As an approach to the neural substrates of memory, this project examines characteristics and functional roles of structural changes that occur in nerve cells in response to behavioral training. The major focus is on changes that occur in the structure of neurons in the forelimb region of rat motor-sensory cortex when they learn to reach into a chamber for food. Prolonged training increases dexterity and, when the innately nonpreferred forepaw is exclusively trained, paw preference for reaching is reversed. Dendritic fields of never cells in a motor-sensory cortex region that appears from lesion, electrical stimulation, unit recording and metabolic activity studies to be critically involved in this behavior increase in size with training. This suggests that new synapses are formed as a consequence of learning and by implication that synapse formation may be a basis for long term memory. To further test this hypothesis, we propose to: 1) delineate the pattern of changes across afferent inputs and intrinsic nerve cell types as a partial description of a """"""""memory circuit"""""""", using quantitative analysis of tissue prepared with Golgi impregnation, Phaseolus vulgaris leucoagglutinin (PHA-L) uptake, and electron microscopic techniques, and 2) test predictions from this anatomical pattern regarding functional organization, beginning by recording responses evoked by electrical stimulation of afferent sources in the in vitro cerebral cortical slice. A separate paradigm, nictitating membrane conditioning in the rabbit using dorsolateral pontine nucleus stimulation as the CS, in which the conditioned response depends critically on identified regions of the cerebellar cortex, will be used in a collaborative study designed to further test the association of synapse formation with learning in a behavioral paradigm in which the physiological circuitry is well-defined. Finally, as a follow-up to the finding that the spines of newly-forming synapses often contain aggregates of ribosomes, we will attempt to isolate and clone the gene whose mRNA is translated by these ribosomes and to use the resultant cDNA and antibodies to the protein it produces to further assess the role of synaptogenesis in the memory process.
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