EMORY CONTE CENTER FOR NEUROSCIENCE OF MENTAL DISORDERS

这份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疾病神经科学中心（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，并确定这种长期中枢神经系统（CNS）改变与成年期情感性障碍（特别是抑郁症）发展的关系。两种早期不良经历的动物模型，其中存在持续神经生物学改变的试点数据，将构成拟议工作的大部分。这两种模型包括一个有详细记录的啮齿类动物的母亲分离模型和一个非人类灵长类动物的早期压力变量觅食需求模型。这些模型还将评估早期生活压力对性别的影响。所有临床前项目都将接受来自每种动物模型的中枢神经系统组织和生物液体。神经回路涉及到压力和焦虑的神经生物学以及抑郁样综合征的神经生物学，包括促肾上腺皮质激素释放因子（Proj 1; PI: Plotsky），血清素（Proj 2; PLC Owens），多巴胺和去甲肾上腺素（Proj 3; PI: Kuhar），信号转导系统（Proj 4; PI: Nestler），海马神经发生和重塑（Proj 5; PI: Gould）和声惊吓可塑性(Proj 6；PI: Davis)将在这些模型中表现出来。此外，还将包括两个临床研究项目。项目7由埃默里大学（PI: Nemeroff）和耶鲁大学（PI: Bremner）共同开展，将研究虐待儿童的神经生物学后果，方法是研究有虐待儿童历史的妇女，她们目前患有严重抑郁症，与一组目前患有抑郁症但没有虐待儿童历史的妇女和一组有虐待儿童历史但没有严重抑郁症的妇女进行比较。最后，项目8将试图确定怀孕期间或产后母亲抑郁对其孩子的神经生物学和行为后果（PI: S.Goodman, Stowe）。这些研究项目将由中心主任领导的行政核心、啮齿动物核心（PI: Plotsky, Weiss）、灵长类动物核心（PI: Insel, Winslow）、分析核心（PI: Bonsall, Ritchie）和综合功能脑成像核心（PI: M. Goodman, Kilts）提供支持。我们假设一个模型，在这个模型中，遗传脆弱性与发育关键可塑性时期的早期创伤相结合，导致神经系统的敏感化，当成年期暴露于即使是轻微的压力源时，神经系统的反应也会增强，从而导致神经生物学上的改变，这是抑郁症的基础。这些研究不仅对抑郁症的神经生物学有重要意义，而且对抑郁症和儿童虐待的新治疗策略的发展也有重要意义。

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.