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: 10379266
• 负责人: Tallie Z. Baram
• 金额: $ 293.15万
• 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/10379266
• 关键词: Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Anhedonia; Animals; Anxiety; Assessment tool; Auditory; Award; Behavior; Behavioral; Brain; Brain scan; Cells; Child; Cognition; Cognitive; Complex; Computer Models; Data; Development; Dimensions; Discipline; Disease; Emotional; Emotions; Environment; Epigenetic Process; Etiology; Excitatory Synapse; Failure; Functional disorder; Genetic; Genetic Risk; Grant; Human; Image; Individual; Infant; Intervention; Knowledge; Life; Life Experience; Link; Marines; Measurement; Mental Depression; Mental Health; Mental disorders; Molecular; Molecular Genetics; Mothers; National Institute of Mental Health; Nature; Outcome; Pattern; Peripheral; Population; Populations at Risk; Post-Traumatic Stress Disorders; Poverty; Predisposing Factor; Psyche structure; Publishing; Research; Research Domain Criteria; Research Priority; Resource Sharing; Rewards; Risk; Risk Factors; Seeds; Sensory; Signal Transduction; Source; Synapses; System; Testing; Training; Training Activity; Visual; Vulnerable Populations; Work; animal data; base; cohort; combat; cost; early life adversity; experimental study; high risk population; improved; infancy; international center; low socioeconomic status; maternal depression; nerve supply; neurobiological mechanism; neuroimaging; novel; pleasure; potential biomarker; predictive marker; predictive modeling; preventive intervention; programs; prospective; resilience; sex; success; symposium; tool; translational impact; virus genetics; vulnerable adolescent; young adult

This is a resubmitted renewal proposal for a Conte Center focused on the contribution of early-life experiences, especially unpredictable and fragmented maternal and environmental signals, to adolescent vulnerabilities and adult mental illness via mechanisms involving disruption of the maturation of cognitive and emotional brain circuits. Complex behaviors involve coordinated activities of brain circuits. During development, environment- derived sensory signals influence circuit maturation (e.g., visual, auditory) and may drive aberrant circuit maturation that can promote emotional and cognitive problems. Yet the nature of the signals that contribute to vulnerabilities to mental illness, and how they disrupt brain circuit maturation is unclear. Among environmental influences, early-life adversity is an established risk factor for mental illness, and aspects of adversity (e.g., maternal depression, poverty) explain a significant portion of mental problems later in life. Yet there are serious gaps in our ability to identify early vulnerability to mental illness. Here, we posit that unpredictable, fragmented sensory signals (FRAG) from the mother and environment constitute a previously unrecognized indicator of early-life adversity. This hypothesis originated from mechanistic animal studies where consistent, predictable patterns of maternal-derived signals promote resilience by modulating excitatory synapse number and function of specific cell populations. By contrast, FRAG promotes aberrant maturation of brain circuits involved in emotion and cognition, with commensurate behavioral deficits. During the original award we focused on several cognitive and emotional vulnerabilities and these remain outcomes in this proposal. Additionally, we identified anhedonia as a robust direct consequence of early-life FRAG in experimental systems, associated with evidence of aberrant pleasure / reward circuit maturation. Anhedonia, a dimensional (RDoC) entity linked to multiple mental disorders, is a recently-identified core feature of PTSD. We emphasize anhedonia in the proposed renewal because we find that it follows FRAG in children, adolescents and young adults and predicts risk for post-combat mental illness in a vulnerable population of Marines. Thus, supported by compelling recently-published and preliminary data and guided by the reviews of the original renewal proposal, we test the Center’s overarching hypothesis: It states that, in concert with established types of early-life adversity, fragmented and unpredictable maternal and environmental signals contribute to vulnerabilities to mental illness via mechanisms involving disruption of the maturation of cognitive and emotional brain circuits. The proposed Center will aim to: 1) Test the relative contribution of FRAG, along with other early-life risk factors, to mental health outcomes including anhedonia, considering sex and using tools enabling assessments across diverse cohorts. 2) Test the mechanisms underlying the effects of FRAG on the developing brain, with sensitivity to age- and sex-specific vulnerabilities and age-appropriate assessment tools. We will employ imaging and computational models focusing on brain circuit disruption; we will employ molecular and viral-genetic tools and capitalize on experimental animal systems to identify the underlying neurobiological mechanisms. 3) Create behavioral and neuroimaging sex-specific developmental trajectories from infancy to adulthood using our 3 prospective, well-characterized cohorts and repeated intra-individual measurements; generate predictive models for risk of anhedonia and vulnerability to mental illness; supported by preliminary data, identify intra-individual epigenetic signatures of FRAG in children as potential biomarkers. 4) Serve as a training forum and a magnet for the study and improved understanding of how early life experiences influence emotional and cognitive outcomes. In summary, guided by the reviews of the original, this resubmitted renewal proposal identifies FRAG as a novel source of aberrant brain circuit development that portends vulnerability to mental illness; it integrates FRAG within existing frameworks and offers novel, age-and sex-specific predictive markers of vulnerability to mental illness, and hence experiment-based, transformative paths for preventative interventions.

