and motor learning
The cerebellum Mitchell
College London, London, UK
University Lesions
of the cerebellum
several
types
of motor
damage the motor
Clickstein
and its associated
learning.
memory
circuitry
It is controversial
or its performance.
in the light of the original suggestions
abolish
whether
Recent work
or impair
these
lesions
is evaluated
by Marr, Albus
and Gilbert that the
cerebellar cortex is a preferred locus for reflex plasticity
and motor learning.
Current
Opinion
in Neurobiology
Introduction Animals and people with large cerebellar lesions are slow to start movements and they are inaccurate in executing them. The connections of the cerebellum are consistent with its role in initiating and guiding movement. The cerebellum receives sensory information from the spinal cord, brainstem, and forebrain, and it influences the cells of origin of all of the descending motor tracts. Although the total weight of the human cerebellum is only about 10% of that of the entire brain, the cerebellar cortex is deeply folded and its surface extent is nearly as great as that of the cerebral cortex. The gran ule cells of the cerebellar cortex are densely packed so that their total number is larger than that of the neurons in the cerebral cortex. The cell types, the atferent fibres, and the interconnections of cells within the cerebellar cortex were described about 100 years ago by Ramon y Cajal. The ultrastructure and physiological organization of the cerebellar cortex were analFed by Eccles and his collaborators some 25 years ago. Despite the regularity of its anatomical and physiological organization, the functions of the cerebellum remain controversial. One of those controversies is addressed here: what is the role of the cerebellum in Pavlovian conditioning, one form of motor learning. Shortly after Eccles’ book was published, Marr [l] suggested that the organization of the cerebellar cortex would make it a particularly appropriate locus for motor learning. He proposed that motor commands might be relayed to the Purkinje cells of the cerebellar cortex by climbing libres. The synaptic strength of the set of parallel fibres that were active at the time when the climbing fibre signal arrived would be increased. With repeated pairing, the parallel fibres alone would activate the Purkinje cell and elicit movement. Marr’s suggestion of a role for the cerebellum in motor learning was extended and modified by subsequent authors. Albus [ 21, like Marr, emphasized the great advantage for information storage capacity of using subsets of the total number of parallel
1992, 2:802-806
fibres as the synapses to be modified. Albus argued, however, that a more likely role of the climbing fibre would be to decrease rather than increase the synaptic efficacy of active parallel fibres. Gilbert [3] proposed a related theory in which the fundamental unit of cerebellar cortical organization was not a single Purkinje cell but a set of them, with the noradrenergic input to the cerebellar cortex serving as a device for promoting long-term storage of the movement. Based on Marr’s and Albus’s ideas, Ito [4] proposed a specific role for the cerebellum in modifying the gain of the vestibulo-ocular reflex (VOR). He suggested that if the gain of the VOR were too great or too small the retinal image slip associated with that inaccurate gain would be signalled to the cerebellum by way of visual climbing fibres. The Purkinje cell target of these climbing fibres would then increase or decrease the gain of the VOR in a direction that would minimize retinal slip when the head is turned. Evidence for cellular mechanisms of long-term changes in the cerebellum has been reviewed [51. After Ito’s proposal was made, evidence began to appear on the possible role of the cerebellum in other types of reflex plasticity or motor learning. Baizer and Glickstein (I Pbysiol [A&r/ 1974, 36:34P) suggested that the cerebellum is necessary for short-term adaptation to prisms. Monkeys, like people, can adapt to a laterally displacing prism within a few trials. When viewing a target through the prism they m&reach, but after a few trials they reach correctly. Removal of the cerebellum abolishes this capacity for short-term prism adaptation. The cerebellum has been shown to be necessary for accurate re-calibration of saccadic eye-movements after an extra-ocular muscle is damaged [6]. Vermian cerebellar lesions have been found to affect long-term habituation of startle reflexes in rats [7*]. Sebastiani et al. [8*] found that the posterior vermis is important for acquisition of the conditioned heart rate slowing. Perhaps the most direct evidence for the Marr-Albus theory, and still controversial, comes from studies of
Abbreviations CR-conditioned response; CS-conditioned stimulus; HVI-hemispheral lobule VI; NMR-nictitating UCR-unconditioned response; UCGunconditioned stimulus; VOR-vestibulo-ocular 802
@ Current
Biology
Ltd ISSN 0959-4388
membrane response; reflex.
