Faculty Bibliography

The rotation axis for each of the six extraocular muscles was determined in four eyes from three perfused rhesus monkeys. Measurements of the locations of muscle insertions and origins were made in the stereotaxic reference frame with the x-y plane horizontal and the x-z plane sagittal. The computed rotation axes of the horizontal recti were close to being in the x-z plane at an angle of about 15 degrees to the z axis. The rotation axes of the vertical recti and the obliques were close to being in the x-y plane at an angle of about 30 degrees to the y axis. In five alert rhesus monkeys, we simultaneously recorded extraocular motoneuron activity and eye position in three dimensions (3D). The activity of 51 motoneuron axons was obtained from the oculomotor (n=34), trochlear (n=11), and abducens nerve (n=6) during spontaneous eye movements. To extend the torsional range of eye position, the animals were also put in different static roll positions, which induced ocular counterroll without dynamic vestibular stimulation. Periods of 100 ms during fixation or slow eye movements (<10 degrees/s) were chosen for analysis. For each motoneuron, a multiple linear regression was performed between firing frequency and 3D eye position, expressed as a rotation vector, in both stereotaxic and Listing's reference frame. The direction with the highest correlation coefficient (average R=0.94+/-0.07 SD) was taken as the on-direction. Each unit's activity could be unequivocally attributed to one particular muscle. On-directions for each motoneuron were confined to a well-defined cone in 3D. Average on-directions of motoneurons differed significantly from the corresponding anatomically determined muscle rotation axes expressed in the stereotaxic reference frame (range of deviations: 11.9 degrees to 29.0 degrees). This difference was most pronounced for the vertical recti and oblique muscles. The muscle rotation axes of the vertical rectus pair and the oblique muscle pair form an angle of 58.3 degrees, whereas the corresponding angle for paired motoneuron on-directions was 105.6 degrees. On-directions of motoneurons were better aligned with the on-directions of semicircular canal afferents (range of deviation: 9.4-18.9 degrees) or with the anatomically determined sensitivity vectors of the semicircular canals (range of deviation: 3.9-15.9 degrees) than with the anatomically determined muscle rotation axes, but significant differences remain to be explained. The on-directions of motoneurons were arranged symmetrically to Listing's plane, in the sense that the torsional components for antagonistically paired muscles were almost equal, but of opposite sign. Thus, the torsional components of motoneuron on-directions cancel when eye movements are confined to Listing's plane. This arrangement simplifies the neuronal transformations for conjugate head-fixed voluntary eye movements, while the approximate alignment with the semicircular canal reference frame is optimal for generating compensatory eye movements.

The inferior olive, which provides the climbing fibers to Purkinje cells in the cerebellar cortex, has been implicated in various functions, such as learning and timing of movements, and comparing intended with achieved movements. For example, climbing-fiber activity could transmit error signals during eye-blink conditioning or adaptation of the vestibulo-ocular reflex, or it could carry motor command signals beating on the rhythm of the oscillating and synchronous firing of ensembles of olivary neurons, or both. In this review, we approach the controversial issue of olivocerebellar function from the perspective of the unique organization of the microcircuitry of the olivary neuropil. The characteristic glomeruli are formed by a core of long dendritic or axonal spines, each of which is innervated by both an inhibitory terminal derived from the hindbrain and an excitatory terminal derived from either an ascending or descending input. The dendritic spines, which originate from dendrites with varicosities carrying dendritic lamellar bodies, are coupled by gap junctions. By drawing a comparison with a computational model by Segev and Rall,which might be applicable to the typical olivary spine with its unique morphological features and combined excitatory and inhibitory input, we propose that the microcircuitry of the inferior olive is capable of functioning both in motor learning and motor timing, but does not directly compare intended with achieved movements

