Vlastislav Bracha - US grants

DESCRIPTION (provided by applicant): The objective of the proposed research is to understand the on-line operation of intermediate cerebellar networks during the motor control and learning of protective eyelid movements. This will be studied using the model of classically conditioned eyeblinks. A series of studies will be performed in rabbits to characterize the function of the inferior olive in movement control and in the acquisition of anticipatory protective reflexes. The proposed research is based on the general hypothesis that the cerebellum, together with extra-cerebellar circuits, is responsible for recognizing a threatening environmental situation and generating adaptive anticipatory behavior. The unique feature of these proposed experiments is their use of an innovative method for manipulating specific synaptic inputs to central neurons without affecting spontaneous tonic activity of investigated neural networks. The first experiments will examine the specific role of sensory signals, carried from the inferior olive to the cerebellum, in the expression and retention of learned movements. In the second series of experiments, the role of the cerebellar inferior olivary input in conditioned response acquisition will be examined. This latter research represents a fundamental test of the popular cerebellar learning hypothesis. The results of this research are important for understanding the mechanisms related to the acquisition and retention of anticipatory defensive behaviors, and also for improving the rehabilitation of patients with deficits in sensorimotor integration through the understanding of the mechanisms underlying motor learning and recovery of motor function.

DESCRIPTION: (Adapted from the Investigator's Abstract) The experiments proposed in this grant application will examine postulates regarding the information processing occurring in the cerebellum during the learning of motor behaviors. These studies will be among the first to employ multiple single unit recording techniques to characterize the learning-related modulation of small populations of neurons simultaneously in both the cortex and nuclei of the cerebellum during the acquisition of three motor tasks: the classically conditioned eye blink in the rabbit and cat, the classically conditioned forelimb withdrawal reflex in the cat, and an instructed delay reaching paradigm, also in the cat. Each of these learned behaviors is dependent on an identified region of the cerebellum. These experiments will use three different paradigms, each requiring a different type of short-term memory process for its performance. In the first of these, the delay paradigm for conditioning the eye blink and withdrawal reflexes, the appropriate timing of the learned behavior is dependent upon the retention of the interval between the conditioned and unconditioned stimuli, an interval which is cued every trial in this paradigm by the duration of the conditioned stimulus. In the second, the trace conditioning of the same reflexes, the interstimulus interval again must be retained, but the interval is not cued on successive trails. Consequently, the proper timing of the conditioned behavior is dependent on an internal representation of the interstimulus interval that is not reinforced by the duration of the CS. The third paradigm, an instructed delay paradigm, employs an operantly conditioned task in which the performance of a reaching movement is dependent upon retaining the target's location for a brief period before the reach is initiated. The changes in information processing occurring simultaneously in functionally related regions of the cerebellar cortex and nuclei during the acquisition of each of these tasks will be examined to test specific hypotheses pertaining to (1) the early modification of neuronal responses preceding the appearance of the conditioned behavior, (2) the action of the climbing fiber system during task acquisition, and (3) the relationship between the learning-related modulation in the cerebellar cortex and that occurring in the cerebellar nuclei. The data processing will assess the relationships among the modulation of the simple spike activity of Purkinje cells, the activation of their climbing fiber inputs, the discharge of cerebellar nuclear neurons, and the characteristics of the conditioned behavior at specific stages of the acquisition process. Because of the unique interrelationships among the paradigms employed in these experiments, the findings not only will elucidate those aspects of information processing that are specific to the learning of each task, but they also will reveal those features which are generalizable across these behaviors.

The objective of the proposed research is to understand the on-line operation of intermediate cerebellar eyeblink networks during the expression of learned anticipatory eyelid movements. This will be studied using models of classically conditioned eyelid movements. A series of studies will be performed in rabbits in order to characterize several fundamental functional properties of eyeblink neural networks. The proposed research is based on the general hypothesis that cerebellum-related neural networks are responsible for recognizing a threatening environmental situation and generating adaptive anticipatory behavior. It is postulated that intermediate cerebellar networks produce motor commands by processing sensory inputs through a system of feedback loops. In addition, we propose that these networks are multi- functional because they control a number of inborn and learned reflexes of several parts of the body. The first experiments will examine the specific role of the excitatory and inhibitory inputs in the modulation of the neurons in the intermediate cerebellum. In the second group of experiments, the role of recurrent feedback loops will be examined. In the third part of the proposal, the multi-functionality of individuals neurons will be examined by recording their activity during different types of reflexive behaviors. The results of this research are important for understanding the mechanisms related to the acquisition and retention of learned anticipatory defensive behaviors and also for the potential rehabilitation of patients with deficits in implicit forms of learning and memory as a consequence of central nervous system pathologies.