The cerebellum
the conditioned nictitating membrane response (NMR) in rabbits. A tone or light conditioned stimulus (CS) is followed by an airpuff directed at the cornea, or a mild electric shock to the edge of the eye, the unconditioned stimulus (UCS). After a number of pairings of CS followed by UCS, the CS alone causes the rabbit to blink, and the nictitating membrane to sweep across the cornea. In 1981, Thompson and his collaborators [9] reported that cerebellar lesions abolished a previously established conditioned NMR and prevented its reacquisition. This review will focus on some of the experiments and controversies that followed this important paper. Two questions will be addressed: first, is the cerebellum the locus of plasticity? And second, if so, is the locus in the cortex or in the nuclei? The evidence suggests [lo] that when the cerebellum is intact, it is the principal site of the synaptic modification underlying NMR conditioning. In the absence of the cerebellum, conditioning may be possible, but is likely to be slower, more variable, and less accurate than normal.
Performance
deficit
Some authors have concluded that the cerebellum is not necessarily involved in conditioning per se. Welsh and Harvey [ 111 argued that since cerebellar lesions also affect performance of the unconditioned response (UCR), the abolition of the conditioned response (CR) may simply reflect a general motor deficit. As the CR is typically less vigorous than the UCR, it might be so weakened as to fail to appear. Alternatively, the CR might be so delayed that it appears very late, and hence becomes masked by the UCR. The explanation that the CR is masked by the UCR can be discounted. Although in their first reports Yeo et al. [ 101 did not report test trials in which the CS was presented alone, in more recent work [12**] in 10 % of trials the tone or light CS was presented without being followed by the US. Such unreinforced trials would have revealed a delayed CS if it were present. They did not. Cerebellar lesions did not merely delay the onset of CRs, they abolished them. The strength of the UCR varies with shock intensity. Lesions of the anterior interpositus nucleus slightly decrease the UCR whilst cerebellar cortical lesions slightly augment it. These effects are small and cannot account, in a simple way, for cases of abolished CRs. Recently, Welsh [13-l analyzed in detail the pattern of response of the nictitating membrane of rabbits to the CS and UCS. Normal animals respond to an auditory CS with two distinct peaks of acceleration. It was the second peak that increased more during conditioning and which was particularly impaired by cerebellar lesions. In some cases, however, cerebellar lesions produced large and permanent impairment in both peaks of acceleration. Welsh argues that his results are indicative of a deficit in performance of the response, but that “the vulnerability of the second component of the CR to cerebellar
and motor
learning
Clickstein
damage reflects an important role for the cerebellum in modulating the degree to which long-latency neural systerns contribute to the ongoing performance of learned and unlearned behaviors”. The impairments that Welsh observed are consistent with a deficit in motor learning,
Reacquisition cerebellar
of conditioned
responses after
lesions
In their original reports Yeo et al. [lo] trained rabbits to respond to both a light and a sound CR. Initial acquisition in almost all cases was complete after 1 week of training. Lesions of hemispheral lobule VI (HVI) of the cerebellar cortex abolished retention of the CR, and the animals did not reacquire the CR when trained for an equivalent number of postoperative trials. The question of possible relearning has recently been re-examined [12-l. With greatly extended postoperative re-training the CR can be reacquired in some cases. However, when the lesions include adjacent areas in lobule V and hemispheral lobule VII some animals fail to recondition even when the postoperative training is extended to 3 weeks. In an attempt to resolve some of the discrepancies in the results of cerebellar lesions from the laboratories of Yeo, and of Welsh and Harvey, they collaborated in a study of the effects of cerebellar cortical lesion on conditioned NMR (lA Harvey, CH Yeo, JP Welsh and AG Romano: Sot Neurosci A&r 1990, 10:268). Their results were mixed. In some animals the CR’s were abolished initially, while in some rabbits the CR’s were retained. Overall, the animals in these experiments were less affected than those in Yeo’s previous study [ 101, It seems likely that the critical factor which distinguishes the two experiments is the amount of pre-operative training. Let us suppose that the critical locus for learning is in the cerebellar cortex. Assume that conditioning involves a synaptic change caused by a pairing of a CS relayed by mossy fibres with a UCS relayed by climbing fibres. The association between CS and UCS could be made on any Purkinje cell or set of Purkinje cells which received the appropriate CS and UCS information. Because of the diffuseness of mossy and climbing libre projections, the change could be made at several sites on the cerebellar cortex. The most likely sites would be within regions of the cerebellar cortex that project to the anterior interpositus nucleus. With a small amount of pre-operative training the association might be formed at a single locus, or at a small number of sites. With additional pre-operative training the sites might be more widely dispersed on the cerebellar cortex. In the Harvey et al. study the animals were trained prior to surgery for 15 days, three times longer than the animals studied by Yeo. If the preferred locus for the association were, in fact, in HVI, but adjacent cerebellar cortical regions could also be modified, the overtrained animals would be less likely to lose the CR after cerebellar lesions. A similar effect of overtraining on retention was described by Chow [ 141, who studied the loss of visual discrimination learning by monkeys, caused by lesions of the inferotemporal cortex. If
803
804
Neural
control
the monkeys were trained until they just reached criterion they lost the response. If they were overtrained prior to the temporal lobe lesion they retained the previously learned task.
