Cerebellar and Brainstem Circuits Involved in Classical Eyeblink Conditioning

Model systems are one useful strategy for the investigation of the mechanisms of learning. Whereas mammalian model systems generally do not offer the ease of identifying circuitry and exploring cellular mechanisms of learning that is realized with invertebrate preparations /37,97/, research involving the rabbit classical eyeblink conditioning paradigm has now reached the state at which much of the basic conditioning neural circuit appears to have been identified /9,65,66,85,89,91/. Despite a dispute as to precisely where in the circuitry convergence of the associated stimuli may occur, there is substantial evidence identifying the stimulus input pathways and motor output pathway. The present summary of this research details these paths. In addition, the proposed sites of convergence of the conditioning stimuli are discussed. Finally, a hypothesized neural circuit responsible for classical eyeblink conditioning is presented along with some suggestions for future research directions.

[1]  J. Farley,et al.  Temporal order sensitivity of associative neural and behavioral changes in Hermissenda. , 1987, Behavioral neuroscience.

[2]  G. M. Shambes,et al.  Fractured somatotopy in granule cell tactile areas of rat cerebellar hemispheres revealed by micromapping. , 1978, Brain, behavior and evolution.

[3]  Richard F. Thompson,et al.  Pharmacological analysis of the magnocellular red nucleus during classical conditioning of the rabbit nictitating membrane response , 1988, Brain Research.

[4]  Cegavske Cf,et al.  Mechanisms of efferent neuronal control of the reflex nicitating membrane response in rabbit (Oryctolagus cuniculus) , 1976 .

[5]  J. Steinmetz,et al.  Acquisition of classical conditioning without cerebellar cortex , 1989, Behavioural Brain Research.

[6]  D. A. McCormick,et al.  Effect of bilateral lesions of the dentate and interpositus cerebellar nuclei on conditioning of heart-rate and nictitating membrane/eyelid responses in the rabbit , 1984, Brain Research.

[7]  G. Mihailoff,et al.  Convergence of cortical and cerebellar projections on single basilar pontine neurons: A light and electron microscopic study in the rat , 1990, Neuroscience.

[8]  K. Berkley,et al.  Projections to the inferior olive of the cat II. Comparisons of input from the gracile, cuneate and the spinal trigeminal nuclel , 1978, The Journal of comparative neurology.

[9]  R. F. Thompson,et al.  Initial localization of the acoustic conditioned stimulus projection system to the cerebellum essential for classical eyelid conditioning. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J E Steinmetz,et al.  Possible conditioned stimulus pathway for classical eyelid conditioning in rabbits. I. Anatomical evidence for direct projections from the pontine nuclei to the cerebellar interpositus nucleus. , 1992, Behavioral and neural biology.

[11]  JOHN W. Moore,et al.  Single-unit activity in red nucleus during the classically conditioned rabbit nictitating membrane response , 1991, Neuroscience Research.

[12]  J. Houk,et al.  Somatotopic alignment between climbing fiber input and nuclear output of the cat intermediate cerebellum , 1987, The Journal of comparative neurology.

[13]  T W Berger,et al.  Lesions of the retrosplenial cortex produce deficits in reversal learning of the rabbit nictitating membrane response: implications for potential interactions between hippocampal and cerebellar brain systems. , 1986, Behavioral neuroscience.

[14]  C. F. Cegavske,et al.  Tone-induced changes in excitability of abducens motoneurons and of the reflex path of nictitating membrane response in rabbit (Oryctolagus cuniculus). , 1976, Journal of comparative and physiological psychology.

[15]  D. Oakley,et al.  Neocortical lesions and Pavlovian conditioning. , 1972, Physiology & behavior.

[16]  David G. Lavond,et al.  Concomitant classical conditioning of the rabbit nictitating membrane and eyelid responses: Correlations and implications , 1982, Physiology & Behavior.

[17]  JOHN W. Moore,et al.  A brain stem region essential for the classically conditioned but not unconditioned nictitating membrane response , 1982, Physiology & Behavior.

