James R. Bloedel

On the cerebellum, cutaneomuscular reflexes, movement control and the elusive engrams of memory ☆

This review focuses on the role of the cerebellum in regulating cutaneomuscular reflexes and provides a hypothesis regarding the way in which this action contributes to the coordination of goal-directed movements of the extremities. Specific attention is directed towards the cerebellums role in conditioned and unconditioned eyeblink reflexes and limb withdrawal reflexes as models of its interactions with the cutaneomuscular reflex systems. The implications regarding the cerebellum as a storage site for motor engrams also is discussed in the context of these two behaviors. The proposed hypothesis suggests that the cerebellum regulates important features of the cutaneomuscular reflex circuits including the integration of their activity with descending pathways in a manner that implements these fundamental reflex circuits in the organization and control of goal-directed movements of the extremities.

Classical conditioning of the eyeblink reflex in the decerebrate-decerebellate rabbit

The purpose of these experiments was to test the hypothesis that a conditioned nictitating membrane reflex can be acquired in decerebrate rabbits in the absence of the cerebellum. Experiments examining the effects of large cerebellar lesions on the acquisition and performance of the conditioned reflex were performed in acutely prepared decerebrate rabbits. Most lesions encompassed all of the cerebellar nuclear regions ipsilateral to the eye receiving the unconditioned stimulus. In all rabbits included in this study the continuity between the cerebellar nuclei and the brainstem was interrupted, even in those preparations in which small regions of the nuclei were present in the lateral hemisphere. The findings demonstrate that these animals could acquire the conditioned reflex independent of whether conditioning had occurred prior to the cerebellectomy. Strong associativity was found between the latency of the conditioned response and the interstimulus interval between the conditioned and unconditioned stimuli. The behavior of the conditioned reflex observed in the decerebrate-decerebellate animals differed from that reported for awake intact rabbits in two ways. Once the conditioned behavior had been acquired, the percent of trials showing conditioned responses was somewhat less in decerebrate-decerebellate rabbits and was also more variable in these animals. The data demonstrate that the nictitating membrane reflex can be classically conditioned in the absence of the cerebellum, indicating that this structure is neither necessary nor sufficient for the acquisition of this type of conditioned behavior. In addition, an hypothesis is presented which addresses the difference between the data reported here and those previously reported by other laboratories based on observations in awake intact animals.

Anatomical and physiological evidence for a cerebellar nucleo-cortical projection in the cat

Combined neuroanatomical and electrophysiological experiments were performed to test the hypothesis that axon collaterals of neurons in the cerebellar nuclei project to the cerebellar cortex in cats. The anatomical studies demonstrated that (a) following the injection of tritiated leucine into the deep cerebellar nuclei, labeled fibers could be traced into the granular layer of the cerebellar cortex, and (b) following the injection of horseradish peroxidase into the cerebellar cortex, retrogradely labeled horseradish peroxidase-positive neurons were identified in the deep nuclei. The electrophysiological experiments confirmed the anatomical findings. Neurons in the dentate and interposed nuclei, identified by their antidromic activation from the brachium conjunctivum, could also be activated antidromically from the cerebellar surface. Collision experiments demonstrated that projections from the deep cerebellar nuclei to the cerebellar cortex are in part collaterals of efferent neurons projecting through the brachium conjunctivum. Care was taken to ensure that all recordings were obtained from the region of cell somata in order to minimize the likelihood of recording from neuronal elements passing through the cerebellar nuclei. These combined neuroanatomical and electrophysiological studies provide strong evidence supporting the existence of a collateral system from cerebellar output neurons to the cerebellar cortex. The existence of this collateral system emphasizes that the cerebellar cortex and cerebellar nuclei may comprise a functional unit in which these collaterals may serve as a substrate for feedback control of the cerebellar cortex by the cerebellar output.