Retention
of conditioning
after cerebellectomy
Bloedel and colleagues [ 15,16*] raised an important challenge to the idea that the cerebellum is the locus of NMR conditioning. They first trained decerebrated animals using a tone CS and an air puff UCS with a very short (S-10 s) intertrial interval. They reported that decerebrate rabbits acquired the CR in the absence of forebrain and diencephalon. In five such animals they found that the CR was retained if the cerebellum was then removed. The results of this study remain controversial. Yeo and his colleagues replicated the experiment using a white noise CS and periocular shock UCS with a standard 30s intertrial interval [17-l. These animals could also be trained as the decerebrates, but they lost the CR and failed to reacquire it after the cerebellar lesion. Thompson and colleagues [18] have questioned whether Bloedel’s training procedures would have yielded true associative conditioning. In their attempted replication, normal rabbits failed to acquire the CR when trained with the very short intertrial interval used by Bloedel’s group. If Bloedel’s results reflect true conditioning they argue that the cerebellum cannot be the only locus. The issue is reminiscent of earlier controversies surrounding attempts to establish conditioning in the spinal cord. Such conditioning is sometimes possible, but is typically weak, variable, and slow to be acquired.
If the cerebellum
is involved
how and where
is it involved?
in conditioning,
As Ito [4] emphasized, the cerebellum forms a sidepath for the brainstem VOR. A similar situation holds for the NMR (reviewed in [ 191). Lesions of the cerebellum or related structures can all abolish CRs. Lesions of cerebellar inputs from the inferior olive, pontine nuclei, and the middle cerebellar peduncle have been reported to abolish or impair conditioning. Similarly, lesions on the output side: the cerebellar nuclei, the brachium conjunctivum, red nucleus or rubro-bulbar pathway can also abolish CRs. Cells in all of these structures can be activated by the CS during NMR conditioning. There are two broad possibilities to account for these results: first, two or more of these structures might be interconnected in a network, with the entire ensemble being modified during conditioning; and second, any one of these structures, or the cerebellar cortex itself, might be the principal locus of the synaptic change associated with conditioning.
Cortex versus nuclei In the initial studies [9] the lesions included cortex and nuclei on the trained side of the animal. In subsequent reports it was clear that nuclear lesions alone would abolish the CRs. As the nuclei receive their major input from Purkinje cells these results are consistent with either a nuclear or cortical locus for the CR. Thompson’s group [ZO] reported that cortical lesions did not abolish CRs; hence they concluded that the locus of the conditioning must be in the nuclei. This conclusion was based on a series of partial lesions of the cerebellar cortex. If the memory trace were stored at a single cortical locus, one of the lesions would be expected to abolish the CR, but none of them did. In contrast, Yeo et al [ 101 found that lesions restricted to cerebellar lobule HVI abolished the CRs in previously trained animals. This apparent discrepancy in results might reflect multiple storage sites in the cerebellar cortex. If the association between CS and US were formed at more than one site, then a subtotal cortical lesion might not abolish the CR. The results are consistent with such an interpretation with the proviso that HVI, when present, is the preferred locus for conditioning.
The inferior
olive, climbing
fibres, and
conditioning HVI lesions cause retrograde degeneration within the rostral dorsal accessory olive and immediately adjacent principal olive. If the critical locus for conditioning were not at the level of the cerebellar cortex but at some precerebellar site which projects to the cerebellar cortex, the cortical lesions might affect conditioning by causing retrograde degeneration in precerebellar structures as a result of damage to their axonal terminals. In order to rule out this possibility Hardiman and Yeo [21] replicated their studies of the effects of cortical lesions by injecting kainic acid into HVI and adjacent regions of the cerebellar cortex. The injection killed cerebellar cortical cells but spared their afferent fibres. In these an imals there was no retrograde degeneration within the olive or other pre-cerebellar nuclei, and yet the lesions abolished CRs in cases where they included critical areas of the cerebellar cortex. One interpretation of the effects of cerebellar cortical lesions on NMR conditioning would be that the association is formed by a conjunction between mossy fibre CS representation and climbing fibre UCS at the level of the cerebellar cortex. The climbing fibre UCS would either facilitate (Marr) or inhibit (Albus) the parallel fibre/Purkinje cell synapses which were active at the time of arrival. If this were the case, olivary lesions might be expected to affect a previously acquired CR in the same way as removing the air puff or shock. The CR would be initially present after the olivary lesions and then gradually extinguish despite continued pairing of CS and UCS. Such an extinction effect following oli-
The cerebellum
vary lesions has been reported [ 221. Yeo and colleagues [23], however, saw an immediate abolition of the CR following olivary lesions. Yeo’s results could be interpreted in terms of the immediate effect of climbing fibre lesion on the spontaneous firing rate of Purkinje cells. Immediately after loss of their climbing libre inputs, Purkinje cells increase their firing rate threefold [24]. Such high spontaneous rates would massively inhibit the cerebellar nuclei, not allowing the subtler changes that are associated with the conditioning to be reflected in the output from the cerebellum.
