Early neurodevelopment origins of anxiety

焦虑的早期神经发育起源

• 批准号: 8913780
• 负责人: Richard J Davidson
• 金额: $ 210.24万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913780
• 关键词: Accounting; Adolescence; Adolescent; Adult; Affect; Age of Onset; Age-Months; Age-Years; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavioral; Brain; Brain region; Cell Line; Cell Nucleus; Cell model; Cellular Neurobiology; Characteristics; Child; Childhood; Chronic; Data; Development; Disease; Early Intervention; Emotional; Environmental Risk Factor; Event; Fathers; Fiber; Fibroblasts; Functional Magnetic Resonance Imaging; Funding; Gene Expression Profile; Genes; Growth; Hormonal; Human; Hydrocortisone; Image; Individual; Infant; Intervention; Laboratories; Lateral; Life; Link; Macaca mulatta; Magnetic Resonance Imaging; Maintenance; Marriage; Measures; Mediating; Mental Depression; Mental disorders; Metabolism; Methods; Modeling; Molecular; Monkeys; Mood Disorders; Moods; Mothers; Multimodal Imaging; National Institute of Mental Health; Neuronal Plasticity; Neurons; Neurosciences; Parents; Pathway interactions; Pattern; Phenotype; Prefrontal Cortex; Primates; Principal Investigator; Prosencephalon; Psychiatry; Psychology; RNA Sequence Analysis; RNA Sequences; Recovery; Regulation; Research Personnel; Risk; Risk Factors; Rodent; Sampling; Severities; Staging; Stem cells; Structure; Substance Use Disorder; System; Temperament; Testing; Tissues; Translating; Twin Multiple Birth; Vision; Wisconsin; Work; affective neuroscience; age related; anxious; anxious temperament; base; emotion dysregulation; emotion regulation; gamma-Aminobutyric Acid; induced pluripotent stem cell; insight; interdisciplinary collaboration; microPET; neural circuit; neurobehavioral; neurodevelopment; neuromechanism; new therapeutic target; nonhuman primate; novel; novel strategies; novel therapeutics; peer; programs; public health relevance; response; screening; sound; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): Childhood anxious temperament (AT) is a key risk factor for developing anxiety and co- morbid depression. In primates, AT is evident early in life, stable, and associated with increased threat reactivity. Early adversity is known to increase the risk of developing extreme AT. While adversity is common, the neural mechanisms linking it to AT are not understood. This understanding would permit identification of novel therapeutic targets with the potential for developing neuroscientifically-informed interventions. This proposal builds on work validating the AT phenotype and identifying the neural circuit underlying AT. Recent microarray and RNA sequencing (RNA-seq) work suggests the hypothesis that extreme AT reflects neuroplasticity deficits in the lateral division of the central nucleus of the amygdala (CeL), a key regulator of amygdalar outflow to regions that give rise to signs of anxiety, and the region most predictive of AT in our imaging work. This proposal aims to understand how peer rearing (PR), a controlled early adversity manipulation, causes extreme AT in primates, something not possible in human studies. The use of primates increases the likelihood that discoveries will translate to at-risk children. PR and maternally- reared (MR) animals will be longitudinally assessed, testing adversity's impact on the development of AT. Repeated multimodal imaging will assess adversity's impact on the development of amygdala reactivity and prefrontal-amygdala anxiety regulation circuits. Importantly, the primate model affords an opportunity to test whether adversity's harmful effects on AT are mediated by alterations in CeL neuroplasticity pathways. Immunohistochemical and RNA-seq analyses will be performed on CeL microdissected neurons. This novel synthesis of tools promises new insights into how adversity-induced molecular alterations manifest in brain function, connectivity, and structure, and how these macroscopic changes contribute to extreme AT- insights not readily available from molecular-level rodent or systems-level human studies. Further, a stem cell model of CeL GABAergic neurons will be created and compared to neurons from CeL. A valid stem cell model would enhance understanding of AT's molecular bases and accelerate the screening of new therapeutics.

描述（由申请人提供）：童年焦虑气质（AT）是发生焦虑和共病抑郁的关键危险因素。在灵长类动物中，AT 在生命早期就很明显，稳定，并且与威胁反应性增加有关。众所周知，早期的逆境会增加患极端 AT 的风险。虽然逆境很常见，但将其与 AT 联系起来的神经机制尚不清楚。这种理解将允许识别新的治疗靶点，并有可能开发神经科学干预措施。这个提议 建立在验证 AT 表型和识别 AT 基础神经回路的工作基础上。最近的微阵列和 RNA 测序 (RNA-seq) 工作提出了这样的假设：极端 AT 反映了杏仁核中央核横向分裂的神经可塑性缺陷 (CeL)，杏仁核流出到引起焦虑迹象的区域的关键调节因子，也是我们影像学工作中最能预测 AT 的区域。该提案旨在了解同伴养育（PR）（一种受控的早期逆境操纵）如何导致灵长类动物出现极端 AT，这在人类研究中是不可能的。使用灵长类动物增加了将发现转化为高危儿童的可能性。 PR 和母养 (MR) 动物将进行纵向评估，测试逆境对 AT 发展的影响。重复的多模态成像将评估逆境对杏仁核反应性和前额叶-杏仁核焦虑调节回路发育的影响。重要的是，灵长类动物模型提供了一个机会来测试逆境对 AT 的有害影响是否是由 CeL 神经可塑性途径的改变介导的。将对 CeL 显微解剖的神经元进行免疫组织化学和 RNA 测序分析。这种新颖的工具综合提供了关于逆境引起的分子改变如何在大脑功能、连接性和结构中表现出来的新见解，以及这些宏观变化如何促成极端 AT 见解，而这些见解是分子水平的啮齿动物或系统水平的人类研究无法轻易获得的。此外，还将创建 CeL GABA 能神经元的干细胞模型，并将其与来自 CeL 的神经元进行比较。有效的干细胞模型将增强对 AT 分子基础的理解并加速新疗法的筛选。