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Symposium on the Role of the Vestibular Organs in Space Exploration (1970)

Chapter: THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS

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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"THE CEREBELLOVESTIBULAR INTERACTION IN THE CAT'S VESTIBULAR NUCLEI NEURONS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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The Cerebellovestibular Interaction in the Cat's Vestibular Nuclei Neurons MASAO ITO University of Tokyo SUMMARY Postsynaptic effects of the vestibular and cerebellar impulses were investigated in the cat's vestib- ular nuclei neurons with intracellular recording techniques. These neurons were identified by their antidromic invasion from the spinal cord or the cerebellum and/or by their location determined with histologically controlled micromanipulation. The vestibular nerve impulses exert monosynaptically an excitatory effect upon many vestibular nuclei neurons, producing the excitatory postsynaptic po- tentials (EPSP's). Polysynaptic actions, however, involve both excitation and inhibition. In con- trast, the cerebellar impulses along Purkinje axons evoke the inhibitory postsynaptic potentials (IPSP's) monosynaptically in any of their target neurons. These vestibular and cerebellar impulses converge upon vestibular nuclei neurons in the fashion that the cerebellum is superposed on the reflex arcs which are primarily formed between the vestibular nerve and certain vestibular nuclei cells. On the basis of these observations, an attempt is made to interpret the role of the cerebellum in terms of basic concepts of the control theory. INTRODUCTION The vestibular nuclear complex consists of four divisions: lateral (Deiters), medial, descend- ing (inferior), and superior (see ref. 1). Synaptic organization in these nuclei has been the subject of extensive histological investigations (refs. 1 and 2). The vestibular nerve fibers supply synapses to all of the four nuclei ipsilaterally, though with certain regional predominance (refs. 3 and 4). Purkinje-cell axons mediating the output signals from the cerebellar cortex also impinge upon the vestibular nuclei ipsi- laterally; those from the cortex of the vermis, predominantly of the anterior lobe and less of the posterior lobe, innervate the relatively dorsal parts of the nucleus of Deiters as well as of the other nuclei (refs. 5 and 6), while those from the so-called vestibulocerebellum cover almost the entire nuclei except for the nucleus of Deiters (ref. 7). Axons from fastigial nuclei form another cerebellar output and have abundant synapses with vestibular nuclei cells (ref. 8). Other inputs are supplied from the spinal cord and medulla as well as from the supramedullary centers (ref. 1). After integration of these input signals, the vestibular nuclei send their output message through the following five projection pathways: (1) descending through the lateral vestibulo- spinal tract, (2) descending through the medial longitudinal fasciculi, (3) cerebellopetal, (4) ascending through the medial longitudinal fasciculi, and (5) intranuclear and internuclear connections, the latter being either homolateral or between the right and left sides. The first type of projection is derived only from the nucleus of Deiters and the third one mainly from the descending nucleus. The second and the fifth arise from both the medial and descending nuclei, and the fourth from all of the four divi- sions (ref. 1). A wealth of anatomical data has facilitated greatly the recent physiological investigations on vestibular nuclei neurons. With microelectrode techniques the nature and efficacy of trans- mission could be determined on each type of

184 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION synapse with histologically defined origin. Of particular importance is the finding that Purkinje cells exert solely inhibitory action upon their target neurons, while both vestibular nerve fibers and fastigial axons have direct excitatory action. These observations now reveal some essential features of the cerebello- vestibular interaction and facilitate conception of some general ideas about the cerebellar control mechanisms. METHODS OF STUDY Under Nembutal anesthesia, the cat's head was fixed in a supine position. Microelectrodes filled with solution containing 3 M KC1, 2 M NaCl, or 2 M K-citrate were inserted through the ventral surface of medullary pyramid in a ventrodorsal direction, usually on the right side (ref. 9). The vestibular nerve branches were exposed in the right vestibule by the method of Andersson and Gernandt (ref. 10). An acu- puncture needle, insulated except for the very tip, was placed lightly on the vestibular nerve branches as a cathode. The anode was formed by another needle placed on the cochlear bone. The ventral surface of the spinal cord at the second or third (C2 or C3) cervical segment was exposed: upon this three needle electrodes were mounted, one on the anterior median fissure and the other two at 2 mm right and left, respectively, to the former. The needle or concentric electrodes were also inserted into the cerebellum stereotaxically. Penetration of neuronal elements within vestibular nuclei was signaled by the sudden appearance of a membrane potential of —40 to —70 mV and also of spikes and postsynaptic potentials in response to stimulation of the spinal cord, cerebellum, and vestibular nerve. Locali- zation of impaled neurons was determined by the following procedure (refs. 9, 11, and 12): After each experiment, the brain tissues were fixed by intracarotid injection of a 10-percent buffered formalin saline solution, with the microelectrode left buried in one of the tracks through vestibular nuclei. Frozen sections were then prepared from the medulla and cere- bellum (transversely with a 40-rnicron thickness) on which the trace of the microelectrode track was found. These sections were first stained with methylene blue, and the contour of their histological structures was traced under a photographic enlarger. The sections were then stained by the Kliiver-Barrera method to reveal details of the cytoarchitecture of the vestibular nuclei. The position at which in- dividual neurons were impaled was plotted on a lattice made up of the microelectrode tracks and lines equal to the depths of microelectrode insertion as measured on the scale of the micro- manipulator. The lattice was then fitted on the histological section by using as a guide the trace of the microelectrode track. CELL IDENTIFICATION BY ANTIDROMIC ACTIVATION Antidromic activation has been employed widely as the most reliable method of identifying certain neuron groups (ref. 9). This was suc- cessfully applied to the following three groups of vestibular nuclei neurons. (1) Deiters' neurons. — When the C2 or Ci segment was stimulated with the needle electrode placed about 2 mm lateral from the anterior median fissure (Ci in fig. 1). conspicuous negative field potentials developed over the region of the nucleus of Deiters on the same side (ref. 9). These field potentials are produced by the antidromic invasion of Deiters' neurons through their vestibulospinal axons. In individual Deiters' neurons, the antidromic spikes show a marked inflection on their ascending phase as in motoneurons (ref. 13) (fig. IA) and are fol- lowed by an afterhyperpolarization of several millivolts that lasts for about 50 msec (fig. 16) (ref. 9). As confirmed by histological exami- nation (ref. 14). the cells projecting onto cervico- thoracic segments of the spinal cord were located relatively ventrad and those onto lum- bosacral segments relatively dorsad, though with a considerable overlap (ref. 9). Unit analysis by Wilson et al. (ref. 15) further con- firmed that the lumbosacral Deiters' neurons tend to be located caudally in relation to the cervico- thoracic ones (ref. 14). The conduction velocity along the vestibulospinal tract fibers ranged from 25 to 140 m/sec, with the mode at 90 to 100 m/sec (refs. 9 and 15).

