Contralateral cerebellar involvement in conditioned eyeblink responses.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
G Hesslow
Publications and source records attributed to G Hesslow.
Involvement of the cerebellum in a new temporal property of the conditioned eyeblink response.
Explore the source record for details and available documents.
Animals↗
Learned movements elicited by direct stimulation of cerebellar mossy fiber afferents.
Definitive evidence is presented that the conditioned stimulus (CS) in classical conditioning reaches the cerebellum via the mossy fiber system. Decerebrate ferrets received paired forelimb and periocular stimulation until they responded with blinks to the forelimb stimulus. When direct mossy fiber stimulation was then given, the animals responded with conditioned blinks immediately, that is, without ever having been trained to the mossy fiber stimulation. Antidromic activation was prevented by blocking mossy fibers with lignocaine ventral to the stimulation site. It could be excluded that cerebellar output functioned as the CS. Analysis of latencies suggests that conditioned responses (CRs) are not generated by mossy fiber collaterals to the deep nuclei. Hence, the memory trace is probably located in the cerebellar cortex.
Afferent Pathways↗
Cerebellum and learning: a complex problem.
Explore the source record for details and available documents.
Animals↗
Bilateral disruption of conditioned responses after unilateral blockade of cerebellar output in the decerebrate ferret.
1. Lesions of the cerebellar cortex can abolish classically conditioned eyeblink responses, but some recovery with retraining has been observed. It has been suggested that the recovered responses are generated by the intact contralateral cerebellar hemisphere. In order to investigate this suggestion, bilaterally acquired conditioned responses were studied after the unilateral blockade of cerebellar output. 2. Decerebrate ferrets were trained with ipsilateral electrical forelimb stimulation (300 ms, 50 Hz, 1 mA) as the conditioned stimulus and bilaterally applied peri-orbital stimulation (40 ms, 50 Hz, 3 mA) as the unconditioned stimulus. The conditioned and unconditioned eyeblink responses were monitored by EMG recordings from the orbicularis oculi muscle. The output from one cerebellar hemisphere was blocked either by injecting small amounts of lignocaine (lidocaine; 0.5-1.0 microliter) into the brachium conjunctivum, or by a restricted mechanical lesion of the brainstem rostral to the cerebellum. 3. As described by previous investigators, the unilateral blockade of cerebellar output abolished ipsilateral conditioned responses. 4. More importantly, such blockade also abolished or strongly depressed contralateral conditioned responses. When mechanical lesions of the brachium conjunctivum were made, contralateral responses, in contrast to ipsilateral responses, recovered within 1-2.5 h. 5. When the unconditioned stimulus was removed on one side, causing extinction of conditioned responses on this side, conditioned responses were temporarily depressed on the trained side as well. 6. Unilateral interruption of cerebellar output had no clear effect on contralateral unconditioned reflex responses. 7. The results demonstrate that one cerebellar hemisphere in ferrets exerts a marked control of contralateral conditioned eyeblink responses, probably via premotor neurones involved specifically in conditioned, and not in unconditioned, responses.
Anesthetics, Local↗
Inhibition of the inferior olive during conditioned responses in the decerebrate ferret.
Output from the interpositus nucleus can inhibit the inferior olive, probably via the GABA-ergic nucleo-olivary pathway. It has been suggested that the function of this inhibition might be to regulate synaptic plasticity resulting from parallel fibre/climbing fibre interaction in cerebellar Purkinje cells, by providing negative feedback information to the olive. Thus, when a learned response, generated by the interpositus nucleus, reaches a sufficient amplitude, the olive would be inhibited and further learning blocked. This suggestion was tested in a classical conditioning paradigm. Decerebrate ferrets were trained using electrical skin stimulation of the forelimb as the conditioned stimulus (CS) and periorbital stimulation as the unconditioned stimulus (US). Climbing fibre responses evoked in Purkinje cells by the US were recorded as surface field potentials in the part of the c3 zone controlling eyeblink. It was found that the CS did not inhibit the olive at the beginning of training, but when conditioned responses were large, the olive was inhibited by the CS in some animals. After a number of unpaired CS presentations, which caused extinction of the conditioned response, the inhibition disappeared. The size of individual conditioned responses correlated negatively with the size of the climbing fibre responses evoked by the US. Climbing fibre responses evoked by direct stimulation of the olive were also inhibited. It was concluded that cerebellar output during performance of a conditioned response inhibits the inferior olive. The results thus support the hypothesis of a cerebellar locus of conditioning and are consistent with the proposed role of cerebello-olivary inhibition.
Animals↗
Effect of ethanol on the excitability of the inferior olive in decerebrate ferret.
