Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

破碎的早期生活经历、异常的电路成熟、情感脆弱

• 批准号: 10186815
• 负责人: Tallie Z. Baram
• 金额: $ 45.8万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-17 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186815
• 关键词: Address; Adolescence; Adolescent and Young Adult; Adult; Age; Age-Months; Amygdaloid structure; Anhedonia; Animal Experimentation; Animals; Behavior; Brain; Brain region; Cell Nucleus; Cells; Child; Childhood; Coupled; Cross-Sectional Studies; DNA Methylation; Data; Development; Emotional; Epigenetic Process; Etiology; Exposure to; Failure; Female; Functional Magnetic Resonance Imaging; Gene Expression; Genes; Goals; Human; Image; Individual; Infant; Intervention; Intervention Studies; Life; Life Experience; Link; Longevity; Magnetic Resonance Imaging; Measures; Medial; Mental Health; Mental disorders; Molecular; Mus; Neurons; Neurosciences; Nucleus Accumbens; Outcome; Pathway interactions; Peripheral; Predictive Value; Prefrontal Cortex; Process; Publishing; Rattus; Research Domain Criteria; Rest; Rewards; Risk Factors; Rodent; Sampling; Scientist; Sensory; Sex Differences; Signal Transduction; Structure; Study Subject; Suggestion; Swab; System; Techniques; Technology; Testing; Tissues; Viral; brain tissue; epigenomics; experimental study; genetic technology; human subject; innovation; insight; inter-individual variation; male; methylation biomarker; methylation pattern; multidisciplinary; network models; neuroimaging; neuropsychiatric disorder; novel; pleasure; predictive marker; prevent; rapid growth; reward circuitry; transcriptome sequencing; virus genetics

The overall Center will integrate a multidisciplinary group of scientists to investigate the developmental origins of vulnerability to mental illness, with a focus on perturbed environmental / sensory signals impacting brain circuits during sensitive developmental periods. Guided by the constructive suggestions of the Reviewers, Project 1 will exploit rat and mouse systems to directly test our overarching hypothesis that fragmented and unpredictable early-life sensory signals (FRAG) promote functional deficits in pleasure and reward-seeking behaviors by disrupting normal maturation of the underlying brain circuits. The studies using experimental animals will enable addressing the hypothesis at molecular, cellular and circuit levels of analysis that are not possible in humans. Coupled with the use of structural and functional neuroimaging approaches, our experimental studies will overlap and integrate with human subject studies aimed at modeling network trajectories, allowing inferences of processes and mechanisms across species. Synergizing with Projects 2-4 and the Imaging and BCDM cores, Project 1 defines trajectories considering sex-dependent differences, truly bridging across species. Importantly, rodent experiments enable direct testing of causality of correlative observations made across species and provide mechanistic insight via intervention studies that target candidate mechanisms. These approaches further capitalize on species-unique opportunities including short life span, access to brain tissue and controlled interventions, utilizing the latest Neuroscience techniques. The goals of Project 1 are: (a) To test the hypothesis that aberrant maturation of pleasure and reward circuits underlies FRAG-evoked anhedonia, using state-of-the-art structural and functional (resting state fMRI) imaging and mechanistic interventions; (b) Test the hypothesis that aberrant function of pleasure and reward circuits is a mechanism for FRAG-evoked anhedonia, using cutting-edge viral-genetic technologies; (c) Test if early-life FRAG creates ‘epigenetic signatures’ using novel within subject analyses, and if these provide predictive markers for emotional vulnerabilities in children.

整个中心将整合一个多学科的科学家小组，调查发展的起源， 易患精神疾病的脆弱性，重点是影响大脑的干扰环境/感觉信号 在敏感的发育时期。在审查员建设性建议的指导下， 项目1将利用大鼠和小鼠系统直接测试我们的总体假设，即碎片化 和不可预测的早期感觉信号（FRAG）促进快乐的功能缺陷， 通过扰乱大脑底层回路的正常成熟来抑制寻求奖励的行为。 使用实验动物的研究将能够在分子、细胞和细胞水平上解决这一假设。 和电路水平的分析，这在人类中是不可能的。再加上使用结构和 功能神经成像方法，我们的实验研究将与人类受试者重叠和整合 研究旨在对网络轨迹进行建模，从而可以推断跨网络的过程和机制。 物种与项目2-4以及成像和BCDM核心协同，项目1定义了轨迹 考虑到性别差异，真正跨越物种。重要的是，啮齿动物实验 能够直接测试跨物种相关观察的因果关系，并提供机制 通过针对候选机制的干预研究获得的见解。这些方法进一步利用了 物种独特的机会，包括寿命短，获得脑组织和控制干预， 利用最新的神经科学技术。 项目1的目标是：（a）测试快乐和奖励回路的异常成熟 使用最先进的结构和功能（静息状态fMRI）成像， （B）检验快乐和奖励回路的异常功能是 使用最先进的病毒遗传技术，研究FRAG诱发快感缺失的机制; FRAG使用新的受试者内分析创建“表观遗传特征”，如果这些特征提供预测性， 儿童情感脆弱的标志