Age/Sex Effects on the Central Serotonin System

描述(申请人提供)：分子生物学和神经成像的进步，加上人口老龄化造成的迫切需要，为更好地理解大脑功能和行为之间的相互作用创造了肥沃的土壤。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。5-羟色胺系统的选择性年龄效应可能会影响老年人终生抑郁和认知障碍的风险和表现。此外，情绪障碍和阿尔茨海默氏症影响了不成比例的女性人数，但这种性别关联的病因和潜在的治疗意义尚未得到充分研究。事实上，年龄对5-羟色胺系统的影响的性别差异对正常衰老和神经退行性疾病中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。 这项建议的目的是确定衰老的作用和性别对5-羟色胺能功能的潜在影响。本研究的重点是两个互补的5-羟色胺受体亚型，5-HT1A和5-HT2A，因为它们与抑郁和记忆功能有关，并可能在抗抑郁治疗反应的机制中发挥作用；此外，这些受体亚型具有良好的药理学特征，适合于通过正电子发射断层扫描(PET)新的高选择性配体在人体内进行研究。定量图像分析将包括PI开发的基于磁共振(MR)成像的部分体积校正，以最大限度地减少脑萎缩的稀释效应，脑萎缩是经常混淆PET老化研究的偏差来源。 这项工作的目的是提供独特和直接的信息，关于年龄的影响和性别对人类5-羟色胺能功能的潜在影响。因此，这个修订的R01应用补充了我们资助的R01(MH59945)，它使用PET和5-羟色胺能配体来研究晚年抑郁症的治疗反应机制。目前的建议进一步加强了PI及其同事的坚定承诺，即应用先进的体内定量成像技术来确定衰老和晚年神经精神障碍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.