paradigm.

Changes in Simple Spike Activity of Some Purkinje Cells in the Oculomotor Vermis during Saccade Adaptation Are Appropriate to Participate in Motor Learning

Adaptation of saccadic eye movements provides an excellent motor learning model to study theories of neuronal plasticity. When primates make saccades to a jumping target, a backward step of the target during the saccade can make it appear to overshoot. If this deception continues for many trials, saccades gradually decrease in amplitude to go directly to the back-stepped target location. We used this adaptation paradigm to evaluate the Marr–Albus hypothesis that such motor learning occurs at the Purkinje (P)-cell of the cerebellum. We recorded the activity of identified P-cells in the oculomotor vermis, lobules VIc and VII. After documenting the on and off error directions of the complex spike activity of a P-cell, we determined whether its saccade-related simple spike (SS) activity changed during saccade adaptation in those two directions. Before adaptation, 57 of 61 P-cells exhibited a clear burst, pause, or a combination of both for saccades in one or both directions. Sixty-two percent of all cells, including two of the four initially unresponsive ones, behaved differently for saccades whose size changed because of adaptation than for saccades of similar sizes gathered before adaptation. In at least 42% of these, the changes were appropriate to decrease saccade amplitude based on our current knowledge of cerebellum and brainstem saccade circuitry. Changes in activity during adaptation were not compensating for the potential fatigue associated with performing many saccades. Therefore, many P-cells in the oculomotor vermis exhibit changes in SS activity specific to adapted saccades and therefore appropriate to induce adaptation.

Encoding of action by the Purkinje cells of the cerebellum

Execution of accurate eye movements depends critically on the cerebellum, suggesting that the major output neurons of the cerebellum, Purkinje cells, may predict motion of the eye. However, this encoding of action for rapid eye movements (saccades) has remained unclear: Purkinje cells show little consistent modulation with respect to saccade amplitude or direction, and critically, their discharge lasts longer than the duration of a saccade. Here we analysed Purkinje-cell discharge in the oculomotor vermis of behaving rhesus monkeys (Macaca mulatta) and found neurons that increased or decreased their activity during saccades. We estimated the combined effect of these two populations via their projections to the caudal fastigial nucleus, and uncovered a simple-spike population response that precisely predicted the real-time motion of the eye. When we organized the Purkinje cells according to each cell’s complex-spike directional tuning, the simple-spike population response predicted both the real-time speed and direction of saccade multiplicatively via a gain field. This suggests that the cerebellum predicts the real-time motion of the eye during saccades via the combined inputs of Purkinje cells onto individual nucleus neurons. A gain-field encoding of simple spikes emerges if the Purkinje cells that project onto a nucleus neuron are not selected at random but share a common complex-spike property.

Subthreshold Activation of the Superior Colliculus Drives Saccade Motor Learning

How the brain learns and maintains accurate precision movements is currently unknown. At times throughout life, rapid gaze shifts (saccades) become inaccurate, but the brain makes gradual adjustments so they again stop on target. Previously, we showed that complex spikes (CSs) in Purkinje cells of the oculomotor cerebellum report the direction and amplitude by which saccades are in error. Anatomical studies indicate that this error signal could originate in the superior colliculus (SC). Here, we deliver subthreshold electrical stimulation of the SC after the saccade lands to signal an apparent error. The size of saccades in the same direction as the simulated error gradually increase; those in the opposite direction decrease. The electrically adapted saccades endure after stimulation is discontinued, exhibit an adaptation field, can undergo changes in direction, and depend on error timing. These electrically induced adaptations were virtually identical with those produced by the visually induced adaptations that we report here for comparable visual errors in the same monkeys. Therefore, our experiments reveal that an additional role for the SC in the generation of saccades is to provide a vector error signal that drives dysmetric saccades to adapt. Moreover, the characteristics of the electrically induced adaptation reflect those of error-related CS activity in the oculomotor cerebellum, suggesting that CS activity serves as the learning signal. We speculate that CS activity may serve as the error signal that drives other kinds of motor learning as well.

Complex spike activity signals the direction and size of dysmetric saccade errors.

The cerebellar oculomotor vermis (OMV) receives inputs from both the superior colliculus (SC) via the nucleus reticularis tegmenti pontis as mossy fibres and the inferior olive as climbing fibres. Lesion studies show that the OMV is necessary for the saccade amplitude adaptation that corrects persistent motor errors. In this study, we examined whether the complex spike (CS) activity due to climbing fibre inputs could serve as an error signal to drive saccade adaptation. When there was an error during behaviourally induced saccade dysmetrias, the probability of CS occurrence depended on the direction and size of the error. If this CS activity actually drives saccade adaptation, we speculate that adaptation should be equally efficient in all directions and that the course of adaptation could have two operating modes.

Effect of inactivation and disinhibition of the oculomotor vermis on saccade adaptation.