Is the locus of conditioning cerebellar
within
the
References
Conclusion The idea that the cerebellum is involved in motor learning remains controversial [ 11,16*]. However, lesions of the cerebellum and its associated circuitry abolish or impair several types of motor learning. Cells in the cerebellar circuits are activated by the CS in conditioning trials. As Marr, Albus, and Gilbert suggested, the cerebellar cortex may be the preferred locus for reflex plasticity and motor learning. The next problem will be to specify in detail the synaptic events that underlie these changes.
and recommended
Papers of particular interest, published view, have been highlighted as of special interest . .. of outstanding interest 1.
MARR D: A Theory 202:437470.
2.
Aldus JS: A Theory 10:2FGl.
3.
GILBERT
ments.
learning
Clickstein
reading
within the annual period of re-
of CerebeIlar of CerebeIIar
Cortex. Function.
PFC: How the Cerebellum Nature 1975, 254X%&689.
Could
.I Pby~iol 1969, Math Biosci 1971, Memorize
Move-
4.
IT0 M: Neural Design of the Cerebellar Motor Control System. Bruin Res 1972 40~81-84.
5.
IT0
6.
OPTICAN LM, RORINSON DA: Cerebellar-Dependent Adaptive Control of the Primate Saccadic System. J Neurophyioll980, 44:1058-1065.
nuclei?
Welsh and Harvey [25-l have provided important new evidence about the possible role of the cerebellar nuclei and cortex in conditioning. They conditioned the NMR to a tone CS in animals previously implanted with a cannula directed at the anterior interpositus nucleus. When the CR to the tone was well established they began a new series of conditioning trials this time with a light CS. During this training the anterior interpositus nucleus was inactivated with lidocaine. Under these conditions the animals failed to manifest any CRs, either to the previously trained tone CS or to the light. When the block was released, however, not only was the previously acquired response to the tone CS still present, but the rabbits also responded to a light CS as well. As the animals were seen to be fully conditioned, the CR must have been established at some locus other than the anterior interpositus nucleus, and most likely prior to it. There are two obvious candidates, the cerebellar cortex and the inferior olive. Both provide major projections to the cerebellar nuclei. In a related experiment, Welsh and Harvey (Sot Neurosci A&r 1990, 16:268) followed a similar procedure, this time inactivating the inferior olive during the conditioning trials. With the olive inactivated no new conditioning could be established despite training during the block. One obvious conclusion from these experiments (which Welsh and Harvey appear not to share) is that the storage site for the conditioning is in the cerebellar cortex.
and motor
M: Long-Term 12:85-102
Depression.
Annu
Rev Neurasci
1989,
LEATONRN, S~JPPLEWF: Medial Cerebellum and Long-Term Habituation of Acoustic Startle in Rats. Behuzj Neurosci 1991, 105:804-816. This paper generalizes the role of the cerebellum in learning by demonstrating that it is necessaty for another form of long-term behavioural change. 7. .
8. .
SEBKITANI L, Ls NOCE A,
9.
MCCORMICK
PATONJFR, GHEIARDUCCIB: Influence of the CerebeIIar Posterior Vermis on the Acquisition of the Classically Conditioned Bradycardiac Response in the Rabbit. Exp Brain Res 1992, 88:193-198. This paper generalizes the role of the cerebellum in conditioning by showing its role in conditioned cardiovascular adjustments. DA,
IAVOND
DA,
CLUK
GA,
KETTNER RE,
RISING
CE, THOMPSON RF: The Engram Found Role of the Cerebellum in the Classical Conditioning of Nictitating Membrane and Eyelid Responses. Bull Psychmom Sot 1981, 18:103_105. CH, HARIXMANMJ, GUCKSTEIN M: Classical Conditioning of the Nictitating Membrane Response of the Rabbit: II. Lesions of the Cerebellar Cortex. Exp Brain Res 1985, 60:9%113.
10.
YEO
11.
WEISH
JP, HAU~EY JA: Cerebellar Lesions and the Nictitating Membrane Reflex: Performance Deficits of the Conditioned and Unconditioned Response. J Neuroui 1989, 9:29‘+311.
12. YEO CH, HARDIMANMJ: Cerebellar Cortex and Eyeblink Con.. ditioning: a Re-examination. Exp Bruin Res 1992, 88:62M38. A thorough study of the effects of cerebellar cortical lesions on simple conditioned and unconditioned responses. The data reaffirm the importance of lobule HVI of the cerebellar cortex for NMR conditioning. With additional post-operative training many animals reacquired the CR. The results are consistent with multiple storage sites on the cerebellar cortex. 13. ..