CEREBELLOVESTIBULAR INTERACTION 185 (2) DMLF cells. — Antidromic activation of these neurons was brought about most effec- tively with the C,,, electrode placed on the anterior median fissure (fig. 1) (ref. 12). The difference in threshold for this activation be- tween C,- and C,,, or between C,. and C,,, elec- trodes was usually more than fivefold; these cells should be sending axons through the descending medial longitudinal fasciculi (DMLF). Their action potentials were similar to those of Deiters' neurons in that they had an inflection on the ascending phase (fig. 1C). The DMLF cells presently studied were impaled mostly in the rostral pole of the descending vestibular nucleus which extrudes underneath the nucleus FiGLRE I. —Identification of vestibular nuclei neurons by their antidromic activation. The diagram on the top illus- trates axonal projections for five types of neurons. I-V: Indicated in the text. CER: Cerebellum. Fast: Fastigial nucleus. Hoc.: Floccular lobe. N: Nodulus. VS: Ves- tibulospinal tract. A: Intracellular recording from a Deiters' neuron during antidromic invasion from C3 level. Arrow marks the inflection on the spike ascending phase. B: Afterhyperpolarization following an antidromic spike (from ref. 9). C. Antidromic spike of a DMLF cell in re- sponse to C2 stimulation; arrow mark similar to A; note that the stimulus intensity was set at threshold where anti- dromic invasion failed in about half the trials. D: Direct response of a vestibular nerve fiber to the vestibular nerve stimulation (from ref. 18). E: Antidromic invasion of a de- scending vestibular nucleus neuron to thejuxtafastigial stim- ulation. Arrow indicates as in A and C. F: Afterhyper- polarization following an antidromic spike from juxta- fastigial region (from refs. V, 12, and 18). of Deiters (cf. ref. 1). These cells were acti- vated from the cervical cord with relatively short latencies (mean 0.82 msec from C2), comparable to those for ventrally located Deiters' neurons (0.81 msec from CD) (ref. 12). These neurons may have similar conduction velocities and so probably have similarly large-sized cell somata. On the basis of histology findings, the majority of DMLF cells appear to be located within the medial vestibular nucleus (ref. 16); this was confirmed recently by unit recording (ref. 17). These medial cells, however, were not particularly sought out in the present investigations. (3) Cerebellar-projecting cells. — Cells in the descending nucleus often responded antidrom- ically to the juxtafastigial stimulation by generat- ing action potentials similar to those of Deiters' and DMLF neurons; spikes have an inflected ascending phase (fig. IE) and are followed by an afterhyperpolarization (fig. IF). The other components of vestibular nuclei were less well identified. The cells impaled within the superior vestibular nucleus may be taken as representative of those cells sending axons craniad through the ascending medial longitudi- nal fasciculi (AMLF) and are grouped as type IV, since most of the cells in this region appear to be directed rostrally (ref. 1). A number of neurons impaled in the descending and medial vestibular nuclei could not be activated anti- dromically, either from the spinal cord or from the cerebellum. Such neurons may include those cells projecting rostrally through the AMLF, but at least a part of them may be serving as connections among vestibular nuclei and thus may be grouped as type V. Axons were also often penetrated within ves- tibular nuclei. Some of them could be identified as the vestibular nerve fibers by their direct response to the vestibular nerve stimulation (fig. ID). The evoked spike showed the steep as- cending phase with no inflection and was followed by little afterpotential, features characteristic of axons (ref. 18). Some others were identified as Purkinje-cell axons of cerebellovestibular pro- jection or cerebellar afferent fibers (or their col- laterals) running through the vestibular nuclei (refs. 9 and 19).

186 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION STUDY WITH VESTIBULAR STIMULATION Monosynaptic Action of Vestibular Nerve Volleys The most conspicuous event which happens in many vestibular nuclei cells during stimula- tion of the ipsilateral vestibular nerve with brief electric pulses (0.1- to 0.2-msec duration) is initiation of excitatory postsynaptic potentials (EPSP's) with extremely short latencies. They are illustrated in figures 2A through E for a Deiters' neuron, in F through H for a cerebellar- projecting cell, and in / through K for a superior nucleus neuron (refs. 12 and 18). with various stimulus intensities. At two to five times the threshold of excitation of the vestibular nerve. FIGURE 2. — Monosynaptic excitation of vestibular nuclei neurons by the vestibular nerve volley. Top diagram shows the direct innervation by the vestibular nerve fibers. L: Lateral nucleus. VN: Vestibular nerve. Intracellular re- cording from a Deiters' neuron (A through E), from a de- scending nucleus neuron (F through H), and from a superior nucleus neuron (I through K). Lower traces in A through C and F through H, and middle traces in D indicate extra- cellular control potentials. The bottom trace in D shows the upper and middle traces in superposition; the down- ward arrow indicates their diverging point. In A, the in- tensity of the vestibular nerve stimulation was just at thresh- old for the EPSP, and increased to I.I times in B. 1.5 times in C, and 3.8 times in D over that in A. E: Same as in the upper traces of D but taken with a low amplification. Similarly, the vestibular nerve stimulation is of threshold intensity in F and increased by a factor of 1.5 in {',, by 5 in H, 1.03 in I, 1.06 in J, and 3.6 in K. foliage scale of 2 mV applies to A through D and F through H and that of 5 mV to I through K. (From refs. 12 and I8.\ there was usually orthodromic firing of impaled cells (E). The latency of the vestibular-evoked EPSP's distributes multimodally, with the earliest group at 0.6 to 1.0 msec and later ones at 1.0 to 1.8 msec. The earliest EPSP's have a mean latency of 0.76 msec (±0.08 msec SD) in 44 Deiters' neurons and of 0.72 msec (±0.08 msec SD) in 43 non-Deiters' vestibular nuclei cells (refs. 12 and 18). These EPSP's must be produced mono- synaptically because their latencies are longer, just by a monosynaptic delay time, than the latency of arrival of the primary vestibular im- pulses at the vestibular nuclei. The latter latency is 0.33 msec (ref. 18) at the f-wave of the field potential (ref. 20): at the foot of spikes in individual vestibular nerve fibers it is 0.46 msec (ref. 18). Distribution The monosynaptic EPSP's were seen in 29 percent of the Deiters' neurons examined (44 of 151). These vestibular-excited cells are located relatively ventrad. as confirmed by histological data (ref. 4) and unit analysis (ref. 15). The monosynaptic EPSP's occurred in 6 of 7 DMLF cells examined, in 9 of 14 cerebellar- projecting ones, in 9 of 12 superior nuclei cells, and in 19 of 30 descending and medial nucleus neurons with identified projection. These frequencies of occurrence appear to be considerably higher than those given with unit analysis (36 percent for medial and 40 percent for descending nuclei, ref. 21), but the discrepancy may, at least partly, be due to the fact that the intracellular recording presently adopted reveals existence of the EPSP's even if they are subthreshold for orthodromic excita- tion that is detected only by the extracellular unit recording. It is also to be considered that the intracellular recording preferentially samples relatively large cells which might more commonly receive the monosynaptic EPSP's than do relatively small cells. Unitary Composition The gradation in size of the monosynaptic EPSP's. which varied according to the intensity of the vestibular nerve stimulation (fig. 2,4 through K). indicates that a number of vestibular

