Age/Sex Effects on the Central Serotonin System

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DESCRIPTION (provided by applicant): Advances in molecular biology and neuroimaging, coupled with the imperative caused by the aging of the population, have created fertile ground for improved understanding of the interaction between brain function and behavior. It is well recognized that the integrity of the central serotonin (5-HT) neurotransmitter system is essential for the proper regulation of mood, behavior, and memory. Selective age effects on the 5-HT system may impact risk and manifestations of depression across the lifespan and cognitive impairment in the elderly. Further, mood disorders and Alzheimer's disease affect a disproportionate number of women, yet the etiology and potential treatment implications of this gender association are understudied. Indeed, sex differences in the effect of age on the 5-HT system is of etiologic and therapeutic importance to potential gender influences on susceptibility, course, and treatment of mood and cognitive disturbances in normal aging and in association with neurodegenerative disease. The aim of this proposal is to define the role of aging and the potential influence of gender on serotonergic function. This study focuses on two complementary 5-HT receptor subtypes, 5-HT1A and 5-HT2A, because of their association with depression and memory function and putative role in mechanisms of antidepressant treatment response; further, these receptor subtypes are pharmacologically well-characterized and amenable to in vivo study in humans with new highly selective ligands for positron emission tomography (PET). Quantitative image analysis will include a magnetic resonance (MR) imaging-based partial volume correction developed by the PI in order to minimize the diluting effects of cerebral atrophy, a source of bias that frequently confounds PET studies of aging. The goal of this work is to provide unique and direct information on the effect of age and potential influence of sex on human serotonergic function. Thus, this revised R01 application complements our funded R01 (MH59945), which uses PET and serotonergic ligands to investigate treatment response mechanisms in late-life depression. The current proposal further reinforces the strong commitment by the PI and colleagues to apply advanced quantitative in vivo imaging techniques to define neurobiologic correlates of aging and neuropsychiatric disorders of late life.