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: 10379268
• 负责人: Tallie Z. Baram
• 金额: $ 45.86万
• 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/10379268
• 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; 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来调查发育的起源 精神疾病的易感性，重点关注影响大脑的扰乱的环境/感觉信号 敏感发育期的神经回路。在评审员建设性建议的指导下， 项目1将利用老鼠系统来直接测试我们支离破碎的总体假设 而不可预测的早期感觉信号(FRAG)会促进愉悦和 通过扰乱基本大脑回路的正常成熟来寻求奖励的行为。 使用实验动物进行的研究将能够在分子、细胞 和电路水平的分析，这在人类是不可能的。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体对象重叠和整合 旨在对网络轨迹进行建模的研究，允许推断整个过程和机制 物种。与项目2-4以及成像和BCDM核心协同工作，项目1确定了轨迹 考虑到性别差异，真正跨越了物种之间的桥梁。重要的是，啮齿动物实验 能够直接测试跨物种进行的相关观察的因果关系，并提供机械性 通过干预研究的洞察力，以候选机制为目标。这些方法进一步利用了 物种-独特的机会，包括短寿命、获得脑组织和受控干预， 利用最新的神经科学技术。 项目1的目标是：(A)检验快乐和奖赏回路的异常成熟假设 使用最先进的结构和功能(静息状态fMRI)成像技术，为裂隙诱发的快感缺乏症奠定基础 和机械干预；(B)检验以下假设：愉悦和奖励回路的异常功能是 使用尖端病毒基因技术的裂片诱发快感缺乏症的机制；(C)测试早期生命 FRAG在主题分析中使用小说创建了‘表观遗传特征’，如果这些提供了预测性的 儿童情绪脆弱的标志。