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

这是一份重新提交的关于孔蒂中心的续签提案，该中心专注于早期生活经验的贡献， 尤其是不可预测和支离破碎的孕产妇和环境信号，对青少年的脆弱性和 成人精神疾病，涉及认知和情绪脑成熟障碍的机制 电路。 复杂的行为涉及大脑回路的协调活动。在发展过程中，环境- 派生的感觉信号影响回路成熟(例如，视觉、听觉)，并可能驱动异常回路 成熟可以促进情绪和认知问题。然而，信号的性质是 精神疾病的易感性，以及它们如何扰乱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既定风险因素， 逆境的各个方面(例如，母亲的抑郁、贫穷)后来解释了很大一部分心理问题 在生活中。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。在这里，我们假设 来自母亲和环境的不可预测的、支离破碎的感觉信号(FRAG)构成了 以前未被认识到的早年逆境的指标。这一假说源于机械论。 动物研究表明，一致的、可预测的母体信号模式通过以下方式促进韧性 调节特定细胞群的兴奋性突触数量和功能。相比之下，FRAG促进了 涉及情绪和认知的大脑回路异常成熟，与之相称的行为 赤字。 在最初的颁奖过程中，我们关注了几个认知和情感上的弱点，这些弱点仍然存在 这项提案的结果。此外，我们发现快感缺乏症是早期精神分裂的直接后果。 在实验系统中，与异常愉悦/奖赏回路成熟有关的证据。快感缺乏症，一个 维度(RDoC)实体与多种精神障碍有关，是最近发现的创伤后应激障碍的核心特征。我们 在建议的更新中强调快感缺乏症，因为我们发现它在儿童、青少年和 并预测在脆弱的海军陆战队人群中患上战斗后精神疾病的风险。 因此，在令人信服的最近公布的初步数据的支持下，并在对 在最初的更新提案中，我们测试了中心的总体假设：它指出，与 已确定的早年逆境类型、支离破碎和不可预测的母体和环境 信号通过涉及脑电活动中断的机制导致精神疾病易感性 认知和情绪大脑回路的成熟。拟建中心的目标是： 1)测试FRAG和其他早期生活风险因素对精神健康的相对贡献 结果包括快感缺乏，考虑性行为和使用工具，使评估能够跨越不同的队列。 2)测试FRAG对发育中大脑的影响的潜在机制，并对 特定年龄和性别的脆弱性和适合年龄的评估工具。我们将采用成像和 专注于大脑回路中断的计算模型；我们将使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 成年期使用我们的3个前瞻性的、特征良好的队列和重复的个体内部测量； 生成快感缺乏风险和精神疾病易感性的预测模型；得到初步支持 数据，确定儿童FRAG的个体内表观遗传特征作为潜在的生物标记物。 4)作为培训论坛和磁石，研究和提高对早期生命的理解 经历会影响情绪和认知结果。 总而言之，根据对原件的审查，重新提交的续展提案查明了 作为大脑回路发育异常的新来源，预示着易患精神疾病；它 将FRAG集成到现有框架中，并提供新颖的、特定于年龄和性别的预测标记 易患精神疾病，因此以实验为基础，具有变革性的预防途径 干预措施。

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.