Aging processes in mammalian species include significant age-related changes in central nervous system function with changes in neurotransmitter receptors as an etiology common to normal and pathological disorders of aging, including Alzheimer's disease. The role of serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in aging has demonstrated an age-related decline of multiple 5-HT selective receptor subtypes and the 5-HT transporter in forebrain and brainstem regions, including the frontal cortex, hippocampus and dorsal raphe nucleus. To date, the cellular and molecular characteristics of diverse serotonergic binding sites across the lifespan have not been correlated with relevant genetic markers. Additionally, the role of dopamine neurotransmission, specifically the dopamine transporter, while demonstrated to decline with aging, has yet to be correlated with relevant genetic markers. Therefore, these studies will address the neuropharmacology of multiple 5-HT receptors as well as the 5-HT and DA transporters to test the hypothesis that age-related decline in central receptor function correlates with genetic based variability in these neurotransmitter systems. Cellular and molecular biological techniques will assess gender-specific changes in multiple 5-HT receptor subtypes and compare the 5-HT and DA transporters in a panel of BXD recombinant inbred mice and their progenitor strains with respect to age (150, 450 and 750 days). Genetic analysis will subsequently be performed in order to locate chromosomal regions containing the quantitative trait loci (QTL) which effect these receptors. Ultimately, pairing of QTL analysis with the neuropharmacologic characterization of central serotonin and dopamine binding sites in selected brain regions, will permit both the sequencing of genes and the identification of specific products of these genes involved in ventral nervous system aging.
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