WELSH
14.
CHOW KL: Conditions Influencing the Recovery of Visual Discrimination Habits in Monkeys Following Temporal Neocortical Ablations. .I CampPlqsiol f
The cerebellum Mitchell
College London, London, UK
University Lesions
of the cerebellum
several
types
of motor
damage the motor
Clickstein
and its associated
learning.
memory
circuitry
It is controversial
or its performance.
in the light of the original suggestions
abolish
whether
Recent work
or impair
these
lesions
is evaluated
by Marr, Albus
and Gilbert that the
cerebellar cortex is a preferred locus for reflex plasticity
and motor learning.
Current
Opinion
in Neurobiology
Introduction Animals and people with large cerebellar lesions are slow to start movements and they are inaccurate in executing them. The connections of the cerebellum are consistent with its role in initiating and guiding movement. The cerebellum receives sensory information from the spinal cord, brainstem, and forebrain, and it influences the cells of origin of all of the descending motor tracts. Although the total weight of the human cerebellum is only about 10% of that of the entire brain, the cerebellar cortex is deeply folded and its surface extent is nearly as great as that of the cerebral cortex. The gran ule cells of the cerebellar cortex are densely packed so that their total number is larger than that of the neurons in the cerebral cortex. The cell types, the atferent fibres, and the interconnections of cells within the cerebellar cortex were described about 100 years ago by Ramon y Cajal. The ultrastructure and physiological organization of the cerebellar cortex were analFed by Eccles and his collaborators some 25 years ago. Despite the regularity of its anatomical and physiological organization, the functions of the cerebellum remain controversial. One of those controversies is addressed here: what is the role of the cerebellum in Pavlovian conditioning, one form of motor learning. Shortly after Eccles’ book was published, Marr [l] suggested that the organization of the cerebellar cortex would make it a particularly appropriate locus for motor learning. He proposed that motor commands might be relayed to the Purkinje cells of the cerebellar cortex by climbing libres. The synaptic strength of the set of parallel fibres that were active at the time when the climbing fibre signal arrived would be increased. With repeated pairing, the parallel fibres alone would activate the Purkinje cell and elicit movement. Marr’s suggestion of a role for the cerebellum in motor learning was extended and modified by subsequent authors. Albus [ 21, like Marr, emphasized the great advantage for information storage capacity of using subsets of the total number of parallel
1992, 2:802-806
fibres as the synapses to be modified. Albus argued, however, that a more likely role of the climbing fibre would be to decrease rather than increase the synaptic efficacy of active parallel fibres. Gilbert [3] proposed a related theory in which the fundamental unit of cerebellar cortical organization was not a single Purkinje cell but a set of them, with the noradrenergic input to the cerebellar cortex serving as a device for promoting long-term storage of the movement. Based on Marr’s and Albus’s ideas, Ito [4] proposed a specific role for the cerebellum in modifying the gain of the vestibulo-ocular reflex (VOR). He suggested that if the gain of the VOR were too great or too small the retinal image slip associated with that inaccurate gain would be signalled to the cerebellum by way of visual climbing fibres. The Purkinje cell target of these climbing fibres would then increase or decrease the gain of the VOR in a direction that would minimize retinal slip when the head is turned. Evidence for cellular mechanisms of long-term changes in the cerebellum has been reviewed [51. After Ito’s proposal was made, evidence began to appear on the possible role of the cerebellum in other types of reflex plasticity or motor learning. Baizer and Glickstein (I Pbysiol [A&r/ 1974, 36:34P) suggested that the cerebellum is necessary for short-term adaptation to prisms. Monkeys, like people, can adapt to a laterally displacing prism within a few trials. When viewing a target through the prism they m&reach, but after a few trials they reach correctly. Removal of the cerebellum abolishes this capacity for short-term prism adaptation. The cerebellum has been shown to be necessary for accurate re-calibration of saccadic eye-movements after an extra-ocular muscle is damaged [6]. Vermian cerebellar lesions have been found to affect long-term habituation of startle reflexes in rats [7*]. Sebastiani et al. [8*] found that the posterior vermis is important for acquisition of the conditioned heart rate slowing. Perhaps the most direct evidence for the Marr-Albus theory, and still controversial, comes from studies of
Abbreviations CR-conditioned response; CS-conditioned stimulus; HVI-hemispheral lobule VI; NMR-nictitating UCR-unconditioned response; UCGunconditioned stimulus; VOR-vestibulo-ocular 802
@ Current
Biology
Ltd ISSN 0959-4388
membrane response; reflex.