Dendritic lamellar bodies have been reported to be associated with dendrodendritic gap junctions. In the present study we investigated this association at both the morphological and electrophysiological level in the olivocerebellar system. Because cerebellar GABAergic terminals are apposed to olivary dendrites coupled by gap junctions, and because lesions of cerebellar nuclei influence the coupling between neurons in the inferior olive, we postulated that if lamellar bodies and gap junctions are related, then the densities of both structures will change together when the cerebellar input is removed. Lesions of the cerebellar nuclei in rats and rabbits resulted in a reduction of the density of lamellar bodies, the number of lamellae per lamellar body, and the density of gap junctions in the inferior olive, whereas the number of olivary neurons was not significantly reduced. The association between lamellar bodies and electrotonic coupling was evaluated electrophysiologically in alert rabbits by comparing the occurrence of complex spike synchrony in different Purkinje cell zones of the flocculus that receive their climbing fibers from olivary subnuclei with different densities of lamellar bodies. The complex spike synchrony of Purkinje cell pairs, that receive their climbing fibers from an olivary subnucleus with a high density of lamellar bodies, was significantly higher than that of Purkinje cells, that receive their climbing fibers from a subnucleus with a low density of lamellar bodies. To investigate whether the complex spike synchrony is related to a possible synchrony between simple spikes, we recorded simultaneously the complex spike and simple spike responses of Purkinje cell pairs during natural visual stimulation. Synchronous simple spike responses did occur, and this synchrony tended to increase as the synchrony between the complex spikes increased. This relation raises the possibility that synchronously activated climbing fibers evoke their effects in part via the simple spike response of Purkinje cells. The present results indicate that dendritic lamellar bodies and dendrodendritic gap junctions can be downregulated concomitantly, and that the density of lamellar bodies in different olivary subdivisions is correlated with the degree of synchrony of their climbing fiber activity. Therefore these data support the hypothesis that dendritic lamellar bodies can be associated with dendrodendritic gap junctions. Considering that the density of dedritic lamellar bodies in the inferior olive is higher than in any other area of the brain, this conclusion implies that electrotonic coupling is important for the function of the olivocerebellar system

Discusses theories and viewpoints on climbing fiber (CF) function and CF contributions to cerebellar transactions. Proposed CF capabilities cover an impressive spectrum. For many researchers, CFs signal errors in motor performance, either in the conventional manner of frequency modulation or as a single announcement of an 'unexpected event'. More controversial is the effect of CF signals on the simple spike modulation of Purkinje cells. To some, they lead to a long-term depression of the strength of parallel fiber synapses, while, in other hands, they lead to a short-lasting enhancement of the responsiveness of Purkinje cells to mossy fiber inputs or contribute to the often-seen reciprocal relation between complex and simple spike modulation. For still other investigators, CFs serve internal timing functions through their capacity for synchronous and rhythmic firing. These viewpoints are presented in the spirit of trying to reach some consensus about CF function. Each viewpoint is introduced by summarizing first the key observations made by the respective proponents; then the issues of short-lasting enhancement, reciprocity between complex and simple spikes, and synchrony and rhythmicity are addressed in the context of the visual CF system of the vestibulocerebellum.

Replies to comments by 12 authors on the original article discussing theories and viewpoints on climbing fiber (CF) function and CF contributions to cerebellar transactions. Several themes can be identified in the commentaries. The first is that CFs may have more than 1 function; second is that CFs provide sensory rather than motor signals. The authors accept the possibility that CFs may have more than 1 function - hence 'consequence(s)' in the title. Until more is known about the function of the inhibitory input to the inferior olive from the cerebellar nuclei, which are motor structures, we have to keep open the possibility that the climbing fiber signals can be a combination of sensory and motor signals.