[18]  C. Yeo,et al.  The Effect of Kainic Acid Lesions of the Cerebellar Cortex on the Conditioned Nictitating Membrane Response in the Rabbit , 1992, The European journal of neuroscience.

[19]  Richard F. Thompson,et al.  Localization of a memory trace in the mammalian brain. , 1993, Science.

[20]  N. Donegan Priming-produced facilitation or diminution of responding to a Pavlovian unconditioned stimulus. , 1981, Journal of experimental psychology. Animal behavior processes.

[21]  G. A. Clark,et al.  The engram found? Role of the cerebellum in classical conditioning of nictitating membrane and eyelid responses , 1981 .

[22]  R. Clark,et al.  Reversible lesions of the cerebellar interpositus nucleus during acquisition and retention of a classically conditioned behavior. , 1992, Behavioral neuroscience.

[23]  B. Knowlton,et al.  Classical conditioning of the rabbit eyelid response with a mossy-fiber stimulation CS: II. Lateral reticular nucleus stimulation. , 1987, Behavioral neuroscience.

[24]  H. Praag Indoleamines in depression and suicide. , 1986 .

[25]  J. Houk,et al.  Inhibition of sensory responses of cat inferior olive neurons produced by stimulation of red nucleus. , 1990, Journal of neurophysiology.

[26]  T. Land,et al.  Anatomical study of the rabbit's corneal-VIth nerve reflex: Connections between cornea, trigeminal sensory complex, and the abducens and accessory abducens nuclei , 1984, Brain Research.

[27]  Richard F. Thompson,et al.  The role of the middle cerebellar peduncle in acquisition and retention of the rabbit’s classically conditioned nictitating membrane response , 1986 .

[28]  I. Gormezano,et al.  The role of the accessory abducens nucleus in the rabbit nictitating membrane response , 1984, Brain Research.

[29]  R. F. Thompson,et al.  Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M Glickstein,et al.  Tectopontine pathway in the cat: laminar distribution of cells of origin and visual properties of target cells in dorsolateral pontine nucleus. , 1979, Journal of neurophysiology.

[31]  J. W. Moore,et al.  Red nucleus lesions impair acquisition of the classically conditioned nictitating membrane response but not eye-to-eye savings or unconditioned response amplitude , 1985, Behavioural Brain Research.

[32]  N. Donegan,et al.  Potentiation or diminution of discrete motor unconditioned responses (rabbit eyeblink) to an aversive pavlovian unconditioned stimulus by two associative processes: conditioned fear and a conditioned diminution of unconditioned stimulus processing. , 1992, Behavioral neuroscience.

[33]  Richard F. Thompson,et al.  Classical conditioning does not occur when direct stimulation of the red nucleus or cerebellar nuclei is the unconditioned stimulus , 1988, Brain Research.

[34]  J. Harvey,et al.  Pavlovian conditioning in the rabbit during inactivation of the interpositus nucleus. , 1991, The Journal of physiology.

[35]  Richard F. Thompson,et al.  Retention of classically conditioned eyelid responses following acute decerebration , 1987, Brain Research.

[36]  T. Voneida,et al.  Changes in instrumentally and classically conditioned limb-flexion responses following inferior olivary lesions and olivocerebellar tractotomy in the cat , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[37]  Richard F. Thompson,et al.  Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses , 1990, Brain Research.

[38]  F. Walberg,et al.  The olivocerebellar projection in the cat studied with the method of retrograde axonal transport of horseradish peroxidase. III. The projection to the vermal visual area. , 1976, The Journal of comparative neurology.

[39]  J. Steinmetz Neuronal Activity in the Rabbit Interpositus Nucleus during Classical NM-Conditioning with a Pontine-Nucleus-Stimulation CS , 1990 .

[40]  J. Welsh,et al.  Cerebellar lesions and the nictitating membrane reflex: performance deficits of the conditioned and unconditioned response , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[41]  R. F. Thompson,et al.  Disruption of classical eyelid conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit? , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  G. R. Wells,et al.  Visual projections to the pontine nuclei in the rabbit: Orthograde and retrograde tracing studies with WGA‐HRP , 1989, The Journal of comparative neurology.