CEREBELLOVESTIBULAR INTERACTION 187 nerve fibers converge onto single vestibular nuclei neurons. In figure 3/4 the vestibular nerve stimulation was adjusted to a juxtathreshold intensity and was repeated every second. Small monosynaptic EPSP's onset at the left broken vertical line and show a considerable fluctuation in size. As indicated in figure 3C and D for two Deiters' neurons, respectively, the fluctua- tion in amplitude of these EPSP's occurs with the smallest unit of 0.2 to 0.3 mV. Similarly small amplitude EPSP's were usually seen to occur spontaneously as in figure 3B and E. It is probable that a part of these EPSP "noises" is caused by the vestibular impulses which arise spontaneously. In this way the mono- synaptic transmission from the vestibular nerve fibers to Deiters' neurons resembles that from group la muscle afferents to spinal moto- neurons (refs. 22 to 24); it is performed through convergence of a number of afferent fibers, each fiber making only a minute contribution. The action of single vestibular nerve fibers was evaluated approximately by measuring ,nn PP. 0.5 1.0 mV msec 0 FIGURE 3. — Vestibular-evoked and spontaneous unitary EPSP's in Deiters' neurons. A, B: Intracellular recording from two Deiters' neurons; time constant, 0.02 sec. From the top to the bottom are single-sweep records taken every second. In A the vestibular nerve stimulation was at a juxtathreshold intensity. Left vertical broken line indicates the moment of onset of the monosynaptic EPSP's; the right one marks the moment when delayed small EPSP's were induced in some sweeps. In B no stimuli were given. t!: Frequency distribution of amplitudes of the small EPSP's evoked monosynaptically by the juxtathreshold stimulation of the ipsilateral vestibular nerve, partly illustrated in A. D: Similar to C, but for another cell. E: Similar to C and I), but for spontaneous EPSP noises, partly illustrated in B. (From ref. 18.) the least discernible EPSP's evoked with juxtathreshold stimulation and averaged over 20 to 40 sweeps at a repetition rate of 10 per second (fig. 3/4). In 11 Deiters' neurons the mean smallest EPSP's have a peak amplitude of 0.25 to 0.67 mV (average, 0.46 mV), their maximum ascending slope being 0.3 to 2.5 V/sec (average, 1.1 V/sec). In these cells, the maxi- mum ascending slope of the maximal EPSP's was 12 to 61 times (average. 25 times) as large as that of the mean smallest EPSP's (ref. 18). These figures will give a rough measure of the number of the vestibular nerve fibers converging on Deiters' neurons. In non-Deiters' vestibular nucleus cells the size of the unitary EPSP's was often relatively large (see fig. '2F and /). In 12 non-Deiters' neurons the mean smallest EPSP's ranged from 0.27 to 2.0 mV (average, 0.76 mV) and their maxi- mum ascending slopes from 0.6 to 3.6 V/sec (mean, 2.19 V/sec). The ratio of the maximum ascending slope of the mean smallest EPSP's to that of the maximal EPSP's was between 6 and 38, the average being 15 (ref. 12). Therefore, non-Deiters' vestibular nucleus neurons appear to receive a smaller number of vestibular nerve fibers, each of which has a higher efficacy of synaptic transmission than that of Deiters' neu- rons. Actually, Wilson et al. (ref. 25) reported that very little spatial summation is needed to produce monosynaptic firing of a medial nucleus unit by vestibular nerve impulses. It may be said that, in general, the transmission from the vestibular nerve to non-Deiters' neurons is less integrative and thus more of a relay than that to Deiters' neurons. Repetitive Discharges in Vestibular Nerve Fibers A rather peculiar observation with vestibular nerve stimulation is that the monosynaptic EPSP's are followed by prominent late EPSP's with a latency of 1.9 to 2.2 msec (fig. 4/4 to C) and further by those at 3.5 to 4.2 msec (D), there being characteristic multipeaked depolarization. That this successive onset of EPSP's is caused by repetitive discharges in the vestibular nerve fibers is indicated by three lines of observations: First, when examined with double-shock stimula- tion of the vestibular nerve, the refractory curve for testing monosynaptic EPSP's falls down two

188 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION or three times, corresponding exactly to the peaks of EPSP's, as illustrated in figure 4E through J and plotted in K. Second, individual vestibular nerve fibers, as impaled within vestibular nuclei, often responded repeatedly (twice or three times, or even more) to single vestibular nerve stimula- tion (fig. 5A through C). At threshold stimula- tion, the whole train of these spikes behaved in an all-or-none manner (A, B). Therefore, the late spikes in a fiber appear to be triggered by the initial spike in that fiber. Sometimes the FIGURE b. — Multipeaked EPSP's built up in Deiters' neurons during stimulation of the vestibular nerve. A through D: Upper traces, intracellular recording from a Deiters' neuron. Lower traces, extracellular controls. Stimulus intensity is indicated in each record by the multiple of vestibular nerve excitation thresholds. Upward arrows in D point to the moments of late onset of depolarization. E through 1: Double-shock vestibular nerve stimulation in another Deiters' neuron. E: Control obtained with conditioning stimuli with a supramaximal intensity for the mono- synaptic EPSP. m, 1, and 1': Three peaks of EPSP's. In F through i, test stimuli of the same intensity as that of the conditioning ones were given at various intervals after conditioning at the moments indicated by dots. In each record, test stimuli were switched off in about half of the trials. In F and H, the descending phase of the m- and 1-EPSP's is indicated by broken lines which were assumed to follow an exponential curve with time constant of 0.9 msec. Upward and downward arrows show how to measure the amplitudes of test EPSP's. In I and },the test EPSP's were measured from the baseline provided by the condition- ing stimuli alone. Time scale of msec (1.0) applies to E through H and that of 2 msec to I and ). K: Refractory cume for the test monosynapric EPSP's. Ordinates: ampli- tude of the test EPSP relative to that of the m-EPSP which is indicated by horizontal broken line. Abscissae: time intervals between the conditioning and test stimuli. Ver- tical broken lines separate the phases a, b, c of the recovery curves of the test EPSP's, corresponding to the m, I, I' peaks of the conditioning EPSP's. (From ref. 18.) burst of repeated spikes, similar to that evoked by stimulation, occurred spontaneously at a frequency of about 20 per second (fig. 5D). Third, the fact that such repetitive discharges as seen in figure 5A through C take place in many vestibular nerve fibers is demonstrated in figure 5E through / where the refractoriness is tested for the P-wave of the field potentials which represent the volley in the vestibular nerve. As plotted in 7, the refractory curve shows inflections approximately corresponding to the onset of late EPSP's. When the vestibular organ was destroyed, the refractory curve of the P-wave became simpler, indicating that many vestibular nerve fibers ceased to discharge repeatedly. The cause of this multiple firing in vestibular nerve fibers is not clear at the present time. It 1 00 |*) FIGURE 5. —Multiple discharges in vestibular nerve fibers which occurred in response to single vestibular nerve stimulation. A through D: Partial intracellular recording from three vestibular nerve fibers (A, B, C, D) within the nucleus of Deiters. E through I: Extracellular recording from the nucleus of Deiters. Double-shock stimuli, each being supramaximal for P-wave, were given to the vestibular nerve at various intervals. The test stimuli were switched off in about half of the trials at the moments indicated Ay dots. 1: Relates the amplitudes of the test P-wave in the records partly illustrated in E through 1 (ordinate\ to the shock intervals (abscissa). Inset diagram in i indicates how to measure the size of the P-wave, which is the sum of the respective peak amplitudes of the positive (p) and negative (n) phases of P-wave as measured from the potential curves following the conditioning stimuli alone (broken line). K. L: Similar to ), but taken immediately after (K). and about 2 hours after (1.). destruction of the vestibular organ. (From ref. 18.)

