Vlastislav Bracha

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.

Relationship of simultaneously recorded cerebellar nuclear neuron discharge to the acquisition of a complex, operantly conditioned forelimb movement in cats

This study was designed to examine the changes in the modulation of small populations of cerebellar neurons during the acquisition of a complex, operantly conditioned forelimb task in cats. The experiments are based on the general postulate that, during the learning of a complex motor behavior, the cerebellum is important for generating a coordinated movement that meets the tasks objectives, and that, as the cerebellum participates in this process, it acts to reinforce the effective motor pattern once it has been established. This specific study examines whether the changes in the modulation of cerebellar nuclear neurons during the learning of this task are consistent with this view. Cats were required to learn to move the manipulandum through a novel pattern of 2–3 consecutive straight grooves connected end to end in different spatial configurations, e.g., the letter L, an inverted L, and the letter C. Throughout the acquisition process, 6–12 single units were recorded simultaneously in the cerebellar nuclei, and the kinematics of the movement were evaluated using an Optotrak system. Cells were recorded from the two interposed nuclei and the dentate nucleus in these initial studies. Trials were sorted off-line based on the level of skill at which the required movement was performed. This was assessed using several objective criteria such as movement times, kinematic characteristics, and smoothness (number of peaks in the velocity profile). Event-related histograms then were constructed from each group of sorted trials. Changes in modulation related to a specific event were measured in successive histograms for each neuron. One of the most consistent findings across the cells in all nuclei was that the magnitude of the task-related modulation reached a peak at the time the task was first performed reasonably well and then progressively decreased (but did not disappear) as the task became well practiced. Both the initial increase and the subsequent decrease in response amplitude were significant statistically. The implications of these observations are discussed in the context of the role the cerebellum may play in the acquisition of complex motor tasks.

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

Intracranial microinjections of the GABAA agonist muscimol were used to assess the involvement of the dentato-interposed cerebellar nuclear complex in the performance of the conditioned (CR) and unconditioned (UR) nictitating membrane responses in the rabbit. Specifically, the experiments test the hypothesis that the cerebellar nuclei are involved in the performance of both the CRs and URs. The experiments employed temporary nuclear lesions to disrupt the CRs in order to examine parallel effects on URs. Animals were conditioned in a standard delay conditioning paradigm. Injection sites at which the muscimol application disrupted execution of the CRs were identified in each rabbit. Once these sites were found, the effects of muscimol and saline injections were evaluated while alternating paired trials with unpaired trials in which only the unconditioned stimuli were applied. There are two main findings in the present study. First, the activation of the GABAA receptors in the dentato-interposed cerebellar nuclear region reduced the amplitude and increased the latency of the UR. This change in the UR closely paralleled the disruption of the CR. This observation is consistent with the notion that the cerebellum is involved in the regulation of defensive flexion reflexes. Second, cerebellar nuclear inactivation did not eliminate the tone-induced enhancement of the UR. This finding suggests the presence of cerebellum-independent circuits subserving the intermodal interaction between the conditioned and unconditioned stimuli.

Microinjections of anisomycin into the intermediate cerebellum during learning affect the acquisition of classically conditioned responses in the rabbit

The purpose of this study was to examine the effects of protein synthesis inhibition in the intermediate cerebellum on the acquisition and expression of classically conditioned nictitating membrane responses in the rabbit. Animals were conditioned for three days in a standard delay paradigm. Before each training session, either a solution of anisomycin (a protein synthesis inhibitor) or vehicle was bilaterally injected into the interposed cerebellar nuclear. Following these three training sessions, rabbits were tested to determine whether the previous training under the influence of anisomycin or vehicle resulted in the acquisition of conditioned responses. In this test, animals that were injected previously with the protein synthesis inhibitor exhibited significantly less retention of conditioned responses than rabbits injected with vehicle. Additional experiments demonstrated that anisomycin does not block the expression of conditioned responses during conditioning or in well-trained animals. Microinjections of muscimol at the same sites of the previous drug infusions suppressed the expression of conditioned responses, indicating that the protein synthesis inhibitor was applied to the eyeblink-related parts of cerebellar circuits. The obtained data are the first to demonstrate that a manipulation of cerebellar circuits, which does not affect the performance of learned behavior, can affect the process of learning. These results suggest that the synthesis of new proteins in the intermediate cerebellum participates in the formation of plastic changes responsible for eyeblink conditioning.

Selective involvement of the spinal trigeminal nucleus in the conditioned nictitating membrane reflex of the rabbit

These experiments were performed to test the hypothesis that a region associated with the trigeminal nuclear complex is selectively involved in mediating the classically conditioned nictitating membrane reflex in the rabbit. Microinjections of Lidocaine were used to produce a temporary, localized block of neural activity following the conditioning of the reflex using a standard tone/air puff-paired stimulus paradigm. Data indicate that the injection of Lidocaine at the medial pars oralis/reticular formation junction results in a selective suppression of the conditioned reflex.

The human cerebellum and associative learning: dissociation between the acquisition, retention and extinction of conditioned eyeblinks.

The present paper is part of a systematic exploration of the neural substrates of conditioned eyeblink responses in humans. Normal subjects and patients with lesions restricted to the cerebellum were examined for their ability to acquire new classically conditioned eyeblinks to an auditory conditioned stimulus and whether they were able to perform and extinguish a previously learned natural anticipatory eyeblink response - the kinesthetic threat eyeblink response (KTER). In classical conditioning to an auditory conditioned stimulus, cerebellar patients failed to acquire new conditioned responses. In contrast to this impairment, in the KTER task both cerebellar patients and control subjects exhibited a high incidence of anticipatory eyeblinks which were initiated before the forehead tap. These results indicate that the cerebellar circuits, which are critical for the acquisition of new conditioned responses, are not essential for the storage and expression of naturally acquired conditioned responses. In the extinction experiment, cerebellar patients failed to extinguish their KTERs. This finding suggests that in humans, the acquisition of new and the extinction of previously learned conditioned responses depends on a similar set of cerebellar circuits.

