Summary
Intracellular recording from Purkinje cells in cat cerebellar cortex demonstrated an 8–10/sec burst activity following intravenous administration of harmaline (10 mg/kg), a drug known to produce tremor at the same frequency. The burst activation of Purkinje cells was generated by large all-or-none depolarizations similar to climbing fiber (CF) excitatory postsynaptic potentials (EPSPs). Polarization of the cell membrane through the recording electrode (via a Wheatstone bridge) revealed that the all-or-none depolarization had an equilibrium potential and time course identical to the electrically evoked CF-EPSP, demonstrating directly that tremor is associated with specific activation of the CF afferent system.
Interspike frequency histograms of the burst responses of Purkinje cells show that the rhythmic CF activity may continue for several hours with approximately 10% frequency scatter, the actual frequency depending on the level of anesthesia. Simultaneous extracellular recordings from Purkinje cells near the midline vermis indicated that CFs projecting to this area fire in a synchronous manner, while simultaneous recording from three Purkinje cells at different lateralities from the midline showed that the rhythmic activity is reduced in the lateral vermis and may be absent in the cerebellar hemispheres.
Intra- and extracellular recordings from cerebellar nuclear cells (fastigial) disclosed a bursting type of activation following harmaline; a similar type of activity could be recorded in the reticular formation neurons and at inferior olive level. At spinal cord level, harmaline induced a repetitive and rhythmic activation of motoneurons which was not modified by dorsal root section. Cooling of the cerebellar cortex produced a definite desynchronization of the rhythmic motoneuronal firing. However, the basic 10/sec firing of the spinal cord motoneurons could still be observed. Following lesion of the inferior peduncles which interrupted the olivo-cerebellar pathway, the rhythmic activation of Purkinje cells, nuclear cells, vestibular and reticular cells and motoneurons disappeared. However, the rhythmic activity was maintained at inferior olivary level. It is suggested that harmaline acts directly on the inferior olive since in animals with low decerebration, cerebellectomy and spinal transection, rhythmic activity of the inferior olive could still be observed.
The results of these experiments strongly suggest that the inferior olive is able to generate the activation of motoneurons and that such influence can only take place through the activation of the cerebellar nuclei. Possible functions of the inferior olive as a generator of fast muscular transients are discussed.
Similar content being viewed by others
References
Ahmed, A., Taylor, N.R.W.: The analysis of drug-induced tremor in mice. Brit. J. Pharmacol. 14, 350–354 (1959).
Araki, T., Otani, T.: Response of single motoneurones to direct stimulation in toad's spinal cord. J. Neurophysiol. 18, 472–485 (1955).
Armstrong, D.M., Harvey, R.J.: Responses in the inferior olive to stimulation of the cerebellar and cerebral cortices in the cat. J. Physiol. (Lond.) 187, 553–574 (1966).
Bloedel, J.R., Burton, J.E.: Electrophysiological evidence for a mossy fiber input to the cerebellar cortex activated indirectly by collaterals of spinocerebellar pathways. J. Neurophysiol. 33, 308–320 (1970).
Bruggencate, G. ten, Teichmann, R., Weller, E.: Neuronal activity in the lateral vestibular nucleus of the cat. III. Inhibitory actions of cerebellar Purkinje cells evoked via mossy and climbing fiber afferents. Pflügers Arch. 337, 147–162 (1972).
Cannessa, M.: Effect of hallucinogen harmaline on sodium active transport in giant squid axon. Arch. Biol. Med. Exp. 7, R7 (1970).
Coombs, J.S., Eccles, J.C., Fatt, P.: Excitatory synaptic action in motoneurons. J. Physiol. (Lond.) 130, 374–395 (1955).
Crill, W.E.: Unitary multiple-spiked responses in cat inferior olive nucleus. J. Neurophysiol. 33, 199–209 (1970).
Eccles, J.C., Llinás, R., Sasaki, K.: The excitatory synaptic actions of climbing fibres on the Purkinje cells of the cerebellum. J. Physiol. (Lond.) 182, 268–296 (1966a).
—: Parallel fibre stimulation and the responses induced thereby in the Purkinje cells of the cerebellum. Exp. Brain Res. 1, 17–39 (1966b).
—: The mossy fibre-granule cell relay of the cerebellum and its inhibitory control by Golgi cells. Exp. Brain Res. 1, 82–101 (1966c).
—: The action of antidromic impulses on the cerebellar Purkinje cells. J. Physiol. (Lond.) 182, 316–345 (1966d).
—, Sasaki, K., Strata, P.: Interpretation of the potential fields generated in the cerebellar cortex by a mossy fiber volley. Exp. Brain Res. 3, 58–80 (1967).