The cerebellum
the conditioned nictitating membrane response (NMR) in rabbits. A tone or light conditioned stimulus (CS) is followed by an airpuff directed at the cornea, or a mild electric shock to the edge of the eye, the unconditioned stimulus (UCS). After a number of pairings of CS followed by UCS, the CS alone causes the rabbit to blink, and the nictitating membrane to sweep across the cornea. In 1981, Thompson and his collaborators [9] reported that cerebellar lesions abolished a previously established conditioned NMR and prevented its reacquisition. This review will focus on some of the experiments and controversies that followed this important paper. Two questions will be addressed: first, is the cerebellum the locus of plasticity? And second, if so, is the locus in the cortex or in the nuclei? The evidence suggests [lo] that when the cerebellum is intact, it is the principal site of the synaptic modification underlying NMR conditioning. In the absence of the cerebellum, conditioning may be possible, but is likely to be slower, more variable, and less accurate than normal.
Performance
deficit
Some authors have concluded that the cerebellum is not necessarily involved in conditioning per se. Welsh and Harvey [ 111 argued that since cerebellar lesions also affect performance of the unconditioned response (UCR), the abolition of the conditioned response (CR) may simply reflect a general motor deficit. As the CR is typically less vigorous than the UCR, it might be so weakened as to fail to appear. Alternatively, the CR might be so delayed that it appears very late, and hence becomes masked by the UCR. The explanation that the CR is masked by the UCR can be discounted. Although in their first reports Yeo et al. [ 101 did not report test trials in which the CS was presented alone, in more recent work [12**] in 10 % of trials the tone or light CS was presented without being followed by the US. Such unreinforced trials would have revealed a delayed CS if it were present. They did not. Cerebellar lesions did not merely delay the onset of CRs, they abolished them. The strength of the UCR varies with shock intensity. Lesions of the anterior interpositus nucleus slightly decrease the UCR whilst cerebellar cortical lesions slightly augment it. These effects are small and cannot account, in a simple way, for cases of abolished CRs. Recently, Welsh [13-l analyzed in detail the pattern of response of the nictitating membrane of rabbits to the CS and UCS. Normal animals respond to an auditory CS with two distinct peaks of acceleration. It was the second peak that increased more during conditioning and which was particularly impaired by cerebellar lesions. In some cases, however, cerebellar lesions produced large and permanent impairment in both peaks of acceleration. Welsh argues that his results are indicative of a deficit in performance of the response, but that “the vulnerability of the second component of the CR to cerebellar
and motor
learning
Clickstein
damage reflects an important role for the cerebellum in modulating the degree to which long-latency neural systerns contribute to the ongoing performance of learned and unlearned behaviors”. The impairments that Welsh observed are consistent with a deficit in motor learning,
Reacquisition cerebellar
of conditioned
responses after
lesions
In their original reports Yeo et al. [lo] trained rabbits to respond to both a light and a sound CR. Initial acquisition in almost all cases was complete after 1 week of training. Lesions of hemispheral lobule VI (HVI) of the cerebellar cortex abolished retention of the CR, and the animals did not reacquire the CR when trained for an equivalent number of postoperative trials. The question of possible relearning has recently been re-examined [12-l. With greatly extended postoperative re-training the CR can be reacquired in some cases. However, when the lesions include adjacent areas in lobule V and hemispheral lobule VII some animals fail to recondition even when the postoperative training is extended to 3 weeks. In an attempt to resolve some of the discrepancies in the results of cerebellar lesions from the laboratories of Yeo, and of Welsh and Harvey, they collaborated in a study of the effects of cerebellar cortical lesion on conditioned NMR (lA Harvey, CH Yeo, JP Welsh and AG Romano: Sot Neurosci A&r 1990, 10:268). Their results were mixed. In some animals the CR’s were abolished initially, while in some rabbits the CR’s were retained. Overall, the animals in these experiments were less affected than those in Yeo’s previous study [ 101, It seems likely that the critical factor which distinguishes the two experiments is the amount of pre-operative training. Let us suppose that the critical locus for learning is in the cerebellar cortex. Assume that conditioning involves a synaptic change caused by a pairing of a CS relayed by mossy fibres with a UCS relayed by climbing fibres. The association between CS and UCS could be made on any Purkinje cell or set of Purkinje cells which received the appropriate CS and UCS information. Because of the diffuseness of mossy and climbing libre projections, the change could be made at several sites on the cerebellar cortex. The most likely sites would be within regions of the cerebellar cortex that project to the anterior interpositus nucleus. With a small amount of pre-operative training the association might be formed at a single locus, or at a small number of sites. With additional pre-operative training the sites might be more widely dispersed on the cerebellar cortex. In the Harvey et al. study the animals were trained prior to surgery for 15 days, three times longer than the animals studied by Yeo. If the preferred locus for the association were, in fact, in HVI, but adjacent cerebellar cortical regions could also be modified, the overtrained animals would be less likely to lose the CR after cerebellar lesions. A similar effect of overtraining on retention was described by Chow [ 141, who studied the loss of visual discrimination learning by monkeys, caused by lesions of the inferotemporal cortex. If
803
804
Neural
control
the monkeys were trained until they just reached criterion they lost the response. If they were overtrained prior to the temporal lobe lesion they retained the previously learned task.