Multiple branching of cerebellar efferent projections in cats

SummaryThe retrograde labeling of neurons in the deep cerebellar nuclei with horseradish peroxidase was used to compare the morphological characteristics of neurons in the dentate and interposed nuclei projecting in the cerebellothalamic, cerebello-olivary, and cerebellar nucleocortical pathways. The results from these studies demonstrated that cerebellothalamic and nucleocortical projections from the dentate and interposed nuclei originate from similar populations of spindle- and multipolar-shaped neurons with somal diameters throughout the range of cells present in the deep nuclei. However, only spindle-shaped neurons with somal diameters of 9–15 microns project in the cerebello-olivary pathway. From these anatomical studies, it was concluded that some of the neurons in the dentate and interposed nuclei which project to the thalamus, inferior olive, and cerebellar cortex have similar morphological characteristics. Electrophysiological experiments were carried out to investigate whether or not some of these neurons project to all three sites via axon collaterals. From stimulus sites in the thalamus, inferior olive, and cerebellar cortex, numerous neurons were antidromically activated in the cerebellar nuclei. Collision experiments between these antidromic responses confirmed that single neurons projected to all three of these sites. These studies therefore demonstrate that the axons of some neurons in the dentate and interposed nuclei have collateral branches in both the ascending and descending limbs of the brachium conjunctivum as well as in the cerebellar nucleocortical pathway. Functional implications of the collateral branching of cerebellar efferent projections are discussed.

The changes in Purkinje cell simple spike activity following spontaneous climbing fiber inputs

The purpose of these experiments was to systematically examine the characteristics of the excitability change occurring after the inactivation period evoked by the climbing fiber input to Purkinje cells. Ninety-eight Purkinje cells were isolated extracellularly in unanesthetized decerebrate cats. Simple spikes and complex spikes were discriminated separately. Post-stimulus time histograms were constructed from 100 consecutive trials triggered by the occurrence of spontaneous complex spikes. Seventeen Purkinje cells exhibited a reduction of simple spike discharge rate following the inactivation period. However, 14 cells showed no change in simple spike activity, and in 67 cells the discharge rate increased. These changes in excitability following a spontaneous complex spike were independent of the tonic simple spike activity of the Purkinje cell. Single traces of spike train data from Purkinje cells showed that the change in discharge rate was variable, some complex spikes being followed by an increase and others by a decrease in activity. The basis for these observations and the differences between these data and those from studies in which the climbing fiber input was evoked by electrical olivary stimulation are discussed.

The intracerebellar nucleocortical projection in a primate

SummaryExperiments were performed to determine if a nucleocortical system, a projection from the cerebellar nuclei to the cerebellar cortex, was present in primates. Both electrophysiological and neuroanatomical techniques were employed to investigate this question. It was shown that neurons within the dentate and interposed nuclei were antidromically activated by stimuli applied to the cerebellar cortex. In addition, cells in these nuclei were retrogradely labelled following injections of small amounts of horseradish peroxidase in the cerebellar cortex. The injection of tritiated leucine in the deep nuclei resulted in the labelling of fibers projecting from these structures to the cerebellar cortex which appeared to terminate within the granular layer. Additional electrophysiological studies showed that neurons projecting to the cerebellar cortex could also be antidromically activated from the ventrolateral thalamic nucleus, indicating that the nucleocortical projection in the primate arises at least in part as collaterals from neurons in the deep cerebellar nuclei which also project to extracerebellar structures, as was shown in the cat.

The responses of simultaneously recorded Purkinje cells to the perturbations of the step cycle in the walking ferret: a study using a new analytical method — the real-time postsynaptic response (RTPR)

Experiments were performed in ambulating decerebrate ferrets to examine the activity of up to 6 simultaneously recorded Purkinje cells oriented sagittally during unperturbed and perturbed locomotion using a new analytical technique, the real-time postsynaptic response (RTPR), which permits a trial-by-trial assessment of the action of the recorded neurons on a simulated cerebellar nuclear cell. The data illustrate that the responsiveness of the Purkinje cells located in a specific region of lobules V and VI is most dramatically modulated by the perturbations of the locomotor cycle and that this responsiveness in the perturbed trials is related to the degree of synchrony of the activated climbing fiber inputs to the cells of the set. The data were interpreted as supporting the gain change hypothesis of climbing fiber function.

