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，加上人口老龄化的迫切性，为改善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是必不可少的。对5-HT系统的选择性年龄效应可能会影响老年人一生中抑郁症和认知障碍的风险和表现。此外，情绪障碍和阿尔茨海默氏病影响了不成比例的妇女，但这种性别关联的病因和潜在的治疗意义研究不足。事实上，年龄对5-HT系统影响的性别差异对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病因学和治疗重要性。 该提案的目的是确定衰老的作用和性别对肾上腺素能功能的潜在影响。这项研究的重点是两个互补的5-HT受体亚型，5-HT 1A和5-HT 2A，因为它们与抑郁症和记忆功能和抗抑郁药治疗反应机制中的假定作用的关联;此外，这些受体亚型的特征和服从人体内研究与新的高选择性配体的正电子发射断层扫描（PET）。定量图像分析将包括PI开发的基于磁共振（MR）成像的部分容积校正，以最大限度地减少脑萎缩的稀释效应，这是一种经常混淆PET老化研究的偏倚来源。 这项工作的目标是提供独特的和直接的信息，年龄和性别对人类肾上腺素能功能的潜在影响。因此，这项修订后的R 01申请补充了我们资助的R 01（MH 59945），该申请使用PET和多巴胺能配体来研究晚年抑郁症的治疗反应机制。目前的提案进一步加强了PI及其同事的坚定承诺，即应用先进的定量体内成像技术来定义衰老和晚年神经精神疾病的神经生物学相关性。

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.