1. Purkinje cells in the rabbit flocculus that respond best to rotation about the vertical axis (VA) project to flocculus-receiving neurons (FRNs) in the medial vestibular nucleus. During sinusoidal rotation, the phase of FRNs leads that of medial vestibular nucleus neurons not receiving floccular inhibition (non-FRNs). If the FRN phase lead is produced by signals from the flocculus, then the Purkinje cells should functionally lead the FRNs. In the present study we recorded from VA Purkinje cells in the flocculi of awake, pigmented rabbits during compensatory eye movements to determine whether Purkinje cells have the appropriate firing rate phases to explain the phase-leading characteristics of the FRNs. 2. Awake rabbits were sinusoidally rotated about the VA in the light and the dark at 0.05-0.8 Hz with different amplitudes. The phase of the simple spike (SS) modulation in reference to eye and head position was calculated by determining the eye position sensitivity and the eye velocity sensitivity using multivariate linear regression and Fourier analysis. The phase of the SS modulation in reference to head position was compared with the phase of the FRN modulation, which was obtained in prior experiments with the same stimulus paradigms. 3. The SS activity of nearly all of the 88 recorded floccular VA Purkinje cells increased with contralateral head rotation. During rotation in the light, the SS modulation showed a phase lead in reference to contralateral head position that increased with increasing frequency (median 56.9 degrees at 0.05 Hz, 78.6 degrees at 0.8 Hz). The SS modulation led the FRN modulation significantly at all frequencies. The difference of medians was greatest (19.2 degrees) at 0.05 Hz and progressively decreased with increasing frequency (all Ps < 0.005, Wilcoxon rank-sum test). 4. During rotation in the dark, the SS modulation had a greater phase lead in reference to head position than in the light (median 110.3 degrees at 0.05 Hz, 86.6 degrees at 0.8 Hz). The phase of the SS modulation in the dark led that of the FRNs significantly at all frequencies (difference of medians varied from 24.2 degrees at 0.05 Hz to 9.1 degrees at 0.8 Hz; all Ps < 0.005). 5. The complex spike (CS) activity of all VA Purkinje cells increased with ipsilateral head rotation in the light. Fourier analysis of the cross-correlogram of the CS and SS activity showed that the phase lag of the CS modulation in reference to the SS modulation at 0.05 Hz in the light was not significantly different from that at 0.8 Hz (median 199.7 degrees at 0.05 Hz, 198.3 degrees at 0.8 Hz), even though the phases of the SS modulation at these two frequencies were significantly different (P < 0.001). These data indicate that the average temporal reciprocity between CS and SS modulation is fixed across the range of frequencies used in the present study. 6. The CS activity of most Purkinje cells did not modulate during rotation in the dark. Of 124 cases (each case consisting of the CS and SS data of a VA Purkinje cell obtained at 1 particular frequency) examined over the frequency range of 0.05-0.8 Hz, 17 cases (14%) showed CS modulation. In the majority (15 of 17) of these cases, the CS activity increased with contralateral head rotation; these modulations occurred predominantly at the higher stimulus velocities. 7. On the basis of the finding that FRNs of the medial vestibular nucleus lead non-FRNs, we predicted that floccular VA Purkinje cells would in turn lead FRNs. This prediction is confirmed in the present study. The data are therefore consistent with the hypothesis that the phase-leading characteristics of FRN modulation could come about by summation of VA Purkinje cell activity with that of cells whose phase would otherwise be identical to that of non-FRNs. The floccular SS output appears to increase the phase lead of the net preoculomotor signal, which is in part composed of the FRN and non-FRN signals

OBJECTIVE: This study was designed to compare the effects of isoflurane and nitroprusside on spinal cord ischemia when they are used to control proximal hypertension during thoracic aortic cross-clamping (TACC). DESIGN: Prospective, randomized, blinded experimental study. SETTING: Laboratory and animal research facility. PARTICIPANTS: Adult mongrel dogs. INTERVENTIONS: Two groups of eight dogs had TACC for 45 minutes. Proximal aortic, distal aortic, and cerebrospinal pressure was calculated as the distal mean pressure minus the CSF pressure. Group 1 received nitroprusside and group 2 received isoflurane to control proximal hypertension during cross-clamping. The dogs were neurologically evaluated 24 and 48 hours later by an observer blinded as to the study group. Spinal cord segments were obtained for histopathologic examination. MEASUREMENTS AND MAIN RESULTS: Distal perfusion pressure and spinal cord perfusion pressure were significantly higher in the isoflurane group (p < .005). At 24 hours, seven of eight dogs in group 1 had severe neurologic injury (ie, paraplegia), with the eight having mild neurologic injury. This is in contrast to group 2, where 6 of 8 dogs had either minimal or no injury, one had mild injury, and one had severe injury. Similar results were observed at 48 hours (p < .005). CONCLUSIONS: Isoflurane, when used to control proximal hypertension during TACC, produces a higher spinal cord perfusion pressure and is associated with a lower incidence of neurologic injury than nitroprusside in this canine model