CEREBELLOVESTIBULAR INTERACTION 189 can only be pointed out that this may be due to a kind of pseudoreflex at the peripheral end of nerve fibers which occurs in frogskin nerve under certain experimental conditions (ref. 26). Polysynaptic Action of Vestibular Nerve Volleys In some Deiters' neurons, the latency of the vestibular-evoked EPSP's exceeded 1 msec (fig. 6H). These EPSP's were usually of rela- tively small size even with maximal vestibular nerve stimulation (fig. 6A through C). The mean latency for these delayed EPSP's is 1.28 msec (n=18) and is longer by 0.52 msec than that of the monosynaptic EPSP's (0.76 msec; see above). The 0.52 msec is close to the 0.75-msec difference in latency between mono- synaptic EPSP's and disynaptic IPSP's evoked by group la muscle afferents in spinal moto- neurons (ref. 27). Therefore, it is assumed that the delayed EPSP's are produced disynaptically FIGURE 6. — Vestibular-evoked polysynaptic EPSP's. A through C: Intracellular recording from Deiters' neuron. D through (',: From a DMLF cell. Intensity of vestibular nerve stimulation: 1.2T in A. 2.5T in B. 3.8T in C. /.0T in D. 1.21 in E, 1.4T in F, and 1.8T in G. H: Frequency distribution of the latency for the vestibular-evoked EPSP's (abscissa) in Deiters' neurons. Downward arrow indicates latency of the V-wave. Shaded area represents the early group of EPSP's in the monosynaptic range. I: Similar to H but for IPSP's. ] and K: Frequency distributions of vestibular-induced EPSP's and IPSP's, respectively, in non-Deiters' vestibular nucleus neurons. Bottom figure is a diagram of the synaptic connections from the vestibular nerve to vestibular nucleus neurons. Further explanation is in text. (From refs. 12 and 18.) through excitatory interneurons interposed be- tween the vestibular nerve fibers and Deiters' neurons. An alternate possibility that the delayed EPSP's are induced monosynaptically by impulses along relatively slow conducting fibers can be excluded for two reasons. First, the intensity range of the vestibular nerve stimulation effective for evoking the delayed EPSP's is quite similar to that for the mono- synaptic EPSP's, indicating that both the mono- synaptic and delayed EPSP's are evoked through the vestibular nerve fibers which have a similar excitability and hence presumably a similar conduction velocity. Second, delayed EPSP's were encountered widely within the nucleus of Deiters, even in its dorsal portion, as shown in figure 1Q (shaded), where no primary vestibular nerve fibers have appreciable synapses, ac- cording to histological observations (ref. 4). The delayed EPSP's, presumably of disynaptic origin, were seen also in some non-Deiters' neurons (fig. 6J). The inhibitory postsynaptic potentials (IPSP's) were also sometimes observed either in isolation or in superposition upon the monosynaptic EPSP's (fig. 6D through G). The latency of these IPSP's falls within the range of from 1.2 to 1.8 msec, indicating that they have a poly- synaptic (or at least a disynaptic) origin. The neuronal connections between the vestib- ular nerve fibers and vestibular nucleus neurons are illustrated in the diagram at the bottom of figure 6. The cell V2 receives monosynaptic EPSP's and in some cases also polysynaptic PSP's through interneurons V,. and V,-. They involve about one-third of Deiters' neurons and two-thirds of the non-Deiters' neurons examined. V, cells are activated only polysynaptically. They are common in the dorsal part of the nucleus of Deiters. V:i cells, roceiving inhibition only from the ipsilateral vestibular nerve, were found only in non-Deiters' nuclei. They may have other sources of excitatory input. The inter- neurons Ve and Vi should also be located in the vestibular nuclear complex, probably in the medial and/or descending nuclei where short- axoned cells of the interneuron type exist (ref. 1). Some cells impaled in these regions and

190 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION activated monosynaptically from the vestibular nerve might serve as interneurons as postulated here. STUDY WITH CEREBELLAR STIMULATION Inhibitory Action of Purkinje Cells The inhibitory action of the cerebellar Purkinje cell was first noticed in the experiment where microelectrodes were inserted into dorsal Deiters' neurons. During stimulation of the anterior lobe of the cerebellum, IPSP's appeared with monosynaptic latencies (refs. 28 and 29) (fig. 76' through M). The monosynaptic inhibi- tory area for Deiters' neurons expanded longi- tudinally, mainly along the ipsilateral vermis cortex of the anterior lobe (ref. 30). The ipsi- lateral cortex of the posterior lobe was also effec- tive in inhibiting Deiters' neurons, though less prominently than the anterior lobe. The inhibitory fibers could be stimulated in the white matter of the cerebellum, predominantly in the ipsilateral side at rostral regions of nuclei fastigii and interpositus. Further, the mono- synaptic inhibition of the anterior and posterior lobes occurs chiefly in the dorsal portion of the nucleus of Deiters. as shown in figure IN and O. These spatial patterns of distribution of the inhibitory fibers, in both the cerebellum and the nucleus of Deiters, conform to those of the Purkinje-cell axons of corticovestibular projec- tion (refs. 5, 6, and 31). It is also demonstrated that transsynaptic activation of Purkinje cells through cerebellar afferent fibers produces IPSP's in Deiters' neurons with a delay of mono- synaptic range (ref. 33). Similar inhibitory action has been observed recently in the superior vestibular nucleus neurons (Ito, Fukuda, and Kaji, unpublished). In them, stimulation of the ipsilateral floccular lobe was very effective in producing monosynaptic IPSP's, in accordance with the flocculovestibular projection defined histologically (refs. 7 and 34). The vestibular-evoked IPSP's show a fine gradation in their sizes, according to stimulus intensity (fig. 1A through M); there must be convergence of a number of Purkinje cell axons onto single vestibular nuclei cells. The convergence number was calculated for Deiters' neurons as 20 to 50 (Ito et al., unpublished). Histological data (refs. 5 to 7) indicate that Purkinje-cell axons from the cortex of the vermis project onto the dorsal part of the nucleus of Deiters as well as of the other non-Deiters' nuclei. The whole areas of the vestibular nuclei. KIGURE 1. —Monasynaptic IPSfs induced in vestibulur nucleus neurons during stimulation of the cerebellar cortex. Diagram at top shows the cerebellovestibular projections. A through K: Recorded from three superior vestibulur nucleus neurons during stimulation of the floccular lobe. Upper traces: Intracellular records. Lower traces in A and B and D through F are extracellular controls, uhi/e those in C are intracellular but during passage o/Cl- injection hyperpolarizing currents. Intensity of flocculur stimulation (0.2-msec duration) was 2 volts in A. 10 in B. 10 in C. 2 in D.IOin E. and 20 in F. G through M: IPSP's induced in u Deiters' neuron during stimulation of vermis cortex of culmen. Stimulus intensity, 1.9 V in G, 2.1 in H, 1.2 in I, 5.0 in J. 10 in K. 20 in L, and30 in M. Dotted lines in I, and M indicate the time course of the potential changes similar to that in J. Note the different voltage scales for G through I (2 mY\ and J through M |5 mI\. N: Frequency distribution of the depths of penetration of those cells which did not receive monosynaptic inhibition from the cerebellar anterior lobe. O: Similar to N, but for those which received the inhibition. Zero on the abscissa and vertical broken line indicate the mean depth of all the Deiters' neurons in each preparation. Figures itith minus sign represent ventral, and those uith no sign dorsal deviations (from ref. II). P, Q: Illustrating, similarly to N and O, the frequency distribution for those Deiters' neurons with (P) and without (Q) monosynaptic activation from the vestibular nen-e. Shaded in Q are those cells activated only polys\naptically by the vestibulur nerve volley, (From refs. 11 and IS. I

