Cerebellum and conditioned reflexes

doi:10.1016/S1364-6613(98)01219-4

Trends in Cognitive Sciences

Volume 2, Issue 9, 1 September 1998, Pages 322-330

https://doi.org/10.1016/S1364-6613(98)01219-4 Get rights and content

Abstract

The central assumption of existing models of motor learning in the cerebellum is that cerebellar mossy fibres signal information about the context in which a movement is to be performed and climbing fibres signal in relation to a movement error. This leads to changes in the responsiveness of Purkinje cells, which on the next occasion will generate a corrected output in a given context. Support for this view has come mainly from work on adaptation of the vestibulo–ocular reflex. The discovery that classically conditioned eyeblink responses depend critically on the cerebellum offers the possibility to study the learning of a novel behaviour, rather than modification of an existing reflex. After repeated pairing of a neutral stimulus, such as a tone, with a blink-eliciting stimulus, the tone will acquire the ability to elicit a blink on its own. We review evidence from studies employing a wide variety of techniques that the cerebellum is critical in this type of learning as well as evidence that mossy and climbing fibres have roles assigned to them in cerebellar learning models.

Section snippets

Cerebellar lesions and eyeblink: NMR conditioning

In the original study[16], a unilateral lesion of the cerebellum abolished nictitating membrane (NM) conditioned responses (CRs) ipsilateral to the lesion and prevented their reacquisition. CRs developed normally contralateral to the lesion and the unconditioned reflex blink was intact. Subsequent studies refined and extended this observation culminating in a clear agreement that lesions of the anterior interpositus nucleus (AIP) are sufficient to abolish CRs but lesions of the fastigial,

Interpretation of cerebellar lesion effects and the performance hypothesis

The effects of cerebellar lesions upon conditioned eyeblink/NM responses can be summarized simply. Lesions of the AIP produce severe and sustained losses of CRs whereas lesions of the cerebellar cortex have produced effects ranging from abolition to mild impairments. How are these effects to be interpreted and why do the cortical lesion effects appear to vary so widely?

The simplest interpretation of the cerebellar lesion studies is that the neural circuitry supporting plasticity essential for

Recording studies

Single and multiunit recordings have been made from many CNS structures during conditioning. In evaluating such evidence it must be recognized that correlation does not prove causation. For example, it is reported that unit activity in the hippocampus `models' the CR but delay conditioning can proceed normally without the hippocampus. One way to address the correlation/causation problem is to look at lead times. If, for instance, activity in the AIP precedes the CR, it cannot be a consequence

Stimulation studies

A direct test of the CCC model is to replace the peripheral CS and US with direct stimulation of the putative central CS and US pathways, that is the mossy fibres and the climbing fibres. Such stimulus substitution experiments are logically attractive but they have severe methodological problems. It has been reported that electrical stimulation of the pontine nuclei as the CS can produce rapid conditioning47, 48. However, stimulation in the brainstem ortho- and antidromically activates passing

Role of inferior olive in conditioning

The CCC model of NMR conditioning gives the inferior olive/climbing fibre a reinforcing role by signalling the US and modifying CS-related parallel fibre synaptic efficacy. This proposal is one of the most clearly defined components of the model and testing it should provide the best evidence for, or against, the model. It might be thought that central interruption of the putative US pathway by an olive lesion would be equivalent to turning off the US peripherally, which would lead to

Reversible cerebellar inactivations and NMR conditioning

Permanent lesion studies alone cannot resolve whether the cerebellum actively contributes to the acquisition and storage of motor memories or whether the cerebellum only regulates the performance of movements learned in other neural circuitry. Recent studies have addressed this problem using reversible lesion techniques. Conditioning trials can be given during a localized, functional inactivation of the cerebellum. If, after the inactivation is lifted, conditioned responses are present then

Conclusions

A wealth of lesion, inactivation, electrophysiological and stimulation studies provides evidence consistent with a cerebellar cortical learning model of classical conditioning but only a few of them support this model with the exclusion of other possibilities. Taken overall, reversible inactivation studies provide the best support for the critical dependence of this simple form of associative learning upon the cerebellum but the underlying mechanisms have not been identified. In our view the

Outstanding questions

•
The cerebellum is crucial for normal eyeblink conditioning but what is the underlying mechanism? There is clear evidence that CS information is transmitted by the mossy fibres, and US information by the climbing fibres, to the cerebellar cortex. But there is no direct evidence that these two inputs interact to produce conditioned responses. In particular, evidence is weak that the climbing fibres from the inferior olive are exclusively reinforcing.
•
What is the nature of the interaction between

Acknowledgements

Our work has been supported by the UK Medical Research Council and the UK Biotechnology and Biological Sciences Research Council (CHY), and by the Swedish Medical Research Council (project no. 09899) and the the Wallenberg Foundation in cooperation with Astra AB (GH). Our thanks to Shbana Rahman, Magnus Ivarsson and Pär Svensson for help in preparing this paper.

