Mechanisms of Aging in the Olfactory System

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DESCRIPTION (provided by applicant): Aging has profound effects on olfactory function. Olfactory sensitivity and the ability to discriminate among odors both decline, leading not only to decrements in the quality of life, but also to serious nutritional deficits. Moreover, both Alzheimer's and Parkinson's disease, among others, show early onset of olfactory deficits and pathology. Despite these important observations, little has been done in the development of animal models for studying the cellular and molecular sequelae of aging in the olfactory system. Here we propose a coordinated series of studies that begin in the olfactory epithelium, where odors are detected, and proceed through the olfactory bulb and olfactory cortex, the two central areas of odor processing. Drawing on the strengths of each of the four participating laboratories, we employ advanced molecular, cellular, anatomical, electrophysiological and computational analyses. In Project 1 microarrays and physiological experiments will assess the status of the olfactory epithelium and bulb. In Project 2 molecular genetic approaches will be used to evaluate turnover of olfactory sensory neurons, expression of odorant receptors, and axonal projections of olfactory sensory neurons to the bulb. In Project 3 the synaptic organization and the balance of primary afferent and local circuit synapses will be examined. Finally, in Project 4 the representation of molecularly-defined odor pathways in olfactory cortex will be studied. In each project we use the same ages and we will share data and reagents. While each project has its own specific aims, the PPG as a whole is united under the common hypothesis that understanding the nature of olfactory deficits in aging requires a comprehensive knowledge of the molecular and cellular biology of the aging olfactory system. What makes this PPG greater than the simple sum of its parts is our ability to analyze the full continuum of the olfactory pathway in a coordinated manner. We will thus emerge not with isolated views of how particular aspects or levels of the olfactory system are affected in aging, but how the olfactory system is impaired as a whole.