Retention
of conditioning
after cerebellectomy
Bloedel and colleagues [ 15,16*] raised an important challenge to the idea that the cerebellum is the locus of NMR conditioning. They first trained decerebrated animals using a tone CS and an air puff UCS with a very short (S-10 s) intertrial interval. They reported that decerebrate rabbits acquired the CR in the absence of forebrain and diencephalon. In five such animals they found that the CR was retained if the cerebellum was then removed. The results of this study remain controversial. Yeo and his colleagues replicated the experiment using a white noise CS and periocular shock UCS with a standard 30s intertrial interval [17-l. These animals could also be trained as the decerebrates, but they lost the CR and failed to reacquire it after the cerebellar lesion. Thompson and colleagues [18] have questioned whether Bloedel’s training procedures would have yielded true associative conditioning. In their attempted replication, normal rabbits failed to acquire the CR when trained with the very short intertrial interval used by Bloedel’s group. If Bloedel’s results reflect true conditioning they argue that the cerebellum cannot be the only locus. The issue is reminiscent of earlier controversies surrounding attempts to establish conditioning in the spinal cord. Such conditioning is sometimes possible, but is typically weak, variable, and slow to be acquired.
If the cerebellum
is involved
how and where
is it involved?
in conditioning,
As Ito [4] emphasized, the cerebellum forms a sidepath for the brainstem VOR. A similar situation holds for the NMR (reviewed in [ 191). Lesions of the cerebellum or related structures can all abolish CRs. Lesions of cerebellar inputs from the inferior olive, pontine nuclei, and the middle cerebellar peduncle have been reported to abolish or impair conditioning. Similarly, lesions on the output side: the cerebellar nuclei, the brachium conjunctivum, red nucleus or rubro-bulbar pathway can also abolish CRs. Cells in all of these structures can be activated by the CS during NMR conditioning. There are two broad possibilities to account for these results: first, two or more of these structures might be interconnected in a network, with the entire ensemble being modified during conditioning; and second, any one of these structures, or the cerebellar cortex itself, might be the principal locus of the synaptic change associated with conditioning.
Cortex versus nuclei In the initial studies [9] the lesions included cortex and nuclei on the trained side of the animal. In subsequent reports it was clear that nuclear lesions alone would abolish the CRs. As the nuclei receive their major input from Purkinje cells these results are consistent with either a nuclear or cortical locus for the CR. Thompson’s group [ZO] reported that cortical lesions did not abolish CRs; hence they concluded that the locus of the conditioning must be in the nuclei. This conclusion was based on a series of partial lesions of the cerebellar cortex. If the memory trace were stored at a single cortical locus, one of the lesions would be expected to abolish the CR, but none of them did. In contrast, Yeo et al [ 101 found that lesions restricted to cerebellar lobule HVI abolished the CRs in previously trained animals. This apparent discrepancy in results might reflect multiple storage sites in the cerebellar cortex. If the association between CS and US were formed at more than one site, then a subtotal cortical lesion might not abolish the CR. The results are consistent with such an interpretation with the proviso that HVI, when present, is the preferred locus for conditioning.
The inferior
olive, climbing
fibres, and
conditioning HVI lesions cause retrograde degeneration within the rostral dorsal accessory olive and immediately adjacent principal olive. If the critical locus for conditioning were not at the level of the cerebellar cortex but at some precerebellar site which projects to the cerebellar cortex, the cortical lesions might affect conditioning by causing retrograde degeneration in precerebellar structures as a result of damage to their axonal terminals. In order to rule out this possibility Hardiman and Yeo [21] replicated their studies of the effects of cortical lesions by injecting kainic acid into HVI and adjacent regions of the cerebellar cortex. The injection killed cerebellar cortical cells but spared their afferent fibres. In these an imals there was no retrograde degeneration within the olive or other pre-cerebellar nuclei, and yet the lesions abolished CRs in cases where they included critical areas of the cerebellar cortex. One interpretation of the effects of cerebellar cortical lesions on NMR conditioning would be that the association is formed by a conjunction between mossy fibre CS representation and climbing fibre UCS at the level of the cerebellar cortex. The climbing fibre UCS would either facilitate (Marr) or inhibit (Albus) the parallel fibre/Purkinje cell synapses which were active at the time of arrival. If this were the case, olivary lesions might be expected to affect a previously acquired CR in the same way as removing the air puff or shock. The CR would be initially present after the olivary lesions and then gradually extinguish despite continued pairing of CS and UCS. Such an extinction effect following oli-
The cerebellum
vary lesions has been reported [ 221. Yeo and colleagues [23], however, saw an immediate abolition of the CR following olivary lesions. Yeo’s results could be interpreted in terms of the immediate effect of climbing fibre lesion on the spontaneous firing rate of Purkinje cells. Immediately after loss of their climbing libre inputs, Purkinje cells increase their firing rate threefold [24]. Such high spontaneous rates would massively inhibit the cerebellar nuclei, not allowing the subtler changes that are associated with the conditioning to be reflected in the output from the cerebellum.