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We studied nine normal volunteers with a classical conditioning paradigm using a mastoid tap, believed to activate otolith receptors, as an unconditional stimulus (US) and the consequent blink as the unconditioned response (UR). Both visual (alternation of stripes) and an auditory tone were used as conditional stimuli (CS). Recordings were made below the eyes at IO1 and IO2, from over the frontal eye fields (C3′ and C4′) and over the posterior fossa, the latter at sites we have previously reported that we were able to record an evoked climbing fibre response (CFR) at short latency. Behavioural analysis confirmed that weak conditioning did occur early, which subsequently showed extinction on repeated CS alone trials. Further, a UR was more likely to occur following a preceding CFR when preceded by a CS, supporting a correlation between the CFRs and behaviour. For further statistical analysis, the time period of interest was divided into a series of epochs, based around the events occurring at the time. Grand averages, plus analysis of variance, confirmed evidence of weak conditioning for the blink response following both modalities. The EMG associated with the eyeblink for the UR occurred at a similar time to the expected post-CFR pause in the spontaneous cerebellar activity, or electrocerebellogram (ECeG), while hypothesised conditioned pausing in the ECeG was also observed in CS alone trials. A correlation was found between the size of the CFR and the RMS amplitudes of the segments covering the ocular vestibular evoked myogenic potential oVEMP, (periocular) EMG and the EOG. The slope was greater for the non-oVEMP segments than for the oVEMP segment suggesting the correlation was not simply due to differing sizes of the vestibular volley. We suggest that these recorded events fit with the proposed role of the CFR in Purkinje neurons in classical conditioning, gating the excitability of the cerebellar nuclei, and thereby neurons in the reticular formation mediating the otolith blink reflex. This effect appears to apply to polysynaptic reflexes only as there was no evidence of changes to the oVEMP.
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The functional impact of single interneurons on neuronal output in vivo and how interneurons are recruited by physiological activity patterns remain poorly understood. In the cerebellar cortex, molecular layer interneurons and their targets, Purkinje cells, receive excitatory inputs from granule cells and climbing fibers. Using dual patch-clamp recordings from interneurons and Purkinje cells in vivo, we probe the spatiotemporal interactions between these circuit elements. We show that single interneuron spikes can potently inhibit Purkinje cell output, depending on interneuron location. Climbing fiber input activates many interneurons via glutamate spillover but results in inhibition of those interneurons that inhibit the same Purkinje cell receiving the climbing fiber input, forming a disinhibitory motif. These interneuron circuits are engaged during sensory processing, creating diverse pathway-specific response functions. These findings demonstrate how the powerful effect of single interneurons on Purkinje cell output can be sculpted by various interneuron circuit motifs to diversify cerebellar computations.
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Citation Excerpt :
Over the past decades, research on Pavlovian eyeblink conditioning has established the necessity of specific regions in the cerebellar cortex and nuclei for the acquisition of well-timed conditioned behavior [1–4,5–12,138,139].
The eyeblink conditioning paradigm captures an elementary form of associative learning in a neural circuitry that is understood to an extraordinary degree. Cerebellar cortical Purkinje cell simple spike suppression is widely regarded as the main process underlying conditioned responses (CRs), leading to disinhibition of neurons in the cerebellar nuclei that innervate eyelid muscles downstream. However, recent work highlights the addition of a conditioned Purkinje cell complex spike response, which at the level of the interposed nucleus seems to translate to a transient spike suppression that can be followed by a rapid spike facilitation. Here, we review the characteristics of these responses at the cerebellar cortical and nuclear level, and discuss possible origins and functions.
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Trends in Cognitive Sciences

Cerebellum and conditioned reflexes

Abstract

Section snippets

Cerebellar lesions and eyeblink: NMR conditioning

Interpretation of cerebellar lesion effects and the performance hypothesis

Recording studies

Stimulation studies

Role of inferior olive in conditioning

Reversible cerebellar inactivations and NMR conditioning

Conclusions

Outstanding questions

Acknowledgements

Behav. Brain Res.

Math. Biosci.

Brain Res.

Curr. Opin. Neurobiol.

Brain Res.

Behav. Brain Res.

Exp. Neurol.

Exp. Neurol.

Behav. Brain Res.

Exp. Neurol.

Brain Res.

Brain Res.

Neurosci. Lett.

Neuron

Neuron

Brain Res.

A theory of cerebellar cortex

J. Physiol.

Cerebellar control of the vestibulo–ocular reflex: around the flocculus hypothesis

Annu. Rev. Neurosci.

How the cerebellum could memorize movements

Nature

Models of the cerebellum and motor learning

Behav. Brain Sci.

Does the cerebellum learn strategies for the optimal time-varying control of joint stiffness?

Behav. Brain Sci.

On the specific role of the cerebellum in motor learning and cognition: clues from PET activation and lesion studies in man

Behav. Brain Sci.

Saccades and the adjustable pattern generator

Behav. Brain Sci.

Initial localization of the memory trace for a basic form of learning

Proc. Natl. Acad. Sci. U. S. A.

Classical conditioning of the nictitating membrane response of the rabbit. I. Lesions of the cerebellar nuclei

Exp. Brain Res.

The neurobiology of learning and memory

Science

Organization of memory traces in the mammalian brain

Annu. Rev. Neurosci.

Cerebellum and classical conditioning of motor responses

Ann. New York Acad. Sci.

Classical conditioning of the nictitating membrane response of the rabbit. III. Connections of cerebellar lobule HVI

Exp. Brain Res.

Classical conditioning of the nictitating membrane response of the rabbit. II. Lesions of the cerebellar cortex

Exp. Brain Res.

Cerebellar cortex and eyeblink conditioning: a reexamination

Exp. Brain Res.

The effect of kainic acid lesions of the cerebellar cortex on the conditioned nictitating membrane response in the rabbit

Eur. J. Neurosci.

Cerebellum: essential involvement in the classically conditioned eyelid response

Science

Reacquisition of classical conditioning after removal of cerebellar cortex

Exp. Brain Res.

Recoverable and nonrecoverable deficits in conditioned responses after cerebellar cortical lesions

J. Neurosci.

Cerebellar lesions and the nictitating membrane reflex: performance deficits of the conditioned and unconditioned response

J. Neurosci.

Disruption of classical eyelid conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit?

J. Neurosci.

Effects of muscimol inactivation of the cerebellar interposed-dentate nuclear complex on the performance of the nictitating membrane response in the rabbit

Exp. Brain Res.