CEREBELLOVESTIBULAR INTERACTION 191 except for the nucleus of Deiters, are covered also by Purkinje-cell axons from the vestibulo- cerebellum (nodulus, flocculus, ventral uvula, and ventral paraflocculus). Peculiarly, the ven- tral part of the nucleus of Deiters receives little cerebellar corticofugal projection. Accordingly, monosynaptic IPSP's have not been evoked in ventral Deiters' neurons from any part of the cerebellum. Those Deiters' neurons receiving monosynaptic activation from the vestibular nerve showed no trace of the cerebellar inhibi- tion except in a few cells in which both vestib- ular EPSP's and cerebellar IPSP's appeared monosynaptically (Ito et al., unpublished). Recent electron-microscopic study also indicates that some Deiters' neurons have synapses with both vestibular nerve and Purkinje-cell axons (Walberg, personal communication). Dorsal Deiters' neurons may have direct connection with spinal motoneurons, though distinction between the dorsal and ventral Deiters is not clear in the experiment by Lund and Pompeiano (ref. 35). The superior vestibular nuclei neurons may connect with oculomotor neurons (ref. 1), but there is no direct physio- logical evidence. These possible three-neuron FIGURE 8. — Diagrammatic illustration of various types of cerebellar efferent connections. L: Lateral nucleus. I.P.: Interpositus nucleus. F: Fastigial nucleus. VL: Nucleus ventralis lateralis of thalamus. RN: Red nucleus. V: Vestibular nuclei in general. RF: Reticular formation. dD: Dorsal part of nucleus of Deiters. VS: Superior vestibular nucleus. Py: Pyramidal tract neurons. M: Motoneurons. EM: Electromotor neuron. chains from Purkinje cell to vestibular nuclei cell and then to motoneurons are illustrated in figure 8D and E. With the cerebellar nuclei inserted, the con- nection from Purkinje cells to the final common motor path becomes multistepped (fig. 8/4 through C). There is evidence indicating that the Purkinje cells exert solely inhibitory action upon cerebellar nuclei cells (ref. 36). To the contrary, the simplest arrangement has been found in oculomotor neurons of Japanese snake fish which Purkinje cells inhibit directly (fig. 8F) (ref. 37). Recently, Llinas et al. (ref. 38) found in the frog that the cerebellar Purkinje-cell axons pass out of the medulla and innervate the hair cells of the vestibular organ directly (fig. 8//). Here again the action of Purkinje cells seems to be inhibitory (ref. 39). It may also be mentioned that Purkinje cells inhibit basket and Golgi cells in the cerebellar cortex through their axon collaterals. There are no data available on the action of the Purkinje cells involved in the control of electric-organ discharges in electric fish (fig. 8C), but, since the electric plaque is a modification of muscula- ture, it is highly possible that Purkinje cells have inhibitory action similar to that in the motor system. Disinhibition Electric stimulation of the cerebellar cortex usually produced a prolonged delayed depolari- zation lasting for 50 to 500 msec in dorsal Deiters' neurons (refs. 29 and 40). Evidence has been given to indicate that this slow depolarization is caused by depression of Purkinje cells which otherwise are firing spontaneously and so building up a steady hyperpolarization at the membrane of Deiters' neurons (ref. 40). This depression of Purkinje cells seems to be effected through the inhibitory neurons in the cerebellar cortex (basket, superficial stellate, and Golgi cells; ref. 41). Disinhibitory slow depolarization in dorsal Deiters' neurons could also be produced by stimulating the spinocerebellar afferents at C2 level or in the inferior olive (ref. 40). In superior vestibular nucleus cells the stimulation of the vestibular nerve evoked similar dis- inhibition (Ito and Fukuda, unpublished).

192 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION Disinhibition was seen also in cerebellar nuclei (Ito et al., unpublished). It appears to account, at least largely, for the facilitatory action pro- duced by cerebellar stimulation upon muscle tone (refs. 42 and 43). Axon Reflex One of the most important aspects of the cere- bellar organization in the cerebellar efferent sys- tem was revealed by the finding that the cerebellar stimulation evoked not only monosynaptic IPSP's in subcortical neurons but also monosynaptic EPSP's. In the superior vestibular nucleus cell of figure IE and F such EPSP's as these are seen in superposition upon the IPSP's. It has already been suggested (ref. 11) that these FIGURE 9. — Axon reflex from the floccular lobe to vestibular nucleus neurons through vestibular nerve fibers. Diagram on the left indicates the arrangement of recording (m) and stimulating (Si, Si, Si) electrodes, jf: Juxtafastigial region. A through E: Intracellular recording from a ven- tral Deiters' neuron. A: EPSP from floccular lobe. B: EPSP from vestibular nerve. C: Combination of the floccular (conditioning) and vestibular nerve (test) stimuli. Dotted line indicates the time course under no test stimula- tion. D: Combination of jf and VN stimuli, the latter being switched off in about half of the trials. E: Similar to D, but with a shorter stimulus interval. F: Ordinate plots the amplitudes of test \N—EPSP's relative to their control value as function of time intervals after conditioning at floe, or jf. Horizontal broken line indicates the 100-percent value. t/ through K: Extracellular recording within the descending vestibular nucleus. Conditioning stimuli were given to floccular lobe and test ones to the vestibular nerve at various intervals, the latter being switched off in about half the trials. Downward arrows indicate the moments of test stimulation. EPSP's are brought about through the cere- bellar efferents which may have synapses with subcortical cells via their collaterals, as de- scribed previously by Lorente de No (ref. 44). Recently, sources have been identified for some of the excitatory fibers to vestibular nuclei (Ito, Kawai, Udo, and Mano, in prep- aration). One is the vestibular nerve fibers. In figure 9A stimulation of the floccular lobe evoked prominent EPSP's with monosynaptic latency in a ventral Deiters' neuron. In their time course and in their having a late peak superimposed, the floccular-induced EPSP's (A) greatly resemble those produced by vestibular nerve volleys (B). In fact, when evoked at short intervals, these EPSP's interacted with each other in the manner of impulse collision, as seen in figure 9C and plotted in F(O). It is obvious that the floccular stimulation evoked the EPSP's via the vestibular nerve fibers which, after synapsing with ventral Deiters' neurons, pass into the floccular nerve, as indicated histologically (ref. 45). In the cell of figure 9 A through F, stimulation near the fastig- ial nucleus also produced EPSP's with mono- synaptic latency (D), and these EPSP's again infracted with those from the vestibular nerve (E and F). Apparently the vestibular nerve fibers are giving off branches also to the juxta- fastigial region, presumably innervating the nodules and ventral uvula (refs. 7 and 45). The interference curves between the EPSP's from the flocculus (O) or juxtafastigial region • in figure 9F show a fall at 2- or 3-msec in- tervals. This indicates that the vestibular nerve fibers respond to floccular nerve or juxtafastigial stimulation with repetitive discharges, just as seen in vestibular nerve stimulation (see above). That the major portion of the vestibular nerve fibers is involved in this repetitive response is indicated in figure 96' through K where theP-wave evoked by the vestibular nerve stimulation is depressed by the floccular stimulation very effectively in the phase corresponding to the second fall in the interference curve of EPSP's (see /) (Ito, Fukuda, and Kaji, unpublished). Similar EPSP's of vestibular nerve origin were seen in the superior as well as descending vestib- ular nuclei cells. Another type of excitatory fibers was found to

