Mapping Molecular and Cellular Responses to Odorants

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DESCRIPTION (from applicant's abstract): The goal of this project is to characterize olfactory perception at both cellular and molecular levels. Primary olfactory neuronal input is spatially organized in the olfactory bulb in mammals, and we hypothesize that this spatial organization is preserved at higher levels of sensory processing. The experimental approach will be based on an assay for neuronal activation that offers temporal and cellular resolution in awake, freely behaving mice. The expression and intracellular localization of an immediate early gene Arc, as determined by fluorescent in-situ hybridization and confocal microscopy will be validated as a measure of neuronal activation in the olfactory bulb. Then the pattern of neuronal activation will be determined in the olfactory bulb and other areas of the forebrain in response to two structurally related odorants. Next one of the structurally related odorants will be afforded a behavioral significance through cue conditioning; both appetitive and aversive unconditioned stimuli will be employed in the training sessions. Following conditioning, the pattern of neuronal activation in response to the conditioned odorant will be compared to the pattern in the naive mouse as well as to the pattern generated by the structurally related molecule that is either behaviorally neutral or afforded the opposite behavioral significance. Together, these studies will provide a functional map for olfactory perception in the olfactory bulb and higher levels of sensory processing in order to test our hypothesis. In addition, this constitutes an important step towards defining synapses that are modified during a learning process in mammals, and developing a functional assay in transgenic mice to correlate cognitive dysfunction with anatomical changes in disease models of Alzheimer's disease and other neurodegenerative diseases. During the course of this research sponsored by Richard Axel, M.D., the candidate will be trained in creative and rigorous molecular approaches to systems level neuroscience problems. Moreover, the candidate will be trained in cognitive neurology under the direction of Richard Mayeux, M.D. at Columbia University.