Gunn, J.A.: The pharmacological action of harmine. Trans, roy. Soc. Edinb. 48, pt. 1, 83–96 (1911–1912).
Hara, S., Kawamori, K.: Pharmacological studies on the functions of the extrapyramidal system. Report No. 2: Mechanism of the appearance of tremor due to extrapyramidal poisons. Jap. J. Pharmacol. 3, 149–156 (1954).
Henderson, G.L., Woolley, D.E.: Ontogenesis of drug-induced tremor in the rat. J. Pharmacol. exp. Ther. 175, 113–120 (1970).
Ito, M., Yoshida, M., Obata, K.: Monosynaptic inhibition of the intracerebellar nuclei induced from the cerebellar cortex. Experientia (Basel) 20, 575–576 (1964).
—, Kawai, N., Udo, M.: Inhibitory control of intracerebellar nuclei by the Purkine cell axons. Exp. Brain Res. 10, 64–80 (1970).
Jansen, J., Brodal, A.: Aspects of Cerebellar Anatomy. Oslo: Johan Grundt Tanum Forlag 1954.
Kim, J.S., Hassler, R., Kurokawa, M., Bak, I.J.: Abnormal movements and rigidity induced by harmaline in relation to striatal acetylcholine, serotonin and dopamine. Exp. Neurol. 29, 189–200 (1970).
Lamarre, Y., Mercier, L.-A.: Neurophysiological studies of harmaline-induced tremor in the cat. Canad. J. Physiol. Pharmacol. 49, 1049–1058 (1971a).
—, Montigny, C. de, Dumont, M., Weiss, M.: Harmaline-induced rhythmic activity of cerebellar and lower brain stem neurons. Brain Res. 32, 246–250 (1971b).
Llinás, R.: Neuronal operations in cerebellar transactions. In: The Neurosciences: Second Study Program, pp. 409–426. Ed. by F.O. Schmitt. New York: Rockefeller Univ. Press 1970.
—, Bloedel, J.R., Hillman, D.E.: Functional characterization of the neuronal circuitry of the frog cerebellar cortex. J. Neurophysiol. 32, 847–870 (1969).
—, Hillman, D.E.: Physiological and morphological organization of the cerebellar circuits in various vertebrates. In: Neurobiology of Cerebellar Evolution and Development, pp. 43–73. Ed. by R. Llinás. Chicago: Amer. Med. Assn. 1969.
- Volkind, R.A.: Repetitive climbing fiber activation of Purkinje cells in the cat cerebellum following administration of harmaline. Fed. Proc. 31, 377a (1972a).
-- Functional organization of neuronal circuits in cerebellar cortex: Activation of the climbing fiber system by harmaline. Proc. IVth International Biophysics Congress, Moscow 1972b.
Marr, D.: A theory of cerebellar cortex. J. Physiol. (Lond.) 202, 437–470 (1969).
Montigny, C. de, Lamarre, Y.: Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat. (in press).
Neuner, A., Tappeiner, H.: Über bei Wirkungen der Alkaloide von Peganum harmala, insbesondere des Harmalins. Arch. exp. Pathol. Pharmakol. 35, I, 69 (1894).
Poirier, L.J., Singh, P., Boucher, R.: Opposite effect of harmaline on serotonin and on dopamine and its metabolites, homovanillic acid and norepinephrine, in the brain of the cat. Canad. J. Physiol. Pharmacol. 46, 585–589 (1968).
—, Sourkes, T.L., Bouvier, G., Boucher, R., Carabin, S.: Striatal amines, experimental tremor and the effect of harmaline in the monkey. Brain 89, 37–52 (1966).
Precht, W., Llinás, R.: Functional organization of the vestibular afferents to the cerebellar cortex of frog and cat. Exp. Brain Res. 9, 30–52 (1969).
Ramón y Cajal, S.: Histologie du système nerveux de l'homme et des vertébrés. Paris: Maloine 1911.
Sasaki, K., Strata, P.: Responses evoked in the cerebellar cortex by stimulating mossy fiber pathways to the cerebellum. Exp. Brain Res. 3, 95–110 (1967).
Sigg, E.B., Gyermek, L., Hill, R.T., Yen, H.C.Y.: Neuropharmacology of some harmine derivatives. Arch. int. Pharmacodyn. 149, 164–180 (1964).
Villablanca, J., Riobo, F.: Electroencephalographic and behavioral effects of harmaline in intact cats and in cats with chronic mesencephalic transection. Psychopharmacologia (Berl.) 17, 302–313 (1970).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Llinás, R., Volkind, R.A. The olivo-cerebellar system: Functional properties as revealed by harmaline-induced tremor. Exp Brain Res 18, 69–87 (1973). https://doi.org/10.1007/BF00236557
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00236557