CEREBELLOVESTIBULAR INTERACTION 193 be distributed widely within the anterior lobe of the cerebellum and to impinge onto both ventral and dorsal Deiters' neurons. By examining the occlusion due to impulse collision and refractori- ness, the major source of these excitatory fibers was found to be in the dorsomedial portion of the lower medulla which involves the so-called peri- hypoglossal nuclei and also the dorsal part of paramedian reticular formation. Both the peri- hypoglossal nuclei and paramedian reticular for- mation project to the cerebellar anterior and posterior lobes bilaterally (refs. 46 to 48). It appears that the cerebellar afferents of these medullary origins have collateral innervation on Deiters' neurons. Histologically, the dorsal spinocerebellar fibers are shown to synapse with Deiters' neurons (refs. 44 and 49). Actually, occlusion was seen be- tween the EPSP's evoked from the cerebellar anterior lobe and those from C2 lateral funiculus (Ito et al., in preparation). The spinal ascending fibers appear to impinge only onto these Deiters' neurons located dorsocaudally (ref. 49). The neuronal connections thus revealed are illustrated schematically in figure IQA, B, and C for dorsal Deiters', ventral Deiters', and superior vestibular neurons, respectively. Those con- nections via fastigial nucleus are omitted in FIGURE 10.—Synaptic connections from the Purkinje-cell axons and cerebellar afferents to vestibular nuclei neurons. M: Medullary cell of origin of cerebellar afferents which have abundant synapses with Deiters' neurons. P: Purkinje cells. SC: Spinocerebellar fibers. VO: Vestibular orpnn. mf: Mossy fibers. VD: Ventral part of nucleus of Deiters. figure 10. It is known that fastigial axons have only excitatory action upon vestibular neurons and mediate the Purkinje-cell inhibition indirectly by withdrawal of the excitatory fastigial impulses (ref. 43). The cerebello- fastigial influence may act upon dorsal Deiters' and superior vestibular neurons in parallel with the direct projection by Purkinje cells, while it is the only pathway for cerebellar control on ventral Deiters' neurons. CEREBELLOVESTIB ULAR INTERACTION In figure 10 it will be realized that there are two different types of synaptic organizations concerned in cerebellovestibular interaction. Ventral Deiters' neurons (B) appear to form a reflex center driven by vestibular as well as medullary inputs, but there is no direct control from the cerebellar cortex. On the other hand, the excitatory signals to dorsal Deiters' neurons and superior vestibular nucleus cells are fed also into the cerebellar cortex and, after being processed there, are returned as inhibitory signals through Purkinje-cell axons that interact postsynaptically in vestibular nuclei cells with the original excitatory inputs (A, C). It seems that a certain region of the vestibular nuclei forms a reflex center by itself without direct interference from the relevant cerebellar cortex, as shown schematically in figure IIB. The cerebellum would be super- imposed upon the other divisions of vestibular nuclei, as in A, which may be involved in rela- tively complex functions (see below). The simplest reflex arc is the well-known two-neuron arc that serves as the followup length of servomechanism of muscles (ref. 13) (fig. I2B). A comparable two-neuron arc is composed of the vestibular nerve fibers and oculomotor neurons in Japanese snake fish (Kindokoro, personal communication) (fig. 124). Histological data indicate that the vestibular nerve fibers innervate also the cerebellar cortex (ref. 50), and there is now evidence indicating that the cerebellar Purkinje cells pass down their axons directly onto oculomotor neurons (ref. 37). It appears that the cerebellar cortex is there superimposed on the two-neuron arc,

194 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION corresponding to the fact that the system involves a complex control function, having the feedback loop completed from the eye to vestibular organ. The three-neuron arc is formed with the vestibular nerve, ventral Deiters' neurons, and extensor motoneurons, particularly those for neck muscles (fig. 13B) (ref. 51). In this system the function may be relatively straightforward; Q cc FIGURE II. —Relation between the reflex center and the cerebellar cortex, cf: Climbing fiber. E: Effector part of the reflex system concerned. R: Its receptor part. CC: Cerebellar cortex. Explanation is in text. FIGURE 12.-Two-neuron arcs with (A) and without (B) cere- bellar control. MiMotoneurons. OM:Oculomotor neuron. la: Group la muscle afferent. Explanation is in text. FIGURE 13. —Possible three-neuron arcs with (A) or without (B) cerebellar control. VS: Superior vestibular nucleus cell. EM: Extensor motoneuron. Explanation is in text. neck muscles control the head position which is readily reflected in the activity of vestibular receptors. The superior vestibular nuclei cells, receiving the vestibular nerve, may innervate oculomotor neurons directly (ref. 1), though there is no direct evidence at the present time. With reservations because of this uncer- tainty, one may conceive a three-neuron arc on which the cerebellum is superimposed, corre- sponding to the complex task to be performed with this system. A general idea of this sort of origin and evolution of the cerebellum ap- peared in Herrick's article many years ago (ref. 52). GENERAL CONSIDERATIONS ON THE ROLE OF THE CEREBELLAR CONTROL On the basis of present knowledge of the cerebellovestibular system, one may consider a little further the role of the cerebellum in general. Motoneurons in combination with certain receptors and a certain muscle or muscle group would form a simple control system with a nega- tive feedback loop (fig. 144). In an engineering control system, when the dynamic characteristics of the object to be controlled or of the feedback loop are relatively complex, a compensatory element ought to be inserted, usually in series with the object to be controlled. This element (for instance, a differentiator or an integrator) would improve the overall performance of the system. As illustrated schematically in figure 14fi, certain supraspinal neurons, such as ventral

CEREBELLOVESTIBULAR INTERACTION 195 Deiters' neurons, may function in this way. at least to some extent. When the system has to carry out a more complex performance, a modern computer will be introduced instead of a relatively simple compensatory element. The cerebellum appears to be inserted in this way into certain motor control systems (fig. 14C). Examples are those which involve dorsal Deiters' and superior vestibular nuclei cells (figs. 10 and 13). A piece of the cerebellar cortical sheath in combination with a brainstem motor center now appears to form a unit of the compensatory element in a very expanded sense (fig. 15A). Insertion of the cerebellar nuclei between the FIGURE 15. — Diagrammatic illustration of variation in cere- bellar corticosubcortical connections. BS: Brainstem. CN: Cerebellar nuclei. Further explanation is in text. ~) — a i afk/Tl—. ^7 ^vV 7? H FIGURE 14. — Block diagrams illustrating the development of the motor control system. M: Motoneurons. S, S', S": Sensory part of the system. H, H', H": Feedback loop. B: Brainstem neuron, a: Motor nucleus as the object to be controlled, b: Brainstem center as a kind of com- pensator, c: Cerebellar cortex. Further explanation is in text. cerebellar cortex and the brainstem may modify the ability of this unit in two respects. First, the integration of excitatory inputs with the in- hibitory Purkinje-cell signals is performed at the cerebellar nuclei, allowing the brainstem centers to carry out more integration with other signals (fig. 15fl). Second, a reverberating circuit may be formed between the cerebellar nucleus neurons and those originating in certain cerebellar afferents (fig. 15C). There is ana- tomical evidence to suggest a reverberating con- nection between the descending vestibular nucleus and fastigial nucleus (refs. 53 and 54), between the paramedian reticular formation and fastigial nucleus (refs. 1 and 48), and between the pontine nucleus and the intracere- bellar lateral nucleus (ref. 55). These connec- tions would favor the maintenance of a certain standard of activity in the cerebellum-brainstem system. Such activity as this would provide the bias around which the dynamic characteris- tics of the system may be optimum. While the extrapyramidal centers in the brain- stem, together with the phylogenetically older part of the cerebellum, are engaged in respective servo actions, the pyramidal system would carry out the voluntary movement. It would influence the extrapyramidal system by shifting equilibrium so as to fit its achievement (fig. 16). It is known that the fast-conducting pyramidal tract fibers have a disynaptic inhibitory and the slow-con- ducting ones a monosynaptic excitatory linkage with red nucleus neurons (fig. 166) (ref. 56). The