Duality of Cerebellar Motor and Cognitive Functlons

This chapter develops a specific perspective regarding the interrelationship of the cerebellum, motor behaviors, and cognitive processes. The advent of the proposals regarding the cerebellum and cognition has challenged many investigators to examine this issue aggressively and to address the extent to which current concepts, definitions, and experimental approaches are adequate for deriving new insights into the interfaces between the domains of motor execution and adaptive modifications in behavior. This chapter contends that the dichotomy often made between motor processes and cognitive processes is inconsistent with the organization of behaviors in general and that, when a broader, more integrative view is adopted, a role of the cerebellum in cognitive processes is not only expected but also necessary given this structures contribution to motor coordination and behavioral adaptations.

Effects of accuracy constraints on reach-to-grasp movements in cerebellar patients.

Reach-to-grasp movements of patients with pathology restricted to the cerebellum were compared with those of normal controls. Two types of paradigms with different accuracy constraints were used to examine whether cerebellar impairment disrupts the stereotypic relationship between arm transport and grip aperture and whether the variability of this relationship is altered when greater accuracy is required. The movements were made to either a vertical dowel or to a cross bar of a small cross. All subjects were asked to reach for either target at a fast but comfortable speed, grasp the object between the index finger and thumb, and lift it a short distance off the table. In terms of the relationship between arm transport and grip aperture, the control subjects showed a high consistency in grip aperture and wrist velocity profiles from trial to trial for movements to both the dowel and the cross. The relationship between the maximum velocity of the wrist and the time at which grip aperture was maximal during the reach was highly consistent throughout the experiment. In contrast, the time of maximum grip aperture and maximum wrist velocity of the cerebellar patients was quite variable from trial to trial, and the relationship of these measurements also varied considerably. These abnormalities were present regardless of the accuracy requirement. In addition, the cerebellar patients required a significantly longer time to grasp and lift the objects than the control subjects. Furthermore, the patients exhibited a greater grip aperture during reach than the controls. These data indicate that the cerebellum contributes substantially to the coordination of movements required to perform reach-to-grasp movements. Specifically, the cerebellum is critical for executing this behavior with a consistent, well-timed relationship between the transport and grasp components. This contribution is apparent even when accuracy demands are minimal.

Inactivation of interposed nuclei in the cat: classically conditioned withdrawal reflexes, voluntary limb movements and the action primitive hypothesis

Abstractu2002The cerebellar interposed nuclei are considered critical components of circuits controlling the classical conditioning of eyeblink responses in several mammalian species. The main purpose of the present experiments was to examine whether the interposed nuclei are also involved in the control of classically conditioned withdrawal responses in other skeletomuscular effector systems. To achieve this objective, a unique learning paradigm was developed to examine classically conditioned withdrawal responses in three effector systems (the eyelid, forelimb and hindlimb) in individual cats. Trained animals were injected with muscimol in the cerebellar interposed nuclei, and the effects on the three conditioned responses (CRs) were examined. Although the effects of muscimol were less dramatic than previously reported in the rabbit eyeblink preparation, the inactivation of the cerebellar nuclei affected the performance of CRs in all three effector systems. In additional experiments, animals were injected with muscimol at the sites affecting classically conditioned withdrawal responses to determine the effects of these injections on reaching and locomotion behaviors. These tests demonstrated that the same regions of the cerebellar interposed nuclei which control withdrawal reflexes are also involved in the control of limb flexion and precision placement of the paw during both locomotion and reaching tasks. The obtained data indicate that the interposed nuclei are involved in the control of ipsilateral action primitives and that inactivating the interposed nuclei affects several modes of action of these functional units.

Conditioned and unconditioned forelimb reflex systems in the cat: involvement of the intermediate cerebellum

Abstractu2002Temporary inactivation of the cerebellar interposed nuclei was used to assess the role of the intermediate cerebellum in the performance of forelimb cutaneo-muscular reflexes in the cat. The following types of reflexive responses were evaluated: the classically conditioned and unconditioned forelimb withdrawal responses and the forelimb tactile placing, hopping and magnet responses. The experiments tested the hypothesis that the intermediate cerebellum is involved in the performance of all the above forelimb reflexes. The forelimb withdrawal reflex was classically conditioned in a newly developed paradigm in which animals were first operantly conditioned to stand on four elevated platforms. Trained animals were microinjected with a γ-aminobutyric acid (GABA) agonist, muscimol, in the interposed nuclei, and the effects of inactivation of the intermediate cerebellar output on the forelimb reflexes were examined. The main findings of these experiments are that unilateral muscimol inactivation of the interposed nuclei in the cat abolished the expression of the classically conditioned limb flexion reflex, suppressed the performance of the unconditioned withdrawal reflex and, in parallel, downregulated the tactile placing, hopping and magnet postural responses in the ipsilateral forelimb. These observations are inconsistent with concepts indicating exclusive involvement of the intermediate cerebellum in the classically conditioned reflexes elicited by aversive stimuli. On the contrary, they support the hypothesis of a more global involvement of this structure in learned and unlearned defensive flexion reflexes and in automatic postural response systems.