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Following unilateral vestibular damage (UVD), vestibular compensation restores both static and dynamic vestibular reflexes. The cerebellar cortex provides powerful GABAergic inhibitory input to the vestibular nuclei which is necessary for compensation. Metabotropic GABA type B (GABA(B)) receptors in the vestibular nuclei are thought to be involved. However, the contribution of GABA(B) receptors may differ between static and dynamic compensation. We tested static and dynamic postural reflexes and gait in young mice, while they compensated for UVD caused by injection of air into the vestibular labyrinth. The effects of an agonist (baclofen), an antagonist (CGP56433A) and a positive allosteric modulator (CGP7930) of the GABA(B) receptor were evaluated during compensation. Static postural reflexes recovered very rapidly in our model, and baclofen slightly accelerated recovery. However, CGP56433A significantly impaired static compensation. Dynamic reflexes were evaluated by balance-beam performance and by gait; both showed significant decrements following UVD and performance improved over the next 2 days. Both CGP56433A and baclofen temporarily impaired the ability to walk on a balance beam after UVD. Two days later, there were no longer any significant effects of drug treatments on balance-beam performance. Baclofen slightly accelerated the recovery of stride length on a flat surface, but CGP7930 worsened the gait impairment following UVD. Using immunohistochemistry, we confirmed that GABA(B) receptors are abundantly expressed on the vestibulospinal neurons of Deiters in mice. Our results suggest that GABA(B) receptors contribute to the compensation of static vestibular reflexes following unilateral peripheral damage. We also conclude that impairment of the first stage of compensation, static recovery, does not necessarily result in an impairment of dynamic recovery in the long term.

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In the central nervous system, sensory and motor signals at different frequencies are transmitted most effectively by neural elements that have different dynamic characteristics. Dynamic differences may be due, in part, to the dynamics of neurotransmitter receptors. For example, N-methyl-D-aspartate (NMDA) receptors are thought to be a component of the "neural integrator" of the vestibulo-ocular reflex (VOR), which generates a signal proportional to eye position. We measured the effects of blockade of NMDA and AMPA/kainate receptors on the gain and phase of the VOR at frequencies between 0.1 and 8 Hz in alert cats. The competitive NMDA antagonist, APV, and the non-competitive antagonists, MK-801 and ketamine, all caused a pronounced reduction in VOR gain. Gain was more strongly attenuated at low frequencies (0.1-1 Hz) than at higher frequencies (2-8 Hz). The phase lead of the eye with respect to the head was increased up to 30 degrees. In contrast, the reduction in gain associated with drowsiness or surgical anesthesia was not frequency-dependent. Blockade of AMPA/kainate receptors by the competitive antagonists, CNQX and NBQX, reduced the gain of the VOR at all frequencies tested. We evaluated our results using a control systems model. Our data are consistent with participation of NMDA receptors in neural integration, but suggest that NMDA receptors also participate in transmission by other components of the VOR pathway, and that neural integration also employs other receptors. One possibility is that between 0.1 and 10 Hz, higher-frequency signals are transmitted primarily by AMPA/kainate receptors, and lower frequencies by NMDA receptors. This arrangement would provide a biological substrate for selective motor learning within a small frequency range.

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Accurate performance by the vestibulo-ocular reflex (VOR) is necessary to stabilize visual fixation during head movements. VOR performance is severely affected by peripheral vestibular damage; after one horizontal semicircular canal is plugged, the horizontal VOR is asymmetric and its amplitude is reduced. The VOR recovers partially. We investigated the limits of recovery by measuring the VOR's response to ipsilesional and contralesional rotation after unilateral peripheral damage in cats. We found that the VOR's response to rotation at high frequencies remained asymmetric after recovery was complete. When the stimulus was a pulse of head velocity comprising a dynamic overshoot followed by a plateau, gain was partially restored and symmetry completely restored within 30 days after the plug, but only for the plateau response. The overshoot in eye velocity remained asymmetric. The asymmetry was independent of stimulus velocity throughout the known linear velocity range of primary vestibular afferents. Sinusoidal rotation at 0.05-8 Hz revealed that, within this range, the persistent asymmetry was significant only at frequencies above 2 Hz. Asymmetry was independent of the peak head acceleration over the range of 50-500 degrees/s2. When both horizontal canals were plugged, a small residual VOR was observed, suggesting residual signal transduction by plugged semicircular canals. However, transduction by plugged canals could not explain the enhancement of the VOR gain, at high frequencies, for rotation away from the plugged side compared with rotation toward the plug. Also, the high-frequency asymmetry was present after recovery from a unilateral labyrinthectomy. These results suggest that high-frequency asymmetry after unilateral damage is not due to residual function in the plugged canal. The findings are discussed in the context of a bilateral model of the VOR that includes central filtering.