The white matter of the rabbit flocculus is subdivided into five compartments by narrow sheets of densely staining acetylcholinesterase-positive fibers. The most lateral compartment is continuous with the C2 compartment of the paraflocculus and contains the posterior interposed nucleus. The other four compartments are numbered from lateral to medial as floccular compartments 1, 2, 3, and 4 (FC1-4). FC1-3 continue across the posterolateral fissure into the adjacent folium (folium p) of the ventral paraflocculus. FC4 is present only in the rostral flocculus. In the caudal flocculus FC1 and FC3 abut dorsal to FC2. Fibers of FC1-4 can be traced into the lateral cerebellar nucleus and the floccular peduncle. The presence of acetylcholinesterase in the deep stratum of the molecular layer of the flocculus and ventral paraflocculus distinguishes them from the dorsal paraflocculus. The topographical relations to the flocculus and the floccular peduncle with group y and the cerebellar nuclei are discussed.

The localization and termination of olivocerebellar fibers in the flocculus and nodulus of the rabbit were studied with anterograde axonal transport methods [wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) and tritiated leucine] and correlated with the compartments in the white matter of these lobules delineated with acetylcholinesterase histochemistry (Tan et al. J. Comp. Neurol., 1995, this issue). Olivocerebellar fibers originating from the caudal dorsal cap travel through floccular compartments FC2 and FC4 to terminate as climbing fibers in floccular zones FZII and FZIV. Fibers from the rostral dorsal cap and the ventrolateral outgrowth traverse compartments FC1 and FC3, which are interleaved with compartments FC2 and FC4, and terminate in zones FZI and FZIII. Fibers from the rostral pole of the medial accessory olive traverse the C2 compartment and terminate in the C2 zone. FZI-III extend into the adjoining folium (folium p) of the ventral paraflocculus. The C2 zone continues across folium p into other folia of the ventral paraflocculus and into the dorsal paraflocculus. Four compartments and five zones were distinguished in the nodulus. Medial compartment XC1 contains olivocerebellar fibers from the caudal dorsal cap and subnucleus beta that terminate in the XZI zone. Olivocerebellar fibers from the rostral dorsal cap and the ventrolateral outgrowth occupy XC2 and terminate in XZII. The XC4 compartment contains fibers from both the caudal dorsal cap and from the rostral dorsal cap and the ventrolateral outgrowth. The latter terminate in a central portion of the XZIV zone. The dorsomedial cell column projects to the XZIII zone, which is present only in the dorsal part of the nodulus. The rostral medial accessory olive projects to the XZV zone, which occupies the lateral border of the nodulus. These results confirm and extend the conclusions of Katayama and Nisimaru ([1988] Neurosci. Res. 5:424-438) on the zonal pattern in the olivo-nodular projection in the rabbit. Additional observations were made on the presence of a lateral A zone (Buisseret-Delmas [1988] Neurosci. Res. 5:475-493) in the hemisphere of lobules VI and VII. Retrograde labeling of the nucleo-olivary tract of Legendre and Courville ([1987] Neuroscience 21:877-891) was observed after WGA-HRP injections into the inferior olive including the rostral dorsal cap and the ventrolateral outgrowth. The anatomical and functional implications of these observations are discussed.