The ability to adapt a variety of motor acts to compensate for persistent natural or artificially induced errors in movement accuracy requires the cerebellum. For adaptation of the rapid shifts in the direction of gaze called saccades, the oculomotor vermis (OMV) of the cerebellum must be intact. We disrupted the neural circuitry of the OMV by manipulating gamma aminobutyric acid (GABA), the transmitter used by many neurons in the vermis. We injected either muscimol, an agonist of GABA, to inactivate the OMV or bicuculline, an antagonist, to block GABA inhibition. Our previous study showed that muscimol injections cause ipsiversive saccades to fall short of their targets, whereas bicuculline injections cause most ipsiversive saccades to overshoot. Once these dysmetrias had stabilized, we tested the monkeys ability to adapt saccade size to intra-saccadic target steps that produced a consistent saccade under-shoot (amplitude increase adaptation required) or overshoot (amplitude decrease adaptation required). Injections of muscimol abolished the amplitude increase adaptation of ipsiversive saccades, but had either no effect, or occasionally facilitated, amplitude decrease adaptation. In contrast, injections of bicuculline impaired amplitude decrease adaptation and usually facilitated amplitude increase adaptation. Neither drug produced consistent effects on the adaptation of contraversive saccades. Taken together, these data suggest that OMV activity is necessary for amplitude increase adaptation, whereas amplitude decrease adaptation may involve the inhibitory circuits within the OMV.

EFFECTS OF GABA AGONIST AND ANTAGONIST INJECTIONS INTO THE OCULOMOTOR VERMIS ON HORIZONTAL SACCADES

The oculomotor vermis (OMV) of the cerebellum is necessary for the generation of the accurate rapid eye movements called saccades. Large lesions of the midline cerebellar cortex involving the OMV cause saccades to become hypometric and more variable. However, saccades were not examined immediately after these lesions so the interpretation of the resulting deficits might have been contaminated by some adaptation to the saccade dysmetria. Therefore, to better understand the contribution of the OMV to normal saccades, we impaired its operation locally by injecting small amounts of either an agonist or antagonist of γ-aminobutyric acid (GABA), which is a ubiquitous neurotransmitter throughout the cerebellar cortex. Muscimol, a GABA agonist, inactivated part of the OMV, whereas bicuculline, an antagonist, disinhibited it. Muscimol caused all ipsiversive horizontal saccades from 5 to 30° to become hypometric. In contrast, bicuculline produced an amplitude-dependent dysmetria: ipsiversive horizontal saccades elicited by target steps <10° became hypometric, whereas those in response to larger steps became hypermetric. At the transition target amplitude, saccade amplitudes were quite variable with some being hypo- and others hypermetric. After most injections of either agent, saccades had lower peak velocities and longer durations than pre-injection saccades of the same amplitude. The longer durations were associated with a prolongation of the deceleration phase. Both agents produced inconsistent effects on contraversive saccades. These results establish that the oculomotor vermis helps control the characteristics of normal ipsiversive saccades and that GABAergic inhibitory processes are a crucial part of this process.

Behavior of the Oculomotor Vermis for Five Different Types of Saccade.

Single unit and lesion studies have implicated the oculomotor vermis of the cerebellum in the control of targeting saccades to jumping visual targets. However, saccades can be made in a variety of other target situations where they can occur with different reaction times (express or delayed saccades) in response to a remembered target location (memory-guided saccades) or between several targets that are always visible (scanning saccades). Here we ask whether the oculomotor vermis contributes to generating all these types of saccades by examining the simple spike discharge of its Purkinje cells. Twenty-six of 32 P-cells (81%) exhibited qualitatively similar phasic firing patterns for targeting, express, scanning, delayed, and memory-guided saccades. The remaining six exhibited a different pattern for just scanning saccades. Although a sensitive test of discharge patterns revealed significant differences for some pairs of saccade types in ∼29% of P-cells, there was no cell-to-cell consistency as to which pairs were associated with different patterns. Also, a less sensitive comparison identified substantially fewer cells (∼15%) with different patterns. Thus the lack of any consistent difference in firing for different saccade types leads us to conclude that the oculomotor vermis is not likely to contribute differently to targeting, express, scanning, delayed, or memory-guided saccades.

Cerebellar fastigial nucleus influence on ipsilateral abducens activity during saccades.

To characterize the cerebellar influence on neurons in the abducens (ABD) nucleus, we recorded ABD neurons before and after we inactivated the caudal part of the ipsilateral cerebellar fastigial nucleus (cFN) with muscimol injection. cFN activity influences the horizontal component of saccades. cFN inactivation increased the activity of most ipsilateral ABD neurons (19/22 in 2 monkeys) during ipsiversive (hypermetric) saccades, primarily by increasing burst duration. During contraversive (hypometric) saccades, the off-direction pause of most (10/15) ABD neurons was shorter than normal because of the early resumption of ABD activity. Early ABD firing caused the early contraction of antagonist muscles that reduced eye rotation and made contraversive saccades hypometric. Thus the cerebellum controls ipsilateral ABD activity by truncating on-direction bursts during ipsiversive saccades and extending off-direction pauses during contraversive saccades. We conclude that cFN output keeps saccades accurate by controlling when ABD on-direction bursts and off-direction pauses end.