John I. Simpson

Microcircuitry and function of the inferior olive

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.

More on climbing fiber signals and their consequence(s)

The persistence of many contrasting notions of climbing fiber function after years of investigation testifies that the issue of climbing fiber contributions to cerebellar transactions is still unresolved. The proposed capabilities of the climbing fibers cover an impressive spectrum. For many researchers, the climbing fibers 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 these signals on the simple spike modulation of Purkinje cells. In some hands, 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, the climbing fibers serve internal timing functions through their capacity for synchronous and rhythmic firing. The above viewpoints are presented in the spirit of trying to reach some consensus about climbing fiber function. Each point of view 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 climbing fiber system of the vestibulocerebellum.

EYE‐MUSCLE GEOMETRY AND COMPENSATORY EYE MOVEMENTS IN LATERAL‐EYED AND FRONTAL‐EYED ANIMALS*

Our question here has a long history and arises from the following type of observation: when a rabbit is oscillated about the naso-occipital (roll) axis, the compensatory eye movements are vertical, but when a human is oscillated about the same axis, the compensatory eye movements are torsional. What is the basis of such differences in compensatory eye movements among vertebrates with differing interocular angles? While the existence of these appropriate behavioral differences is commonly known, the origin of these differences is, currently, commonly unknown, as a search of the contemporary literature a t t e ~ t ~ . ~ * ’ ~ , ~ ~ * ~ ~ . ~ ~ This is regrettable; subsequent to arriving at our answer to the question posed above, we found that Ohm, in a rarely referenced 1919 paper, had arrived at the same answer.35 The results reported here confirm and extend Ohm’s lucid and accurate study, which had been ‘‘lost’’ to modern investigators of the vestibuloocular reflexes. To answer the question of what underlies the differences in compensatory eye movements among animals with different interocular angles, one must consider the physiological relations between the vestibular labyrinth and the extraocular muscles and also the peripheral anatomy of the labyrinth and of the extraocular muscles. Hogyes was the first to delve into these matters; he deduced a specific set of primary relations and pathways between the labyrinth of one side and the ipsilateral and contralateral eye muscles.22 Indeed, he came quite close to determining the actual arrangement, clarified much later by Szenthgothai.44-46 In the course of his studies, Hogyes also recognized the different requirements for appropriate compensatory eye movements in lateraland frontal-eyed animals, but he did not clearly resolve the question of how the requirements are met. (Hogyes’ achievements in vestibular research were fully appreciated only after his main publication, originally published in Hungarian in the 188Os, appeared in German translation in 1912.jZ3 BBr5ny accurately observed the eye movements elicited in rabbit by natural vestibular ~ t imul i .~ However, he claimed that the actions of rabbit and human extraocular muscles were identical, and thus his description of the relations of individual vertical semicircular canals to specific eye muscles was erroneous. Why BBriny believed the actions of rabbit and human extraocular muscles to be identical is mysterious because the anatomical information about the periphery necessary to arrive at the contrary conclusion was available from his associate Rothfeld and also from W e s ~ e l y ? ~ . ~ ~ BBrAny’s viewpoint was contradicted by Ohm, who demonstrated anatomically

Temporal relations of the complex spike activity of Purkinje cell pairs in the vestibulocerebellum of rabbits

Parasagittal zones in the vestibulocerebellum contain Purkinje cells whose complex spike (CS) activity is modulated in response to rotational optokinetic stimulation (OKS) about either the vertical axis (VA) or a horizontal axis (HA) that is approximately perpendicular to the ipsilateral anterior canal. In rabbits, there are two VA zones in both the ventral nodulus and flocculus, two HA zones in the flocculus, and one HA zone in the ventral nodulus. We investigated the temporal relationship of the CS activity of Purkinje cell pairs in the same or different zones of the vestibulocerebellum in ketamine-anesthetized pigmented rabbits. A synchronous temporal relationship was defined as the tendency of the CS of each Purkinje cell to fire within, at most, 2 msec of one another. Generally, neurons in the same zone showed a tendency to exhibit CS synchrony. Of 82 pairs consisting of two Purkinje cells in the same zone (e.g., two nodulus HA cells), 33 were synchronous. In contrast, none of 26 pairs consisting of two neurons in functionally different zones (e.g., a VA cell paired with an HA cell), showed CS synchrony. Pairs consisting of neurons in spatially separated VA zones in the ventral nodulus also showed a tendency to be synchronously related (6/16), as did pairs consisting of a nodulus VA cell and a flocculus VA cell (3/14). The CS synchrony was higher during OKS in the preferred direction than during spontaneous activity. This is the first demonstration that CS synchrony in the vestibulocerebellum can be manipulated with a natural sensory stimulus.