Climbing fibers, which originate in the inferior olive and project to Purkinje cells and Golgi cells in the cerebral cortex, were activated at low (0.4-Hz) and high (4-Hz) frequencies by periorbital stimulation in decerebrate ferrets. Climbing fiber responses were recorded as field potentials from the c3 zone of the cerebellar surface. When periorbital stimulation was applied at high frequency, the climbing fiber responses became strongly depressed within a few seconds. It has previously been shown that this high frequency depression (HFD) of climbing fiber responses is due to a cerebellar inhibition of the inferior olive, probably via the nucleo-olivary pathway. Acute administration of ethanol had small and variable effects on the amplitude of climbing fiber responses evoked by low-frequency stimulation. In contrast, medium concentrations (0.44-2.90 g/l) of ethanol led to a marked reduction of the HFD. Low ( < 0.44 g/l) systemic concentrations had no measurable effects on the HFD, whereas high concentrations ( > 2.90 g/l) caused either an increased HFD or a nonseptic reduction in olivary excitability. Because HFD has previously been shown to involve cerebello-olivary inhibition, the possibility of an interaction between ethanol and GABA-ergic responses in the interposito-olivary pathway is discussed.
Animals↗
Will neuroscience explain consciousness?
This paper is a defence of a pragmatic version of mind-brain reductionism from a neuroscientist's point of view. It is claimed that there are good reasons to believe that future neuroscience will be able to explain (in a weak and pragmatic sense) the puzzling aspects of mind and consciousness. Opposition to reductionism comes from both philosophical and empirical quarters. It is argued here that philosophical arguments, such as semantic problems with the concept of identity, are unconvincing and should be regarded with the greatest suspicion. The most influential empirical result that has been claimed to constitute a problem for reductionism is the temporal delay and mental antedating of consciousness found by Benjamin Libet. It is argued that these results, far from being a problem for reductionism, constitute evidence for a particular view of the physiological origins of consciousness. Finally, it is argued that many subjective aspects of experience can already be given satisfactory scientific explanations and that scientific progress is likely to rob the mind and subjective experience of their mystery.
Brain↗
Correspondence between climbing fibre input and motor output in eyeblink-related areas in cat cerebellar cortex.
The purpose of the present work was to identify sites in the cerebellar cortex which are likely to control eyeblink. This work was motivated by findings suggesting that the cerebellum is involved in the learning and/or performance of the classically conditioned eyeblink response. The identification was based on climbing fibre input to the cortex and on the effects of electrical stimulation of the cerebellar cortex in cats decerebrated rostral to the red nucleus. The cerebellar surface was searched for areas receiving short latency climbing fibre input on periorbital electrical stimulation. Four such areas were found in the c1 and c3 zones of lobules VI and VII in the anterior lobe of the cerebellum and in the c3 zone in the paramedian lobule. Electrical stimulation of the cerebellar cortex with trains (150-400 Hz) of at least 10 ms duration evoked two types of EMG response in the orbicularis oculi muscle. An early response, time-locked to the onset of the stimulation, was unrelated to climbing fibre input and a delayed response, time-locked to the termination of the stimulation, could only be evoked from areas which received short latency climbing fibre input from the eye, that is, the c1 and c3 zones. The delayed responses had long latencies (up to 50 ms) after the termination of the stimulus train and could be delayed further by prolonging the stimulation. Both types of response were abolished by injections of small amounts of lignocaine into the brachium conjunctivum. A number of characteristics of the delayed responses are described. They could be inhibited by a further shock to the same area of the cerebellar cortex. Their latency could be increased by increasing the stimulation frequency. The period between stimulation and appearance of the response often showed a decrease in spontaneous EMG activity. There was a close topographical correspondence between input and output. Delayed responses could be evoked from all four of the areas in the c1 and c3 zones which have climbing fibre input from the periorbital area. They could not be evoked from other areas. In contrast, early responses were only evoked from areas without such climbing fibre input. It is proposed that the delayed responses were generated by activation of Purkinje cell axons leading to hyperpolarization and a subsequent rebound depolarization and activation of cells in the interpositus nucleus. The cortical areas are therefore probably involved in the control of the orbicularis oculi muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Inhibition of classically conditioned eyeblink responses by stimulation of the cerebellar cortex in the decerebrate cat.
