EMORY CONTE CENTER FOR NEUROSCIENCE OF MENTAL DISORDERS

这项修订后的申请寻求支持埃默里大学医学院精神病学和行为科学系的埃默里精神疾病神经科学中心(ECNMD)。这项五年研究计划的主要目标是表征生命早期不良事件的持续性神经生物学后果，并确定这种长寿的中枢神经系统(CNS)变化与成年后情感障碍，特别是抑郁症发展的关系。两个早期不良体验的动物模型将构成拟议工作的主要部分，其中存在关于持续性神经生物学改变的试点数据。这两个模型包括母体分离的啮齿动物模型和早期应激的非人类灵长类可变觅食需求模型。早期生活压力的性别影响也将在这些模型中进行评估。所有的临床前项目都将接受来自这些动物模型的中枢神经系统组织和生物液。在应激和焦虑的神经生物学以及抑郁样综合征的神经生物学中涉及的神经回路将被仔细研究，包括促肾上腺皮质激素释放因子(L；PI：Plotsky)、5-羟色胺(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：Gold)和声学惊吓可塑性(Proj 6；PI：Davis)。此外，还将包括两个临床研究项目。项目7由埃默里大学(PI：NERMEROFF)和耶鲁大学(PI：Bremner)共同进行，将通过研究有虐儿史、目前患有严重抑郁症的女性和一组没有虐儿史的女性以及一组没有严重抑郁症史的女性，来研究虐待儿童的神经生物学后果。最后，项目8将寻求确定母亲在怀孕期间或产后抑郁对其子女的神经生物学和行为后果(PI：S.Goodman，Stowe)。这些研究项目将得到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，Winlow)、分析核心(PI：Bonsall，Ritchie)和综合脑成像核心(PI：M.Goodman，Kilts)的支持。我们假设了一个模型，在这个模型中，在发育的关键可塑性时期，遗传脆弱性和早期创伤会导致神经系统的敏感化，当成年后暴露于即使是轻微的应激源时，神经系统也会以一种高度敏感的方式做出反应，导致神经生物学变化，这是抑郁症综合征的基础。这些研究不仅对抑郁症的神经生物学有重要意义，而且对抑郁症和虐待儿童的新治疗策略的开发也有重要意义。

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.