Spontaneous Activity Signatures of Morphologically Identified Interneurons in the Vestibulocerebellum

Cerebellar cortical interneurons such as Golgi cells, basket cells, stellate cells, unipolar brush cells, and granule cells play an essential role in the operations of the cerebellum. However, detailed functional studies of the activity of these cells in both anesthetized and behaving animals have been hampered by problems in recognizing their physiological signatures. We have extracellularly recorded the spontaneous activity of vestibulocerebellar interneurons in ketamine/xylazine-anesthetized rats and subsequently labeled them with Neurobiotin using the juxtacellular technique. After recovery and morphological identification of these cells, they were related to statistical measures of their spontaneous activity. Golgi cells display a somewhat irregular firing pattern with relatively low average frequencies. Unipolar brush cells are characterized by more regular firing at higher rates. Basket and stellate cells are alike in their firing characteristics, which mainly stand out by their irregularity; some of them are set apart by their very slow average rate. The spontaneous activity of interneurons examined in the ketamine/xylazine rabbit fit within this general pattern. In the rabbit, granule cells were identified by the spontaneous occurrence of extremely high-frequency bursts of action potentials, which were also recognized in the rat. On the basis of these observations, we devised an algorithm that reliably determined the identity of 75% of the cells with only 2% incorrect classifications. The remaining cells were placed into border categories within which no classification was attempted. We propose that this algorithm can be used to help classify vestibulocerebellar interneurons recorded in awake, behaving animals.

A geometric analysis of semicircular canals and induced activity in their peripheral afferents in the rhesus monkey.

Experiments were carried out to determine anatomically the planes of the semicircular canals of two juvenile rhesus monkeys, using plastic casts of the semicircular canals, and the anatomical measurements were related to the directional coding of neural signals transmitted by primary afferents innervating the same simicircular canals. In the experiments, animals were prepared for monitoring the eye position by the implantation of silver-silver chloride electrodes into the bony orbit. Following the recording of semicircular canal afferent activity, the animals were sacrificed; plastic casting resin was injected into the bony canals; and, when the temporal bone was demineralized and removed, the coordinates of points spaced along the circumference of the canal casts were measured. A comparison of the sensitivity vectors determined in these experiments and the anatomical measures showed that the average difference between a sensitivity vector and its respective normal vector was 6.3 deg.

Between in and out: linking morphology and physiology of cerebellar cortical interneurons.

We used the juxtacellular recording and labeling technique of Pinault (1996) in the uvula/nodulus of the ketamine anesthetized rat in an attempt to link different patterns of spontaneous activity with different types of morphologically identified cerebellar cortical interneurons. Cells displaying a somewhat irregular, syncopated cadence of spontaneous activity averaging 4-10 Hz could, upon successful entrainment and visualization, be morphologically identified as Golgi cells. Spontaneously firing cells with a highly or fairly regular firing rate of 10-35 Hz turned out to be unipolar brush cells. We also found indications that other types of cerebellar cortical neurons might also be distinguished on the basis of the characteristics of their spontaneous firing. Comparison of the interspike interval histograms of spontaneous activity obtained in the anaesthetized rat with those obtained in the awake rabbit points to a way whereby the behaviorally related modulation of specific types of interneurons can be studied. In particular, the spontaneous activity signatures of Golgi cells and unipolar brush cells anatomically identified in the uvula/nodulus of the anaesthetized rat are remarkably similar to the spontaneous activity patterns of some units we have recorded in the flocculus of the awake rabbit. The spontaneous activity patterns of at least some types of cerebellar interneurons clearly have the potential to serve as identifying signatures in behaving animals.