[43]  E. Kandel,et al.  Associative Learning in Aplysia: evidence for conditioned fear in an invertebrate. , 1981, Science.

[44]  Richard F. Thompson,et al.  Lesions of the inferior olivary complex cause extinction of the classically conditioned eyeblink response , 1985, Brain Research.

[45]  J. Steinmetz,et al.  Possible CS and US pathways for rabbit classical eyelid conditioning: electrophysiological evidence for projections from the pontine nuclei and inferior olive to cerebellar cortex and nuclei. , 1993, Behavioral and neural biology.

[46]  J. W. Moore,et al.  Red nucleus lesions disrupt the classically conditioned nictitating membrane response in rabbits , 1983, Behavioural Brain Research.

[47]  N. Tsukahara,et al.  Synaptic plasticity in the mammalian central nervous system. , 1981, Annual review of neuroscience.

[48]  Donald J. Weisz,et al.  Reflex facilitation of the nictitating membrane response remains after cerebellar lesions. , 1988 .

[49]  David A. McCormick,et al.  Ipsilateral cerebellar lesions prevent learning of the classically conditioned nictitating membrane/eyelid response , 1982, Brain Research.

[50]  N. Tsukahara,et al.  Classical conditioning mediated by the red nucleus in the cat , 1981 .

[51]  J. Steinmetz,et al.  Acquisition of classically conditioned-related activity in the hippocampus is affected by lesions of the cerebellar interpositus nucleus. , 1990, Behavioral neuroscience.

[52]  P. Huttenlocher Neurological Anatomy in Relation to Clinical Medicine , 1970, The Yale Journal of Biology and Medicine.

[53]  Richard F. Thompson,et al.  Microinjections of local anesthetic into the pontine nuclei reduce the amplitude of the classically conditioned eyelid response , 1988, Physiology and Behavior.

[54]  M. Glickstein,et al.  Discrete lesions of the cerebellar cortex abolish the classically conditioned nictitating membrane response of the rabbit , 1984, Behavioural Brain Research.

[55]  R. F. Thompson,et al.  Cerebellum: essential involvement in the classically conditioned eyelid response. , 1984, Science.

[56]  E. Dietrichs,et al.  Do pontocerebellar mossy fibres give off collaterals to the cerebellar nuclei? An experimental study in the cat with implantation of crystalline HRP-WGA , 1986, Neuroscience Research.

[57]  JOHN W. Moore,et al.  An HRP study of the brainstem afferents to the accessory abducens region and dorsolateral pons in rabbit: Implications for the conditioned nictitating membrane response , 1983, Brain Research Bulletin.

[58]  Do pontocerebellar mossy fibres give off collaterals to the cerebellar nuclei? An experimental study in the cat with implantation of crystalline HRP-WGA , 1986 .

[59]  J. Steinmetz,et al.  Dorsal accessory inferior olive activity diminishes during acquisition of the rabbit classically conditioned eyelid response , 1991, Brain Research.

[60]  E. Kehoe,et al.  Cross-modal transfer as a function of initial training level in classical conditioning with the rabbit , 1987 .

[61]  Joseph E. Steinmetz,et al.  Classical conditioning of the rabbit eyelid response with mossy fiber stimulation as the conditioned stimulus , 1985 .

[62]  Wally Welker,et al.  Fractured cutaneous projections to the granule cell layer of the posterior cerebellar hemisphere of the domestic cat , 1984, The Journal of comparative neurology.

[63]  R. Dow,et al.  The Physiology and Pathology of the Cerebellum , 1958 .

[64]  R. F. Thompson,et al.  Effect of kainic acid lesions of the cerebellar interpositus nucleus on eyelid conditioning in the rabbit , 1985, Brain Research.

[65]  V. Perciavalle,et al.  The cerebellopontine system: an electrophysiological study in the rat , 1991, Brain Research.

[66]  R. F. Thompson,et al.  Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus , 1989, Synapse.

