Functional alterations are now known to occur in the olfactory system during normal aging and in association with diseases of aging. Ibis proposal will examine the hypothesis that neuroplasticity of gene expression is compromised in the aging mammalian olfactory system. The studies will focus on the neuroregenerative capacity of the olfactory epithelium as well as the trophic relationships which exist between the receptor epithelium and olfactory bulb. In the olfactory bulbs of young animals, we have demonstrated that expression of the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH), but not other neurotransmitter biosynthetic enzymes such as aromatic L-amino acid decarboxylase (AADC) and glutamic acid decarboxylase (GAD), is under peripheral afferent transneuronal regulation. The proposed experiments use molecular biological techniques to investigate neurotransmitter-specific gene expression in the aging rodent and human olfactory systems. 1) Age-associated changes win be determined in the expression of the neurotransmitter enzyme genes, TH, AADC and GAD, in the olfactory bulbs of both mice and rats. Olfactory marker protein (OMP), a protein expressed in mature olfactory receptor cells and their processes, will be assessed to indicate the integrity of olfactory afferent innervation; 2) Plasticity of enzyme gene expression will be assessed following deafferentation and/or odor deprivation, especially following reversible lesions, in young, middle aged and old animals. OMP expression will monitor the regenerative capacity of the olfactory epithelium; 3) Age-related alterations will be investigated in the transport of ligands such as lectins from the olfactory epithelium to the brain. The neurotoxic effects of the ligands also will be determined; 4) The distribution of neurotransmitter biosynthetic enzymes and their mRNAs will be examined in human olfactory bulb from normal subjects spanning the age spectrum and individuals with age-related disorders such as Alzheimer's disease. The proposed studies may indicate if the functional deficits are associated with age-related changes in the regenerative capacity of the olfactory epithelium and/or the ability of the olfactory bulb to respond to perturbation.
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