Intraburst and Interburst Signaling by Climbing Fibers

Although cerebellar Purkinje cell complex spikes occur at low frequency (∼1/s), each complex spike is often associated with a high-frequency burst (∼500/s) of climbing fiber spikes. We examined the possibility that signals are present within the climbing fiber bursts. By intracellularly recording from depolarized, nonspiking Purkinje cells in anesthetized pigmented rabbits, climbing fiber burst patterns were investigated by determining the number of components in the induced compound EPSPs during spontaneous activity and during visual stimulation. For our sample of 43 cells, >70% of all EPSPs were of the compound type composed of two or three EPSPs. During spontaneous activity, the number of components in each compound EPSP was not related to the latency to the succeeding compound EPSP. Conversely, the number of components in each compound EPSP was related to its latency after the preceding compound EPSP. This latency increased from 0.62 s for one-component EPSPs to 1.69 s for compound EPSPs with four or more components. The effect of visual stimulation on the climbing fiber activity was studied in 19 floccular Purkinje cells whose low-frequency interburst climbing fiber response was modulated by movement about the vertical axis. During sinusoidal oscillation (0.1 Hz, ±10°), compound EPSPs with a larger number of components tended to be more prevalent during movement in the excitatory direction than in the inhibitory direction. Thus, climbing fibers can, in addition to modulation of their low interburst frequency, transmit signals in the form of the number of spikes within each high-frequency burst.

The accessory optic system: Analyzer of self-motion.

Accessory optic system (AOS) neurons in the medial, lateral, and dorsal terminal nuclei (MTN, LTN, and DTN) of the rabbit have contralateral receptive fields and the common property of direction and speed selectivity in response to movement of large, textured Neurons in each nucleus prefer slow speeds, on the order of 0So/sec, but differ in their direction preferences. DTN neurons prefer horizontal movement, whereas MTN and LTN neurons prefer near-vertical movement. An unusual feature of the direction selectivity of MTN and LTN neurons is that their preferred excitatory and inhibitory directions are noncollinear. This geometrical arrangement has been further studied in conjunction with an investigation of the spatial organization of direction selectivity within the receptive field of neurons in the MTN and the neighboring visual tegmental relay zone (VTRZ) of the ventral midbrain. In the rabbit, many DTN neurons project directly to the dorsal cap of the inferior olive, but only a few MTN and LTN neurons do so.&* The caudal half of the dorsal cap receives an input directly from the ipsilateral DTN, while the rostral half of the dorsal cap and its lateral extension, the ventrolateral outgrowth (VLO), receive an input from neurons located ipsilaterally in a crescent-shaped region immediately dorsal to the MTN. These neurons are within the visual tegmental relay zone (VTRZ), which is the part of the ventral tegmentum to which contralateral MTN neurons project, largely via the posterioi c o ~ i ~ m i s s u r e . ~ ~ ~ The anatomical data indicating that VTRZ neurons are interposed between the MTN and the rostral dorsal cap raises questions about the nature of the intermediate processing of the transmitted visual signals. With respect to direction selectivity, the structure of the receptive field of rostral dorsal cap neurons is substantially more complicated than that of the usual MTN Neurons in the rostral dorsal cap

Orienting otolith-ocular reflexes in the rabbit during static and dynamic tilts and off-vertical axis rotation.

Orienting otolith-ocular reflexes were assessed in rabbits using static tilt, off-vertical axis rotation (OVAR) and sinusoidal oscillation about earth-horizontal axes. In all paradigms, head pitch produced ocular counter-pitch and vergence, and head roll produced ocular counter-roll and conjugate yaw version. Thus, vergence and version are essential components of orienting reflexes along the naso-occipital and bitemporal axes. Vergence and version caused misalignment between the axes of eye and head movement during pitch and roll head movements. Semicircular canal input broadened the band-pass of these orienting reflexes, which would make them more appropriate when compensating for head movement during active motion.