The purpose of the present study was to test the hypothesis that neurones in the anterior interpositus nucleus, under the control of Purkinje cells in the c1 and c3 zones of the cerebellar cortex, exert some control over classically conditioned responses. In particular, the experiments were designed to determine whether the cerebellar control of conditioned and unconditioned responses is different. The experiments were performed on cats decerebrated rostral to the red nucleus under halothane anaesthesia. The cats were conditioned using either a 1000 Hz tone or trains of stimuli through the skin of the proximal forelimb as the conditioned stimulus, and periorbital electrical stimulation as the unconditioned stimulus. A large proportion of the animals acquired conditioned responses at normal rates. It could be shown that these were true conditioned responses and did not result from sensitization or pseudoconditioning. For instance, unpaired presentations of conditioned and unconditioned stimuli caused rapid extinction. Cerebellar areas controlling eyeblink were identified by recording climbing fibre responses in the cerebellar cortex and recording EMG activity in the eyelid evoked by stimulation of the cerebellar cortex. When single shocks of 40-70 microA were applied to these areas during the emission of conditioned eyeblink responses, the latter were strongly inhibited. The inhibition had a latency of about 10 ms and a duration of 25-75 ms. It was shown that this inhibition of the conditioned responses was topographically specific and could only be evoked from cortical sites identified as controlling eyeblink. Stimulation of the periphery of an eyeblink area caused little or no inhibition. The effect of cortical stimulation on unconditioned reflex responses in the orbicularis oculi muscle was also tested. Some inhibition of unconditioned responses was observed, but quantitative analysis showed that this inhibition was considerably weaker than the corresponding inhibition of conditioned responses. The magnitude of the inhibition was determined for unconditioned responses of different sizes including responses which were weaker than the conditioned responses. It is concluded that conditioned eyeblink responses are under strong cerebellar control from areas in the c1 and c3 zones receiving climbing fibre input from the periorbital area. This effect is not likely to be due to a reduction in the background facilitation of facial motoneurones. In contrast, the weak inhibition of the unconditioned response was probably due to this mechanism. The results, therefore, suggest that the conditioned responses are dependent on the cerebellum in a way that is not true of unconditioned responses.
Animals↗
Suppression of cerebellar Purkinje cells during conditioned responses in ferrets.
Decerebrate ferrets were conditioned, using electrical stimulation of the forelimb as conditioned stimulus and periorbital stimulation as unconditioned stimulus, until they produced conditioned eyeblink responses. The latency of these was 125-250 ms. Microelectrode recordings were made from single Purkinje cells in an eyeblink controlling area in the c3 zone of the cerebellar cortex. Whereas Purkinje cells in animals, which had only received unpaired stimulus presentations, responded weakly or not at all to the conditioned stimulus, some cells in conditioned animals responded with a powerful suppression of simple spike firing. The latency of this suppression was 50-200 ms. The results support the hypothesis that classical conditioning involves plastic changes in cerebellar Purkinje cells.
Animals↗
Do we need a concept of disease?
The terms "health", "disease" and "illness" are frequently used in clinical medicine. This has misled philosophers into believing that these concepts are important for clinical thinking and decision making. For instance, it is held that decisions about whether or not to treat someone or whether to relieve someone of moral responsibility depend on whether the person has a disease. In this paper it is argued that the crucial role of the 'disease' concept is illusory. The health/disease distinction is irrelevant for most decisions and represents a conceptual straightjacket. Sophisticated and mature clinical decision making requires that we free ourselves from the concept of disease.
Clinical Medicine↗
Bilateral control of the orbicularis oculi muscle by one cerebellar hemisphere in the ferret.
Reports that lesions of the anterior interpositus nucleus in the cerebellum or of the cerebellar cortex abolish classically conditioned eyeblink responses were originally taken to indicate that the cerebellum is the locus of learning. This interpretation has recently been questioned by reports that conditioned responses may recover after ipsilateral cerebellar lesions. It cannot be excluded, however, that the recovered responses were produced by the intact contralateral hemisphere. In order to determine if cerebellar outflow to the orbicularis oculi muscle is bilateral, we stimulated both the brachium conjunctivum and a cortical area in the c3 zone of the cerebellar cortex which controls eyeblink. Both kinds of stimulation elicited EMG activity in both the ipsi- and the contralateral eyelids. The results thus show that there is a bilateral control of eyeblink from each cerebellar hemisphere and they raise the possibility that recovery of conditioning after ipsilateral cerebellar lesions is due to the intact hemisphere. Reports of such recovery after unilateral lesions are therefore inconclusive.
Animals↗
Evidence for a GABA-mediated cerebellar inhibition of the inferior olive in the cat.
1. Climbing fibres were activated by peripheral nerve stimulation at 'high' frequencies (greater than 3 Hz) for 15-25 s and then at 0.9 Hz for about 1 min. The high frequency activation induced a post-conditioning inhibition, lasting up to about 1 min, of climbing fibre responses recorded from the cerebellar surface. 2. Electrolytic lesions were made in the superior cerebellar peduncle (brachium conjunctivum). After the lesion, the post-conditioning inhibition was completely eliminated. 3. Injections of the GABA-receptor blocker bicuculline methiodide into the inferior olive reversibly blocked the post-conditioning inhibition. 4. The results support the hypothesis proposed by Andersson and Hesslow (1987a), that post-conditioning inhibition is mediated by a GABA-ergic interposito-olivary pathway.
