Early neurodevelopment origins of anxiety

焦虑的早期神经发育起源

• 批准号: 9323568
• 负责人: Richard J Davidson
• 金额: $ 200.76万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323568
• 关键词: 5 year old; Adolescence; Adolescent; Adult; Affect; Age of Onset; Age-Months; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavioral; Brain; Brain region; Cell Line; Cell Nucleus; Cell model; Cellular Neurobiology; Characteristics; Child; Childhood; Chronic; Comorbidity; Data; Development; Disease; Early Intervention; Electrophysiology (science); 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; Pharmacology; Phenotype; Prefrontal Cortex; Primates; Principal Investigator; Prosencephalon; Psychiatry; Psychology; Recovery; Regulation; Research Personnel; Risk; Risk Factors; Rodent; Sampling; Severities; Stem cells; Structure; Substance Use Disorder; System; Temperament; Testing; Tissues; Translating; Twin Multiple Birth; Vision; Wisconsin; Work; affective neuroscience; anxious; anxious temperament; base; emotion dysregulation; emotion regulation; gamma-Aminobutyric Acid; human imaging; induced pluripotent stem cell; insight; interdisciplinary collaboration; microPET; negative affect; 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; 5 year old; Adolescence; Adolescent; Adult; Affect; Age of Onset; Age-Months; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavioral; Brain; Brain region; Cell Line; Cell Nucleus; Cell model; Cellular Neurobiology; Characteristics; Child; Childhood; Chronic; Comorbidity; Data; Development; Disease; Early Intervention; Electrophysiology (science); 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; Pharmacology; Phenotype; Prefrontal Cortex; Primates; Principal Investigator; Prosencephalon; Psychiatry; Psychology; Recovery; Regulation; Research Personnel; Risk; Risk Factors; Rodent; Sampling; Severities; Stem cells; Structure; Substance Use Disorder; System; Temperament; Testing; Tissues; Translating; Twin Multiple Birth; Vision; Wisconsin; Work; affective neuroscience; anxious; anxious temperament; base; emotion dysregulation; emotion regulation; gamma-Aminobutyric Acid; human imaging; induced pluripotent stem cell; insight; interdisciplinary collaboration; microPET; negative affect; 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）：儿童焦虑气质（AT）是发展焦虑和病态抑郁症的关键危险因素。在灵长类动物中，AT在生命的早期很明显，稳定，并且与威胁反应性的增加有关。众所周知，早期的逆境会增加发展极端的风险。尽管逆境很普遍，但与AT相关的神经机制尚不清楚。这种理解将允许鉴定新的治疗靶标，并有可能发展神经科学知识的干预措施。这个建议 建立在验证AT表型并识别基础神经电路的工作的基础上。最近的微阵列和RNA测序（RNA-Seq）的工作表明，极端的假设反映了杏仁核中心核的侧分裂中的神经可塑性缺陷 （CEL），杏仁核流出的关键调节剂，引起了引起焦虑迹象的区域，以及在我们的成像工作中最可预测的区域。该提案旨在了解同伴饲养（PR）是一种受控的早期逆境操纵，导致灵长类动物的极端情况，这在人类研究中是不可能的。灵长类动物的使用增加了发现会转化为高危儿童的可能性。 PR和母体饲养的（MR）动物将进行纵向评估，以测试逆境对AT发育的影响。重复的多模式成像将评估逆境对杏仁核反应性发展和前额叶 - 杏仁核调节回路的影响。重要的是，灵长类动物模型提供了一个机会，可以测试逆境对AT的有害影响是否是由CEL神经可塑性途径的改变介导的。免疫组织化学和RNA-seq分析将在CEL微解剖神经元上进行。这种新型工具的合成有望对逆境诱导的分子改变如何在大脑功能，连通性和结构中表现出来，以及这些宏观变化如何促进分子水平啮齿动物或系统水平的人类研究不易获得的极端见解。此外，将创建CEL GABA能神经元的干细胞模型，并将其与CEL的神经元进行比较。有效的干细胞模型将增强对AT分子碱基的理解，并加速筛查新的治疗剂。