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The vestibulo-ocular reflex (VOR) stabilizes gaze adequately under a variety of conditions because it is capable of a simple form of motor learning. Learning is induced by changed visual conditions or to compensate for vestibular sensory loss. We asked whether the mechanisms that are triggered by visual signals can fully account for recovery from vestibular damage. We addressed this question by comparing the effects of optically induced motor learning (i.e., changes in gain induced by telescopic lenses) and recovery from a unilateral horizontal canal plug on the dynamics of the cat VOR. Optically induced learning modified the gain of the VOR more effectively for rotation at low frequencies (below 5 Hz) than for higher-frequency stimuli. During recovery from a plug, the gain of the VOR increased at all frequencies tested, with a similar time course for all frequencies. After recovery the gain for rotation at 5 Hz or above was relatively enhanced. After recovery reached its upper limit, optically induced learning could bring about further changes in gain. The results are interpreted with respect to partially (but not completely) shared mechanisms for optically induced learning and recovery after a unilateral canal plug.

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The vestibulo-ocular reflex (VOR) allows clear vision during head movements by generating compensatory eye movements. Its response is reduced following damage to the vestibular endorgan, but recovers over time. The VOR is mediated by both direct and indirect anatomical pathways; most direct pathways include only two central synapses, both located in the brainstem. To investigate the possibility that a direct pathway is modified during the recovery of VOR gain, we measured the oculomotor response to single current pulses delivered to the vestibular labyrinth of two alert cats after plugging the contralateral horizontal canal. The response was also measured after motor learning induced by continuously worn lenses (optically induced motor learning) in two cats. The gain of the VOR was monitored concurrently. The eye movement evoked by a current pulse increased more than 100% during recovery from a plug. The electrically evoked eye movement did not change during optically induced motor learning either before the plug or after recovery. The gain of the VOR was modified in both situations. We conclude that direct VOR pathways are modified significantly during recovery after a plug, but not during optically induced learning. Our results suggest that significant modification of direct pathways may require a change in vestibular sensory input.

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1. We made extracellular recordings from neurons in the abducens nuclei of alert rhesus monkeys during electrical stimulation of the vestibular labyrinths with brief current pulses and during smooth pursuit, steady fixation, and the vestibuloocular reflex (VOR) evoked by passive head turns. The responses to electrical stimuli were compared with quantitative measures of the sensitivity of each neuron to eye position and eye velocity. We also compared the strengths of the vestibular inputs from the labyrinths ipsilateral and contralateral to the side of recording. 2. Abducens neurons showed transient excitation after a current pulse was applied to the contralateral labyrinth and transient inhibition after stimulation of the ipsilateral labyrinth. The latency of excitation had a mean value of 1.7 ms and a median value of 1.5 ms. Latency was unimodally distributed with little variation among neurons. Neurons with large responses showed a second phase of excitation that started 2.5 ms after the stimulus. 3. In two of three monkeys, the excitatory responses of abducens neurons to electrical stimulation of the contralateral labyrinth were approximately 3 times as large as their inhibitory responses to stimulation of the ipsilateral labyrinth. The difference in response size was not observed in the third monkey. The asymmetry in the size of the electrically evoked inputs from the two labyrinths was associated with a smaller asymmetry in responses of abducens neurons during the VOR evoked by passive head turns. The increase in firing rate during head rotation away from the side of the recording was almost always larger than the decrease in firing rate during head rotation toward the side of the recording. 4. The size of the neuronal response to electrical stimulation was correlated with the magnitude of the change in discharge rate during eye movements. Single or multiple regression of measures of response amplitude against eye position threshold, sensitivity to eye position, sensitivity to eye velocity, and baseline discharge rate yielded correlation coefficients that ranged from 0.26 to 0.92 in different monkeys. The existence of positive correlations is consistent with a role of the intrinsic properties of abducens neurons in determining recruitment order. However, the existence of large amounts of variability within most of the samples suggests that the recruitment order of abducens neurons also depends on the discharge properties of the afferents to each abducens neuron.

