Age/Sex Effects on the Central Serotonin System

描述（由申请人提供）：分子生物学和神经影像学的进步，加上人口老龄化带来的迫切需要，为提高对大脑功能和行为之间相互作用的理解创造了肥沃的土壤。众所周知，中枢5-羟色胺（5-HT）神经递质系统的完整性对于情绪、行为和记忆的适当调节至关重要。选择性年龄对5-羟色胺系统的影响可能影响整个生命周期中抑郁症的风险和表现以及老年人的认知障碍。此外，情绪障碍和阿尔茨海默病影响了不成比例的女性，但这种性别关联的病因学和潜在治疗意义尚未得到充分研究。事实上，年龄对5-羟色胺系统影响的性别差异在病因学和治疗上具有重要意义，对于正常衰老和与神经退行性疾病相关的情绪和认知障碍的易感性、病程和治疗的潜在性别影响具有重要意义。

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.