这是重新提交的康特中心更新提案，重点关注早期生活经历的贡献， 特别是不可预测和支离破碎的母亲和环境信号，对青少年的脆弱性和 成人精神疾病的机制涉及认知和情感大脑成熟的破坏 电路。 复杂的行为涉及大脑回路的协调活动。 衍生的感觉信号影响电路成熟（例如视觉、听觉）并可能驱动异常电路 成熟可能会引发情感和认知问题，但其本质却是这样的。 导致精神疾病的脆弱性，而它们如何破坏大脑回路的成熟尚不清楚。 在环境影响中，早年的逆境是精神疾病的一个确定的危险因素， 逆境的各个方面（例如，产妇抑郁、贫困）解释了后来出现的很大一部分精神问题 然而，我们在识别早期易患精神疾病的能力方面存在严重差距。 来自母亲和环境的不可预测的、碎片化的感觉信号（FRAG）构成了 以前未被认识到的早期生活逆境的指标。这一假设源于机械论。 动物研究表明，一致的、可预测的母源信号模式通过以下方式提高复原力： 相比之下，FRAG 可以调节特定细胞群的兴奋性突触数量和功能。 涉及情绪和认知的大脑回路的异常成熟，以及相应的行为 赤字。 在最初的颁奖过程中，我们重点关注了几个认知和情感上的弱点，这些仍然存在 此外，我们将快感缺乏视为早期 FRAG 的强烈直接后果。 在实验系统中，与异常的快乐/奖励回路成熟相关，是一种快感缺失。 与多种精神障碍相关的维度（RDoC）实体是最近确定的 PTSD 的核心特征。 在提议的更新中强调快感缺乏，因为我们发现它遵循儿童、青少年和儿童的 FRAG 年轻人并预测了海军陆战队弱势群体战后精神疾病的风险。 因此，以最近发布的令人信服的初步数据为支持，并以 最初的更新提案，我们测试了该中心的总体假设：它指出，与 早年不幸的既定类型、支离破碎且不可预测的母亲和环境 信号通过涉及破坏的机制导致精神疾病的脆弱性 认知和情感大脑回路的成熟。拟建中心的目标是： 1) 测试 FRAG 以及其他生命早期危险因素对心理健康的相对贡献 结果包括快感缺失、考虑性别以及使用能够跨不同人群进行评估的工具。 2) 测试 FRAG 对发育中大脑影响的机制，并对以下因素敏感 我们将采用针对年龄和性别的脆弱性和适合年龄的评估工具。 专注于脑回路破坏的计算模型；我们将采用分子和病毒遗传工具 并利用实验动物系统来确定潜在的神经生物学机制。 3) 创建从婴儿期到性别特定的行为和神经影像发展轨迹 成年期使用我们的 3 个前瞻性、特征明确的队列和重复的个体内测量； 生成快感缺失风险和精神疾病易感性的预测模型，并得到初步支持； 数据，将儿童 FRAG 的个体内表观遗传特征识别为潜在的生物标志物。 4）作为培训论坛和研究的磁石，提高对早期生活如何进行的理解 经历影响情绪和结果。 总之，在对原件的审查的指导下，这份重新提交的续订提案确定了 FRAG 作为异常大脑回路发育的新来源，预示着容易患精神疾病； 将 FRAG 集成到现有框架中，并提供新颖的、针对年龄和性别的预测标记 易患精神疾病，因此需要基于实验的变革性预防途径 干预措施。