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1. We have identified a group of brain stem cells called "flocculus target neurons" (or FTNs) because they are inhibited at monosynaptic latencies by stimulation of the flocculus and the ventral paraflocculus with single electrical pulses. We report the responses of FTNs, as well as those of other brain stem cells, during horizontal eye movements with the head stationary and during natural vestibular stimulation in monkeys. 2. FTNs discharged primarily in relation to eye movements. The majority (71%) showed increased firing for eye movement away from the side of the recording ("contraversive"), which is consistent with their inhibition by Purkinje cells that show increased firing for eye movement toward the side of recording. However, a significant and surprisingly large percentage (29%) of FTNs showed increased firing for eye movement toward the side of recording ("ipsiversive"). 3. The firing rate of FTNs showed strong modulation during pursuit of sinusoidal target motion with the head stationary and during the compensatory eye movements evoked by fixation of an earth-stationary target with sinusoidal head rotation. In addition, firing rate was related to eye position during steady fixation at different positions. Of the FTNs that showed increased firing for contraversive eye motion during pursuit with the head stationary, most had an infection in the relationship between firing rate and eye position so that the sensitivity to eye position was low for eye positions ipsilateral to straight-ahead gaze and high for eye positions contralateral to straight-ahead gaze. 4. When the monkey canceled the vestibuloocular reflex (VOR) by tracking a target that moved exactly with him during sinusoidal head rotation, the firing rate of FTNs was modulated much less strongly than during pursuit with the head stationary. In the FTNs that showed increased firing for contraversive eye motion during pursuit, firing rate during cancellation of the VOR increased for contraversive head motion during sinusoidal vestibular rotation at 0.4 Hz but was only weakly modulated during rotation at 0.2 Hz. 5. The position-vestibular-pause cells (PVP-cells), previously identified as interneurons in the disynaptic VOR pathways, were not inhibited by stimulation of the flocculus and ventral paraflocculus and had response properties that were different from FTNs. The majority (69%) showed increased firing for contraversive eye motion during pursuit and for ipsiversive head motion during cancellation of the VOR, whereas some (31%) showed the opposite direction preferences under both conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

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1. We recorded from neurons in the brain stem of monkeys before and after they had worn magnifying or miniaturizing spectacles to cause changes in the gain of the vestibuloocular reflex (VOR). The gain of the VOR was estimated as eye speed divided by head speed during passive horizontal head rotation in darkness. Electrical stimulation in the cerebellum was used to identify neurons that receive inhibition at monosynaptic latencies from the flocculus and ventral paraflocculus (flocculus target neurons or FTNs). Cells were studied during smooth pursuit eye movements with the head stationary, fixation of different positions, cancellation of the VOR, and the VOR evoked by rapid changes in head velocity. 2. FTNs were divided into two populations according to their responses during pursuit with the head stationary. The two groups showed increased firing during smooth eye motion toward the side of recording (Eye-ipsiversive or E-i) or away from the side of recording (Eye-contraversive or E-c). A higher percentage of FTNs showed increased firing rate for contraversive pursuit when the gain of the VOR was high (> or = 1.6) than when the gain of the VOR was low (< or = 0.4). 3. Changes in the gain of the VOR had a striking effect on the responses during the VOR for the FTNs that were E-c during pursuit with the head stationary. Firing rate increased during contraversive VOR eye movements when the gain of the VOR was high or normal and decreased during contraversive VOR eye movements when the gain of the VOR was low. Changes in the gain of the VOR caused smaller changes in the responses during the VOR of FTNs that were E-i during pursuit with the head stationary. We argue that motor learning in the VOR is the result of changes in the responses of individual FTNs. 4. The responses of E-i and E-c FTNS during cancellation of the VOR depended on the gain of the VOR. Responses tended to be in phase with contraversive head motion when the gain of the VOR was low and in phase with ipsiversive head motion when the gain of the VOR was high. Comparison of the effect of motor learning on the responses of FTNs during cancellation of the VOR with the results of similar experiments on horizontal-gaze velocity Purkinje cells in the flocculus and ventral paraflocculus suggests that the brain stem vestibular inputs to FTNs are one site of motor learning in the VOR.(ABSTRACT TRUNCATED AT 400 WORDS)