Animals↗
Inferior olive excitability after high frequency climbing fibre activation in the cat.
1. Climbing fibre responses (CFRs) were evoked by limb nerve stimulation and recorded from the cerebellar surface in barbiturate anaesthetized cats. Climbing fibres were activated at frequencies of usually 2.5-7.5 Hz for periods of 15-30 s, after which the stimulation frequency was reduced to below 1 Hz. 2. The high-frequency stimulation induced a strong depression of CFR-amplitude, lasting up to 60 s. The magnitude of this depression was dependent on both the frequency and the duration of the high-frequency stimulation. 3. The depression occurred in the c1, c2 and c3 zones of the pars intermedia and in the x zone in the vermis but not in the b zone in the vermis. 4. Recordings of olivary reflex responses demonstrated that the depression occurred in the inferior olive. 5. It is suggested that the inhibition of the inferior olive occurs because the high-frequency stimulation leads to a disinhibition of neurones in the interpositus nucleus which inhibit the olivary neurones.
Afferent Pathways↗
Activity of Purkinje cells and interpositus neurones during and after periods of high frequency climbing fibre activation in the cat.
The activity of cerebellar Purkinje cells and interpositus neurones was recorded during and after periods of high frequency (2.5-7.5 Hz) climbing fibre activation in barbiturate-anaesthetized cats. 1. During the high frequency conditioning stimulation, the Purkinje cell simple spike (SS) firing was initially silenced in all zones studied. After a few seconds, the SS reappeared and the frequency increased to well above that of the control level after approximately 10 s. Thereafter, the SS rate started to decline so that, after 15-20 s, the Purkinje cells fired no more SS. This SS silence lasted up to 60 s, whether or not the stimulation was continued. 2. The Purkinje cells responded with a complex spike (CS) to every stimulus. If the high-frequency stimulation lasted for at least 15 s, the spontaneous CS discharge of the Purkinje cells in the c1, c2, and c3 zones was suppressed after the conditioning stimulation had ended. This suppression lasted for approximately the same length of time as the SS silence. In the b zone, however, no CS suppression was observed. 3. Interpositus neurones displayed an increased discharge rate after periods of conditioning stimulation, thus displaying a mirror image of the Purkinje cell SS firing. 4. The behaviour of the neurones agrees well with the behaviour predicted by an hypothesis of the olivo-cerebello-olivary loop (Andersson and Hesslow 1987). 5. The results suggest that the cerebello-olivary projection is topographically organized and matches the microzonal organization in the olivo-cerebellar projection.
Afferent Pathways↗
Inhibition of inferior olivary transmission by mesencephalic stimulation in the cat.
Cerebellar climbing fiber responses (CFRs) evoked in anesthetized cats by stimulation of peripheral nerves, contralateral inferior olive and cerebellar white matter were investigated by recording unit activity and surface field responses in anterior lobe of cerebellar cortex. When nerve and olive stimulation was preceded at long intervals (greater than 35 ms) by weak electrical stimulation of an ipsilateral mesencephalic area close to the locus coeruleus and brachium conjunctivum, CFRs could be virtually abolished in the pars intermedia but not in the vermis. White-matter evoked CFRs were not affected; thus the site of the inhibition was the inferior olive.
Animals↗
The secondary spikes of climbing fibre responses recorded from Purkinje cell somata in cat cerebellum.
Extracellularly recorded climbing fibre responses in Purkinje cell somata in the cerebellar cortex were investigated in cats deeply anaesthetized with barbiturate. The effects on the amplitude of initial and secondary spikes of preceding climbing fibre activation, on-beam parallel fibre activation and off-beam parallel fibre activation were studied. When a climbing fibre response was preceded by climbing fibre activation there was a decrease in the amplitude of the initial spike of the second response at intervals up to 25 ms and little effect at longer intervals. Secondary spike amplitude was greatly increased at intervals up to 100 ms. When a complex spike was preceded by on-beam parallel fibre activation there was a decrease in the initial spike amplitude at short intervals and an increase in the amplitude at long intervals. Secondary spike amplitude was increased up to 150 ms after an on-beam parallel fibre volley. When a complex spike was preceded by off-beam parallel fibre stimulation there was an increase in initial spike amplitude at intervals up to about 200 ms and a decrease in secondary spike amplitude at intervals up to about 150 ms. The results show that the amplitude of the secondary spikes can be modified by a preceding input to the Purkinje cell. The results also suggest that the secondary spikes are generated in the Purkinje cell dendrites and the initial spike in the soma.
Action Potentials↗