19 6 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION FIGURE 16. — The pathways through which pyramidal tract system influences the extrapyramidal one. A: Diagram similar to figure I4C. Thick curved arrow indicates the pyramidal tract signals. B: Connection from the cerebral motor cortex to brainstem centers. fPt: Fast-conducting pyramidal tract fibers. sPt: Slow-conducting pyramidal tract fibers. Per: Corticorubral projection fiber. IP: Interpositus nucleus. F: Fastigial nucleus. PH: Perihy- poglossal nuclei. Possible connections from pyramidal tract fibers to PH are indicated by broken lines. reticulospinal neurons, on the other hand, appear to receive monosynaptic excitation from fast-conducting pyramidal tract fibers (Mano, personal communication) (fig. 16B). There is no direct connection between the pyramidal tract fibers and Deiters' neurons (ref. 1). How- ever, the perihypoglossal nuclei receive pyramidal tract fibers and so may mediate the cerebral influence onto Deiters' neurons (see above) (fig. 16B). Besides modifying the extrapyramidal system, the pyramidal system appears to utilize the phylo- genetically newer part of the cerebellum for its own achievement. In cats the pontine nucleus receives projection fibers from the cerebral sen- sorimotor area, a certain portion of which appears to be the collaterals of pyramidal tract fibers (ref. 57). The pontine nucleus neurons, in turn, project to the cerebellar cortex, chiefly to the hemisphere, having excitatory synapses with the lateral nucleus neurons (Ito et al.. unpublished) and eventually terminating in the cerebellar cor- tex as mossy fibers. The lateral nucleus neurons, after receiving Purkinje-cell axons, project ros- trally to the ventrolateral part of the thalamus which, in turn, innervates the fast-conducting pyramidal tract neurons monosynaptically (ref. 58). The functional significance of this loop has been discussed by Eccles (ref. 59). Here, one might recall the way in which a feedback control system is converted into a feedforward one (ref. 60). This is done by replacing the original feedback loop with a side loop which in- volves in itself the "dummy" for the element skipped by this shortcut. In figure I1A, the original loop for a voluntary movement is closed through the external world. It is assumed that the voluntary action starts from the association cortex and is transferred through the motor cortex to lower motor centers. The effects would be checked through the sensory system and be fed back into the association area. An equivalent performance would be possible if the motor area is equipped with the cerebellar side loop in which all the elements in the control system except for the motor area are miniaturized, as diagram- matically illustrated in figure 17B. There the voluntary movement would be performed in the way programed in the cerebellum without re- ferring to its actual end effect. This seems to be the case with learned, skilled movement. Objection to the above view may arise from the fact that the neocerebellum receives signals not only from the motor cortex but also from other parts of the cerebral cortex through pontine nucleus and the lateral reticular nucleus as well as the inferior olive (refs. 61 to 63). The outputs from fastigial nucleus and rubrospinal tract fibers also enter the neocerebellum through the lateral reticular nucleus (ref. 61). Existence of these FlGURE VI. —Illustrating diagrammatically the possible control svstem activitv involved in voluntarv movements. Association: association cortex. Circles filled uith dots indicate the origin of will. Further explanation is in text.

CEREBELLOVESTIBULAR INTERACTION 197 projections, however, may be understandable from the viewpoint of control theory as an arrange- ment required for a kind of adaptive control mechanism. To carry out a high-ordered func- tion, the dynamic characteristics of the elements involved in a control system have to be examined on line to maintain adequate conditions. In a similar way, the miniaturized dummies in the neocerebellum will always be modified by the signals coming in from the original elements (fig. 17B, indicated by broken lines and arrows). Of course, this may be nothing more than one of the many possible ways of thinking, but it seems to deserve consideration because the functional significance of the arrangement in the cerebellar control system still remains so obscure. REFERENCES 1. BRODAL, A.: POMPEIANO, O.; AND WALBERG. F.: The Vestibular Nuclei and Their Connections. Anatomy and Functional Correlations (Ramsay Henderson Trust Lectures). 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M.: Postsynaptic Influences on the Vestibular Non-Deiters' Nuclei From the Primary Vestibular Nerve. Exptl. Brain Res., vol. 8, 1969, pp. 190-200. 13. ECCLES, J. C.: The Physiology of Synapses. Julius Springer (Berlin), 1964. 14. POMPEIANO, O.; AND BRODAL, A.: The Origin of Ves- tibulospinal Fibers in the Cat. An Experimental- Anatomical Study. With Comment on the Descending Medial Longitudinal Fasciculus. Arch. Ital. Biol.. vol. 95, 1957. pp. 166-195. 15. WILSON, V. J.: KATO, M.; PETERSON. B. W.; AND WYLIE, R. M.: A Single-Unit Analysis of the Organization of Deiters' Nucleus. J. Neurophysiol., vol. 30, 1965, pp. 603-619. 16. NYBERG-HANSEN, R.: Origin and Termination of Fibers From the Vestibular Nuclei Descending in the Medial Longitudinal Fasciculus. An Experimental Study With Silver Impregnation Methods in the Cat. J. Comp. Neurol., vol., 122. 1964, pp. 355-367. 17. WILSON, V. J.; WYLIE, R. M.; AND MARCO, L. A.: Organi- zation of the Medial Vestibular Nucleus. J. 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198 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION tic Inputs to Cells in the Medial Vestibular Nucleus. J. Neurophysiol., vol. 31,1968, pp. 176-185. 26. SATO, M.: Pseudoreflex From End Plate and Sensory Nerve Ending. J. Neurophysiol., vol. 16, 1953, pp. 101-115. 27. ARAKI, T.; ECCLES, J. C.: AND ITO, M.: Correlation of the Inhibitory Postsynaptic Potential of Motoneurones With the Latency and Time Course of Inhibition of Monosynaptic Reflexes. J. Physiol., vol. 154, 1960, pp. 354-377. 28. ITO, M.: AND YOSHIDA, M.: The Cerebellar-Evoked Monosynaptic Inhibition of Deiters' Neurones. Ex- perientia, vol. 20,1964, p. 515. 29. ITO, M.; AND KAWAI, N.: IPSP-Receptive Field in the Cerebellum for Deiters' Neurones. Proc. Jap. Acad.. vol. 40, 1964, pp. 762-764. 30. ITO. M.; KAWAI, N.; AND UDO. M.: The Origin of Cere- bellar-Induced Inhibition of Deiters' Neurones. III. Localization of the Inhibitory Zone. Exptl. Brain Res., vol. 4, 1968, pp. 310-320. 31. EAGER. R. P.: Efferent Cortico-Nuclear Pathways in the Cerebellum of the Cat. J. Comp. Neurol., vol. 120, 1963, pp. 81-104. 32. ITO, M.; OBATA, K.: AND OCHI, R.: Initiation of IPSP in Deiters' and Fastigial Neurones Associated With the Activity of Cerebellar Purkinje Cells. Proc. Jap. Acad., vol. 40,1964, pp. 765-768. 33. ITO, M.; OBATA, K.; AND OCHI, R.: The Origin of Cerebellar-Induced Inhibition of Deiters' Neurones. II. Temporal Correlation Between the Trans-Synaptic Activation of Purkinje Cells and the Inhibition of Deiters' Neurones. Exptl. Brain Res., vol. 2, 1966, pp. 350-364. 34. Dow, R. S.: Efferent Connections of the Flocculo-Nodular Lobe in Macaca mulata. J. Comp. Neurol., vol. 68, 1938, pp. 297-307. 35. LUND, S.; AND POMPEIANO, O.: Descending Pathways With Monosynaptic Action on Motoneurones. Experi- entia, vol. 21, 1965, p. 602. 36. ITO. M.; YOSHIDA, M.; AND OBATA. K.: Monosynaptic Inhibition of the Intracellular Nuclei Induced From the Cerebellar Cortex. Experientia, vol. 20, 1964, pp. 295-296. 37. KIDOKORO. Y.: Direct Inhibitory Innervation to Teleost Oculomotor Neurones by Cerebellar Purkinje Cells. Brain Res., vol. 10, 1968, pp. 453-456. 38. LLINAS, R.; PRECHT, W.; AND KITAI, S. T.: Cerebellar Purkinje Cell Projection to the Peripheral Vestibular Organ in the Frog. Science, vol. 158, 1967, pp. 1328- 1330. 39. LLINAS, R.; PRECHT, W.; BRACHI, F.: AND HUERTAS, J.: The Inhibitory Cerebello-Vestibular System in the Frog. Proc. Intern. Union Physiol. Sci., vol. 7, 1968, p. 269. 40. ECCLES, J. C.; LLINAS. R.; AND SASAKI, K.: The Mossy Fiber-Granule Cell Relay in the Cerebellum and Its Inhibition by Golgi Cells. Exptl. Brain Res., vol. 1, 1966, pp. 82-101. 41. ANDERSEN. P.; ECCLES. J. C.; LLINAS, R.: AND VOOR- HOEVE. P. E.: Postsynaptic Inhibition of Cerebellar Purkinje Cells. J. Neurophysiol., vol. 27, 1964. pp. 1138-1153. 42. MORUZZI, G.: Problems in Cerebellar Physiology. Charles C Thomas, 1950. 43. ECCLES, J. C.; ITO, M.; AND SZENTAGOTHAI, J.: The Cerebellum as a Neuronal Machine. Springer-Verlag, 1967. 44. LoRENTE DE No, R.: Vestibulo-Ocular Reflex Arc. Arch. Neurol. Psychiat., vol. 30, 1933, pp. 245-291. 45. BRODAL, A.; AND H0WIK, B.: Site and Mode of Termina- tion of Primary Vestibulocerebellar Fibers in the Cat. Arch. Ital. Biol., vol. 102, 1964, pp. 1-21. 46. BRODAL, A.: Experimental Demonstration of Cerebellar Connexions From the Peri-Hypoglossal Nuclei (Nucleus Intercalatus, Nucleus Praepositus Hypoglossi and Nu- cleus of Roller) in the Cat. J. Anat., vol. 86, 1952, pp. 110-129. 47. TORVIK, A.; AND BRODAL, A.: The Cerebellar Projection of the Perihypoglossal Nuclei (Nucleus Intercalatus. Nucleus Praepositus Hypoglossi and Nucleus of Roller) in the Cat. J. Neuropath. Exptl. Neurol., vol. 13,1954. pp. 515-527. 48. BRODAL, A.; AND TORVIK, A.: Cerebellar Projection of Paramedian Reticular Nucleus of Medulla Oblongata in Cat. J. Neurophysiol., vol. 17, 1954, pp. 483-495. 49. POMPEIANO, O.; AND BRODAL, A.: Spino- Vestibular Fibers in the Cat. An Experimental Study. J. Comp. Neurol.. vol. 108, 1957, pp. 353-481. 50. LARSELL, O.: The Comparative Anatomy and Histology of the Cerebellum from Myxinoids Through Birds, J. Jansen, ed., Univ. Minnesota Press, 1967. 51. WILSON, V. J.; AND YOSHIDA, M.: Vestibulospinal and Reticulospinal Effects on Hindlimb. Forelimb. and Neck Alpha Motoneurons of the Cat. Proc. Nat. Acad. Sci., vol. 60, 1968. pp. 836-840. 52. Ill uiiic K, C. P.: Origin and Evolution of the Cerebellum Arch. Neurol. Psychiat., vol. 11, 1924, pp. 621-652. 53. BRODAL. A.; AND TORVIK, A.: i'ber den Ursprung der sekundaren vestibulocerebellaren Fasern bei der Katze. Fine experimentellanatomische Studie. Arch. Psy- chiat. Nervenkr., vol. 195. 1957. pp. 550-567. 54. WALBERG, F.; POMPEIANO, O.; BRODAL, A.: AND JANSEN, J.: The Fastigio-Vestibular Projection in the Cat. An Experimental Study With Silver Impregnation Methods. J. Comp. Neurol., vol. 118, 1962, pp. 49-76. 55. BRODAL, A.: The Reticular Formation of the Brain Stem. Anatomical Aspects and Functional Correlation (Ramsey Henderson Trust Lectures). Oliver & Boyd (Edinburgh, London), 1957. 56. TSUKAHARA, N.: FULLER, D. R. G.; AND BROOKS, V. B.: Influences From Pyramidal Collaterals on Cells of the Red Nucleus. Proc. of XXIV Intern. Union Physiol. Sci.. vol. 7. 1968. p. 441. 57. BRODAL, P.: The Corticopontine Projection in the Cat. I. Demonstration of a Somatotopically Organized Pro- jection From the Primary Sensorimotor Cortex. Exptl. Brain Res., vol. 5.1968, pp. 210-234. 58. YOSHIDA, M.; YAJIMA, K.; AND UNO, M.: Different Acti- vation of the Two Types of the Pyramidal Tract Neu-

