The ultimate purpose of this proposal is to study the fundamental molecular mechanism of aging brain and neurodegenerative disorders. The olfactory system will be used as a model system of aging because 1) the olfactory system shows changes in aging and neurodegenerative disorders such as Alzheimer's diseases; 2) it has ideal anatomic segregation of afferent inputs for detailed anatomical work; and 3) the recycling nature of its peripheral afferent receptor cells makes the study of neuronal interactions quite feasible. Aging rat and mouse brain will be studied to investigate the changes in neurotransmitter levels and transmitter synthesizing enzyme activities, correlating with previously noted morphological changes in the olfactory system. If changes in neurotransmitter phenotypes are noted, further characterization of the regulation of neurotransmitter gene expression will be undertaken by immunotitration for the amount of enzyme protein molecules, Northern and dot blot analyses for quantitation of corresponding mRNA levels, and in vitro transcription assay, if the changes are sufficiently large. Afferent regualtion of neurtransmitter phenotype in the olfactory cells will also be studied at the level of gene expression and its change with aging will be investigated. This will be the first attempt to study the gene expression in aging brain at the fundamental level by use of specific probes. The immediate focus of the proposal preceding the above project will be the basic science training period. The candidate will acquire basic metholology and understanding of biochemcial techniques, molecular biological principles, and modern anatomic methodologies through on-going laboratory projects in the sponsor's laboratory. The development of independent research program will allow the candidate to intergrate it with his clinical training in neurodegenerative disorders of aging.
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