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

基本信息

批准号：
10595594
负责人：
Tallie Z. Baram
金额：
$ 47.34万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-17 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595594
关键词：
Address Adolescence Adolescent and Young Adult Adult Age Age Months Amygdaloid structure Anhedonia Animal Experimentation Animal Experiments Behavior Brain Brain region Cell Nucleus Cells Child Childhood Collaborations 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 Induction 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

项目摘要

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.

整个中心将整合多学科科学家小组来研究发育起源容易患精神疾病，重点是影响大脑的环境/感觉信号受到干扰在审稿人的建设性建议的指导下，敏感发展时期的电路。项目 1 将利用大鼠和小鼠系统来直接测试我们的总体假设，即支离破碎的不可预测的早期生命感觉信号（FRAG）会导致快乐和快乐的功能缺陷通过破坏潜在大脑回路的正常成熟来寻求奖励行为。使用实验动物的研究将能够在分子、细胞方面解决这一假设和电路水平的分析，这在人类中是不可能的，再加上结构和分析的使用。功能神经影像方法，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，从而推断跨网络的过程和机制项目 1 与项目 2-4 以及成像和 BCDM 核心相协同，定义了轨迹。考虑到性别依赖性差异，真正跨物种的桥梁。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，并提供机制这些方法进一步利用了针对候选机制的干预研究的洞察力。物种独特的机会，包括寿命短、获取脑组织和受控干预，利用最新的神经科学技术。项目 1 的目标是： (a) 检验快乐和奖励回路异常成熟的假设使用最先进的结构和功能（静息态功能磁共振成像）成像，揭示了 FRAG 诱发的快感缺失 (b) 检验快乐和奖励回路功能异常的假设使用尖端病毒遗传技术研究 FRAG 诱发的快感缺乏机制 (c) 测试生命早期是否存在； FRAG 使用新颖的受试者分析创建“表观遗传特征”，如果这些特征能够提供预测儿童情绪脆弱的标志。