EMORY CONTE CENTER FOR NEUROSCIENCE OF MENTAL DISORDERS

埃默里康特精神障碍神经科学中心

• 批准号: 2906558
• 负责人: CHARLES B NEMEROFF
• 金额: $ 255.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906558
• 关键词: clinical depression; disease /disorder proneness /risk; early experience; environmental stressor

This revised application seeks support for the Emory Center for the Neuroscience of Mental Disorders (ECNMD) in the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine. The major goal of this five year research plan is to characterize the persistent neurobiological consequences of adverse events early in life and to determine the relationship of such long-lived central nervous system (CNS) alterations to the development of affective disorders, particularly depression, in adulthood. Two animal models of early adverse experience, for which pilot data on persistent neurobiological alterations exist, will comprise the bulk of the proposed work. These two models include a particularly well documented rodent model of maternal separation and a non-human primate variable foraging demand model of early stress. Gender-specific effects of early life stress will also be evaluated in these models. All of the preclinical projects will receive CNS tissue and biological fluids from each of these animal models. Neural circuits that have been implicated in both the neurobiology of stress and anxiety as well as the neurobiology of depression-like syndrome will be scrutinized, including corticotropin-releasing factor (Proj l; PI: Plotsky), serotonin (Proj 2; PLC Owens), dopamine and norepinephrine (Proj 3; PI: Kuhar), and signal transduction systems (Proj 4; PI: Nestler), hippocampal neurogenesis and remodeling (Proj 5; PI: Gould) and acoustic startle plasticity (Proj 6; PI: Davis) will be characterized in these models. In addition two clinical research projects will be included. Project 7, conducted both at Emory University (PI: Nemeroff) and Yale University (PI: Bremner), will examine the neurobiological consequences of child abuse by studying women with a past history of child abuse who are currently suffering from an episode of major depression versus a group of women who are currently depressed without a history of child abuse and a group of women with a history of child abuse without major depression. Finally, Project 8 will seek to determine the neurobiological and behavioral consequences of maternal depression during pregnancy or in the postpartum period on their children (PI: S.Goodman, Stowe). These research projects will be supported by an administrative core led by the Center Director, a rodent animal core (PI: Plotsky, Weiss), a primate animal core (PI: Insel, Winslow), an assay core (PI: Bonsall, Ritchie), and an integrated functional brain imaging core (PI: M. Goodman, Kilts). We postulate a model in which genetic vulnerability coupled with early trauma in a critical plastic period of development results in sensitization of neural systems which when exposed to even mild stressors in adulthood responds in a heightened manner, resulting in the neurobiological alterations that underlie the syndrome of depression. These studies have important implications not only for the neurobiology of depression but the development of novel treatment strategies for both depression and child abuse.

此修订后的申请寻求埃默里大学医学院精神病学和行为科学系埃默里精神障碍神经科学中心（ECNMD）的支持。这项为期五年的研究计划的主要目标是描述生命早期不良事件的持续神经生物学后果，并确定这种长寿的中枢神经系统（CNS）改变与成年期情感障碍（特别是抑郁症）发展的关系。两种早期不良经历的动物模型将构成拟议工作的大部分，其中存在有关持续神经生物学改变的试点数据。这两个模型包括一个特别有据可查的啮齿动物模型的母亲分离和非人灵长类动物变量觅食需求模型的早期压力。还将在这些模型中评估早年压力对性别的影响。所有临床前项目都将接受来自这些动物模型的CNS组织和生物液体。神经回路，已牵连在这两个神经生物学的压力和焦虑，以及神经生物学的抑郁样综合征将仔细审查，包括促肾上腺皮质激素释放因子（项目1; PI：Plotsky），血清素（项目2; PLC Owens）、多巴胺和去甲肾上腺素（项目3; PI：Kuhar）和信号转导系统（项目4; PI：Nestler）、海马神经发生和重塑（项目5; PI：Gould）和声学惊吓可塑性（项目6; PI：Davis）将在这些模型中表征。此外，还将包括两个临床研究项目。在埃默里大学（PI：Nemeroff）和耶鲁大学（PI：Bremner）进行的项目7将通过研究过去有虐待儿童史的妇女目前患有重度抑郁症，与一组目前患有抑郁症但没有虐待儿童史的妇女和一组有虐待儿童史但没有重度抑郁症的妇女来检查虐待儿童的神经生物学后果。最后，项目8将寻求确定怀孕期间或产后母亲抑郁症对孩子的神经生物学和行为后果（PI：S.Goodman、斯托）。这些研究项目将得到中心主任领导的行政核心、啮齿动物核心（PI：Plotsky，韦斯）、灵长类动物核心（PI：Insel，温斯洛）、测定核心（PI：邦索尔，里奇）和综合功能脑成像核心（PI：M. Goodman，Kilts）.我们假设一个模型，其中遗传脆弱性加上早期创伤在一个关键的塑料发展时期的结果在敏感的神经系统，当暴露于即使是轻微的压力在成年后的反应，在一个高度的方式，导致神经生物学的改变，抑郁症的综合征的基础。这些研究不仅对抑郁症的神经生物学，而且对抑郁症和虐待儿童的新治疗策略的发展具有重要意义。