[67]  N. Tsukahara,et al.  Classical conditioning mediated by the red nucleus in the cat. , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[68]  J. Houk MODEL OF THE CEREBELLUM AS AN ARRAY OF ADJUSTABLE PATTERN GENERATORS. , 1987 .

[69]  A. L. Beggs,et al.  Classical conditioning of a flexor nerve response in spinal cats: effects of tibial nerve CS and a differential conditioning paradigm. , 1985, Behavioral neuroscience.

[70]  M. Mauk,et al.  Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[71]  G. Mihailoff Cerebellar nuclear projections from the basilar pontine nuclei and nucleus reticularis tegmenti pontis as demonstrated with PHA‐L tracing in the rat , 1993, The Journal of comparative neurology.

[72]  J. Steinmetz Classical nictitating membrane conditioning in rabbits with varying interstimulus intervals and direct activation of cerebellar mossy fibers as the CS , 1990, Behavioural Brain Research.

[73]  Paul R. Solomon,et al.  Lesions of the middle cerebellar peduncle disrupt acquisition and retention of the rabbit's classically conditioned nictitating membrane response. , 1987, Behavioral neuroscience.

[74]  R. F. Thompson,et al.  Neuronal responses of the rabbit cerebellum during acquisition and performance of a classically conditioned nictitating membrane-eyelid response , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[75]  K. J. Quinn,et al.  Accessory abducens nucleus and conditioned eye retraction/nictitating membrane extension in rabbit , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[76]  J S Buchwald,et al.  Classical conditioning with auditory discrimination of the eye blink in decerebrate cats. , 1977, Science.

[77]  C. Yeo,et al.  Recoverable and nonrecoverable deficits in conditioned responses after cerebellar cortical lesions , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[78]  R. Clark,et al.  Reversible lesions of the red nucleus during acquisition and retention of a classically conditioned behavior in rabbits. , 1993, Behavioral neuroscience.

[79]  J. W. Moore,et al.  Brachium conjuntivum and rubrobulbar tract: Brain stem projections of red nucleus essential for the conditioned nictitating membrane response , 1985, Physiology & Behavior.

[80]  Y Shinoda,et al.  Axon collaterals of mossy fibers from the pontine nucleus in the cerebellar dentate nucleus. , 1992, Journal of neurophysiology.

[81]  J. Bloedel,et al.  Classical conditioning of the eyeblink reflex in the decerebrate-decerebellate rabbit , 1990, Behavioural Brain Research.

[82]  Richard F. Thompson,et al.  Are eyeblink responses to tone in the decerebrate, decerebellate rabbit conditioned responses? , 1991, Behavioural Brain Research.

[83]  C. Yeo,et al.  Somatosensory Trigeminal Projections to the Inferior Olive, Cerebellum and other Precerebellar Nuclei in Rabbits , 1992, The European journal of neuroscience.

[84]  L. Aitkin,et al.  Acoustic input to the lateral pontine nuclei , 1978, Hearing Research.

[85]  David A. McCormick,et al.  Superior cerebellar peduncle lesions selectively abolish the ipsilateral classically conditioned nictitating membrane/eyelid response of the rabbit , 1982, Brain Research.

[86]  M. M. Patterson,et al.  Fixation of spinal reflex alterations in spinal rats by sensory nerve stimulation. , 1985, Behavioral neuroscience.

[87]  J. Steinmetz,et al.  Rabbit classically conditioned eyelid responses do not reappear after interpositus nucleus lesion and extensive post-lesion training , 1992, Behavioural Brain Research.

[88]  JOHN W. Moore,et al.  A supratrigeminal region implicated in the classically conditioned nictitating membrane response , 1983, Brain Research Bulletin.

[89]  M. M. Patterson Mechanisms of classical conditioning and fixation in spinal mammals. , 1976, Advances in psychobiology.

[90]  Richard F. Thompson,et al.  A nonrecoverable learning deficit , 1984 .

[91]  D J Rosen,et al.  Classical conditioning of the rabbit eyelid response with a mossy-fiber stimulation CS: I. Pontine nuclei and middle cerebellar peduncle stimulation. , 1986, Behavioral neuroscience.