Is the locus of conditioning cerebellar
within
the
References
Conclusion The idea that the cerebellum is involved in motor learning remains controversial [ 11,16*]. However, lesions of the cerebellum and its associated circuitry abolish or impair several types of motor learning. Cells in the cerebellar circuits are activated by the CS in conditioning trials. As Marr, Albus, and Gilbert suggested, the cerebellar cortex may be the preferred locus for reflex plasticity and motor learning. The next problem will be to specify in detail the synaptic events that underlie these changes.
and recommended
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MARR D: A Theory 202:437470.
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Aldus JS: A Theory 10:2FGl.
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PFC: How the Cerebellum Nature 1975, 254X%&689.
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nuclei?
Welsh and Harvey [25-l have provided important new evidence about the possible role of the cerebellar nuclei and cortex in conditioning. They conditioned the NMR to a tone CS in animals previously implanted with a cannula directed at the anterior interpositus nucleus. When the CR to the tone was well established they began a new series of conditioning trials this time with a light CS. During this training the anterior interpositus nucleus was inactivated with lidocaine. Under these conditions the animals failed to manifest any CRs, either to the previously trained tone CS or to the light. When the block was released, however, not only was the previously acquired response to the tone CS still present, but the rabbits also responded to a light CS as well. As the animals were seen to be fully conditioned, the CR must have been established at some locus other than the anterior interpositus nucleus, and most likely prior to it. There are two obvious candidates, the cerebellar cortex and the inferior olive. Both provide major projections to the cerebellar nuclei. In a related experiment, Welsh and Harvey (Sot Neurosci A&r 1990, 16:268) followed a similar procedure, this time inactivating the inferior olive during the conditioning trials. With the olive inactivated no new conditioning could be established despite training during the block. One obvious conclusion from these experiments (which Welsh and Harvey appear not to share) is that the storage site for the conditioning is in the cerebellar cortex.
and motor
M: Long-Term 12:85-102
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1989,
LEATONRN, S~JPPLEWF: Medial Cerebellum and Long-Term Habituation of Acoustic Startle in Rats. Behuzj Neurosci 1991, 105:804-816. This paper generalizes the role of the cerebellum in learning by demonstrating that it is necessaty for another form of long-term behavioural change. 7. .
8. .
SEBKITANI L, Ls NOCE A,
9.
MCCORMICK
PATONJFR, GHEIARDUCCIB: Influence of the CerebeIIar Posterior Vermis on the Acquisition of the Classically Conditioned Bradycardiac Response in the Rabbit. Exp Brain Res 1992, 88:193-198. This paper generalizes the role of the cerebellum in conditioning by showing its role in conditioned cardiovascular adjustments. DA,
IAVOND
DA,
CLUK
GA,
KETTNER RE,
RISING
CE, THOMPSON RF: The Engram Found Role of the Cerebellum in the Classical Conditioning of Nictitating Membrane and Eyelid Responses. Bull Psychmom Sot 1981, 18:103_105. CH, HARIXMANMJ, GUCKSTEIN M: Classical Conditioning of the Nictitating Membrane Response of the Rabbit: II. Lesions of the Cerebellar Cortex. Exp Brain Res 1985, 60:9%113.
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JP, HAU~EY JA: Cerebellar Lesions and the Nictitating Membrane Reflex: Performance Deficits of the Conditioned and Unconditioned Response. J Neuroui 1989, 9:29‘+311.
12. YEO CH, HARDIMANMJ: Cerebellar Cortex and Eyeblink Con.. ditioning: a Re-examination. Exp Bruin Res 1992, 88:62M38. A thorough study of the effects of cerebellar cortical lesions on simple conditioned and unconditioned responses. The data reaffirm the importance of lobule HVI of the cerebellar cortex for NMR conditioning. With additional post-operative training many animals reacquired the CR. The results are consistent with multiple storage sites on the cerebellar cortex. 13. ..
WELSH
14.
CHOW KL: Conditions Influencing the Recovery of Visual Discrimination Habits in Monkeys Following Temporal Neocortical Ablations. .I CampPlqsiol f
