The objective of the proposed research is to understand the role of the cerebellum in the learning and expression of anticipatory automatic defensive behaviors. This will be studied using the model of the classically conditioned eye blink response. A series of studies will be performed in rabbits and humans in order to characterize neural circuits sub-serving anticipatory eye blink responses and to localize the parts of these circuits that are responsible for learning new responses. The proposed research is based on the general hypothesis that cerebellum-related neural networks are involved both in the execution as well as in the conditioning of eye blink reflexes. It is postulated that the intermediate cerebellum, red nucleus and other associated brain structures form a network within which are distributed plastic changes responsible for the learning of new conditioned responses. The first experiments will examine neuroanatomically network components connecting the cerebellum with eye blink premotoneuronal groups in rabbits. Data from this study will be used as a basis for neuropharmacological experiments which will determine the brain structures involved in the long-term plastic changes responsible for the acquisition of conditioned eye blinks in the rabbit. These studies will identify at which nodes of the network the synthesis of new proteins is required for learning to occur. The second part of the proposed studies will examine how the knowledge of conditioning substrates in the rabbit model applies to learning in humans. In these studies, the cerebellum's role in eye blink conditioning in humans and rabbits will be compared. It is proposed that the cerebellum's participation in the acquisition and retention of the classically conditioned eye blink in these two species is process-dependent. Specifically, in the rabbit the cerebellum is critical for both the acquisition and the retention of conditioned responses. In contrast, it is hypothesized that in humans the cerebellum is essential for response acquisition but is not required for the retention of learned responses. A series of lesion studies in the rabbit and experiments in patients with cerebellar lesions will be performed to analyze the role of cerebellum-dependent networks in eye blink conditioning. Results of this research will be important for understanding the mechanisms related to the acquisition and retention of learned anticipatory defensive behaviors in humans and potentially also for rehabilitating patients with deficits in implicit forms of learning and memory as a consequence of central nervous system pathologies.
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