The proposed research project is the continuation of an analysis of developmental changes in the central nervous systems that underlie the ontogeny of eyeblink classical conditioning in rats. The cerebellum and its synaptic connections with the pontine nuclei and inferior olive are essential components of the eyeblink conditioning neural circuitry. The mossy fiber projection from the pontine nuclei to the cerebellum forms the input pathway for the conditioned stimulus (CS) and the climbing fiber pathway from the inferior olive to the cerebellum forms the unconditioned stimulus (US) pathway. The initial findings of this project demonstrate that the ontogeny of eyeblink conditioning is correlated with developmental changes in stimulus-elicited and learning-related neuronal activity in the cerebellum. The input pathways to the cerebellum also undergo significant developmental changes. One of the most striking developmental changes in the input pathways is the development of neural feedback from the cerebellum to the inferior olive. Cerebellar feedback regulates the input pathways and thereby regulates the induction of learning-specific plasticity in the cerebellum. The initial studies suggest that the ontogeny of eyeblink conditioning is due to the development of interactions between the cerebellum, pontine nuclei, and inferior olive. The findings of the initial experiments of this project are promising, but additional studies are required to determine the origins and mechanisms of the aforementioned developmental changes in the cerebellum and its interactions with brainstem nuclei. The first specific aim of the proposed project will examine the anatomical development of the CS and US pathways. The second specific aim will examine the physiological mechanisms underlying the developmental changes in the CS pathway using electrical stimulation of the pontine nuclei, reversible inactivation of the cerebellum and red nucleus, and behavioral methods. The third specific aim will examine the mechanisms underlying the development of the US pathway using electrical stimulation of the inferior olive, pharmacological manipulations of the inferior olive, and behavioral methods. The fourth specific aim will examine developmental changes in the induction of neural plasticity within the cerebellum using in vivo and in vitro neurophysiological techniques. Elucidating the neural mechanisms underlying the ontogeny of eyeblink conditioning may lead to the discovery of general principles concerning the relationship between neural and behavioral development. In addition to the basic research goals of this project, the results of the proposed studies may lead to a better understanding of the functional pathology associated with various developmental disorders that affect the nervous system including fetal alcohol syndrome, exposure to environmental neurotoxins, infantile autism, and Down's syndrome.
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