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1. Previous studies have described a subpopulation of interneurons in the vestibuloocular reflex (VOR) pathways that express large changes in their responses to head turns in conjunction with motor learning in the VOR. These neurons are called flocculus target neurons (FTNs) because they are inhibited at monosynaptic latencies by stimulation of the flocculus and ventral paraflocculus. 2. Electrical stimulation of the vestibular labyrinth revealed that FTNs receive excitatory monosynaptic inputs from the ipsilateral vestibular labyrinth and longer-latency, excitatory inputs from the contralateral labyrinth. 3. Our data show that commissural inhibition, which has been thought to be an important feature of vestibular processing, does not provide the dominant inputs from the contralateral labyrinth to FTNs. Instead, the inputs from both labyrinths are excitatory and may be functionally antagonistic. Changes in the balance of excitatory inputs from the two horizontal canals to FTNs could contribute to motor learning in the VOR.

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1. The vestibuloocular reflex (VOR) undergoes long-term adaptive changes in the presence of persistent retinal image motion during head turns. Previous experiments using natural stimuli have provided evidence that the VOR is subserved by parallel pathways, including some that are modified during learning and some that are not. We have used electrical stimulation of the vestibular labyrinth to investigate the temporal properties of the signals that are transmitted through the modified pathways. 2. Electrodes were implanted chronically in the superior semi-circular canal, the horizontal canal, or the vestibule for electrical activation of the vestibular afferents. Learning was induced by fitting the monkeys with spectacles that magnified or miniaturized vision. Before, during, and after motor learning, we measured the eye movements evoked by electrical stimulation of the labyrinth as well as the gain of the VOR, defined as eye speed divided by head speed during natural vestibular stimulation in the dark. 3. Trains of pulses applied to the labyrinth caused the eyes to move away from the side of stimulation with an initial rapid change in eye velocity followed by a steady-state plateau. Changes in the gain of the VOR caused large changes in the trajectory and magnitude of eye velocity during the plateau, showing that our stimulating electrodes had access to the modified pathways. 4. A single, brief current pulse applied to the labyrinth evoked an eye movement that had a latency of 5 ms and consisted of a pulse of eye velocity away from the side of the stimulation followed by a rebound toward the side of stimulation. To quantify the effect of motor learning on these eye movements, we pooled the data across different VOR gains and computed the slope of the relationship between eye velocity and VOR gain at each millisecond after the stimulus. We refer to the slope as the "modification index." 5. In comparison with the evoked eye velocity, the modification index took longer to return to baseline and showed a large peak at the time of the rebound in eye velocity. Increases in stimulus current increased both the amplitude and the duration of the modification index and revealed several later peaks. These observations suggest that the full expression of motor learning requires activation of multisynaptic pathways and recruitment of primary vestibular afferents with higher thresholds for electrical stimulation. 6. The modification index was almost always positive during the initial deflection in eye velocity, and the latency of the first change in the modification index was usually the same as the latency of the evoked eye movement.(ABSTRACT TRUNCATED AT 400 WORDS)

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