CEREBELLOVESTIBULAR INTERACTION 199 rones Through the Cerebello-Thalamocortical Pathway. Experientia, vol. 22, 1966, pp. 331-332. 59. ECCLES, J. C.: Circuit in the Cerebellar Control of Move- ment. Proc. Nat. Acad. Sci., vol. 58, 1967, pp. 336- 343. 60. FuJII, M.: Control Engineering. (In Japanese.) Iwanami (Tokyo), 1968. 61. BRODAL. P.; MARSALA, J.; AND BRODAL, A.: The Cerebral Cortical Projection to the Lateral Reticular Nucleus in DISCUSSION Borison: One pathway which was not given much atten- tion in your analysis is the one concerned in motion sickness. Do you think that Deiters' nucleus might be implicated in a cerebellovestibular pathway that has a feeder input to the reticular formation? Ito: Actually. I cannot answer such a question because we are working on Nembutalized cats and never see motion sickness in them. However, my guess is perhaps that the cerebellovestibular system is involved in it. Snider: I was particularly fascinated by your difficulty with handling the EPSP's which you picked up in Deiters' nucleus. I am curious to know how the explanation you gave negates the possibility that there might be Purkinje cells that are excitatory rather than inhibitory. I know this is of special interest to you and should be brought out. Ito: Very strictly speaking, I have to say there is no evi- dence indicating that any Purkinje cells are excitatory. the Cat, With Special Reference to the Sensorimotor Cortical Areas. Brain Res., vol. 6, 1967, pp. 252-274. 62. WALBERG, F.: Descending Connections to the Inferior Olive. An Experimental Study in the Cat. J. Comp. Neural., vol. 104, 1956, pp. 77-173. 63. WALBERG, F.: Further Studies on the Descending Con- nections to the Inferior Olive; Reticulo-Olivary Fibers; An Experimental Study in the Cat. J. Comp. Neurol., vol. 114, 1960, pp. 79-87. When we see EPSP's in vestibular neurons during stimulation of the cerebral cortex, we can always show that these EPSP's are produced through axon collaterals, just using the impulse collision technique. This was so with the vestibular nerve, with the fibers originating from perihypoglossal nuclear regions and also with some spinocerebral fibers. Of course, it is necessary to do further experiments to exclude positively the possibility that you mentioned. Nyberg-Hansen: Dr. Ito is quite correct concerning the contribution to the medial vestibulospinal tract from the descending nucleus. As I showed in my study, the lesions did not hit the rostral part of that nucleus. If they had, I would have destroyed vestibulospinal fibers from the lateral nucleus coursing through the rostral part of the descending nucleus. When you thus cannot demonstrate fibers with retrograde cellular changes, and you cannot do it with antero- grade degeneration either, you have to do it physiologically, and you and Dr. Wilson have done it.

SESSION VII Chairman: WOLFGANG A. PRECHT Institute for Biomedical Research

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