Responses of interposed and dentate neurons to perturbations of the locomotor cycle

SummaryThis study examined the relationship of antidromically identified neurons in the dentate and interposed nuclei to perturbed and unperturbed locomotion in the pre-collicular, mid-mamillary, decerebrate cat. During treadmill locomotion two methods were used to perturb the step cycle. In the first, the treadmill was braked in different phases of the step cycle, the “treadmill” perturbation. In the second, the motion of the ipsilateral forelimb was interrupted by a rod placed transiently in the limbs path, the “single limb” perturbation. Most interposed cells were modulated during locomotion, their discharge being highly correlated with the EMG of the ipsilateral biceps or triceps. When the locomotion was perturbed, the modulation ceased for the duration of the perturbation. A few interposed cells displayed activity patterns unrelated to the EMG but were responsive to perturbations of a single limb. These responses may be explained by the putative activation of peripheral afferents produced by the perturbation. Most dentate cells were not modulated during unperturbed locomotion but did respond to features of the treadmill perturbation. Usually the response was coupled to the resumption of treadmill motion. A minority of dentate neurons was modulated slightly during unperturbed locomotion. Their modulation was less dramatic than that of interposed cells and was only weakly related to limb movement or EMG activity. Like the interposed neurons, these dentate cells responded to the treadmill perturbation with a cessation of modulation. All dentate cells were unresponsive to single limb perturbations. In a preparation lacking cerebral cortical input, the findings show that neurons of the interposed and dentate nuclei are modulated differently during perturbed and unperturbed treadmill walking in the decerebrate cat. The activity of interposed neurons is related to specific features of EMG activity recorded from muscles in the ipsilateral forelimb. Although some dentate cells were weakly modulated during unperturbed locomotion, the majority of these neurons responded most dramatically to the occurrence of a perturbation which completely stopped the walking behavior.

Movement accuracy constraints in Parkinson's disease patients.

This study examined the hypothesis that the kinematics of movements performed by PD (Parkinsons disease) patients are differentially affected depending on whether or not the aiming movement has an accuracy constraint. The aiming movements required elbow extension in the horizontal plane on a digitizer. There were two movement conditions: (1) one having a spatial accuracy requirement in which the subjects moved to the defined target and stopped on it; and (2) one requiring the subjects to move toward the defined target without stopping precisely on it. Subjects were instructed to make their movements as fast and as accurate as possible in response to the auditory imperative signal. PD patients modified the movement speed and kinematics depending on the two accuracy conditions. However, when the accuracy constraint was imposed, movement slowness observed in the patients was much more pronounced. The most revealing result was localized to the deceleration phase, particularly as the target was approached. The patients also were found to make a higher number of acceleration zero crossings from negative to positive to reach the target, indicating that the movements were more irregular. For the patients, the first acceleration zero crossing from negative to positive occurred much earlier in the movement than that for the controls. In addition, when movement accuracy was constrained, the number of zero crossings was accentuated. These data show that when PD patients make aiming movements to a target, their deceleration phase becomes longer and more variable.

A new conditioning paradigm: Conditioned limb movements in locomoting decerebrate ferrets

These experiments address the hypothesis that the trajectory of a forelimb in decerebrate ambulating ferrets can be conditioned to avoid an obstacle encountered during the locomotor cycle. The perturbation was produced by interjecting a bar into the trajectory of the forelimb during swing phase. Over 5-15 steps the flexion of the elbow progressively increased until the forelimb was elevated over the bar. Avoiding the bar often required that the maximum height of the paw during swing phase was doubled. When the bar was no longer thrust into the trajectory of the forelimb, the conditioned behavior persisted for several step cycles. The results indicate that decerebrate ferrets are capable of acquiring a conditioned limb movement that is not a typical conditioned reflex but rather an accentuation of a component of the step cycle performed to avoid an interruption of swing phase.