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

这是一个重新提交的关于孔蒂中心的更新建议，该中心专注于早期生活经验的贡献， 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， 成人精神疾病通过涉及认知和情感大脑成熟中断的机制 电路. 复杂的行为涉及大脑回路的协调活动。在开发过程中，环境- 导出的感觉信号影响回路成熟（例如，视觉、听觉），并可能驱动异常电路 成熟，可能会促进情绪和认知问题。然而，信号的性质， 导致精神疾病的脆弱性，以及它们如何破坏大脑回路的成熟尚不清楚。 在环境影响中，早期生活逆境是精神疾病的既定风险因素， 逆境的方面（例如，母亲的抑郁症，贫困）解释了后来的精神问题的重要部分 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 来自母亲和环境的不可预测的、碎片化的感觉信号（FRAG）构成了一种 以前未被认识到的早期生活逆境的指标。这一假说起源于机械论 在动物研究中，一致的、可预测的母源信号模式通过以下方式促进恢复力： 调节兴奋性突触的数量和特定细胞群的功能。相比之下， 涉及情绪和认知的大脑回路异常成熟， 赤字 在最初的奖项，我们专注于几个认知和情感的弱点，这些仍然存在 这一提案的成果。此外，我们确定快感缺失是早期FRAG的一个直接后果， 在实验系统中，与异常的快乐/奖励回路成熟的证据有关。快感缺乏a 与多种精神障碍相关的多维度（RDoC）实体，是最近确定的PTSD的核心特征。我们 在建议的更新中强调快感缺失，因为我们发现它在儿童，青少年和 年轻的成年人，并预测风险的战斗后精神疾病在一个脆弱的人口海军陆战队。 因此，在最近发表的令人信服的初步数据的支持下，并在对 在最初的更新提案中，我们测试了该中心的总体假设：它指出，与 早期生活逆境的既定类型，支离破碎和不可预测的母亲和环境 信号有助于通过机制，涉及破坏精神疾病的脆弱性， 认知和情感脑回路的成熟。拟建中心的目标是： 1)测试FRAG与其他早期风险因素对心理健康的相对贡献，沿着 结果包括快感缺乏，考虑性别和使用工具，使不同的队列评估。 2)测试FRAG对发育中的大脑的影响的潜在机制， 特定年龄和性别的脆弱性以及适合年龄的评估工具。我们将使用成像技术， 计算模型专注于大脑回路中断;我们将采用分子和病毒遗传工具 并利用实验动物系统来识别潜在的神经生物学机制。 3)创建行为和神经影像学性别特异性的发展轨迹，从婴儿期到 成年期使用我们的3个前瞻性，充分表征的队列和重复的个体内测量; 生成快感缺失风险和易患精神疾病风险的预测模型;由初步 数据，确定儿童中FRAG的个体内表观遗传特征作为潜在的生物标志物。 4)作为一个培训论坛和磁铁的研究和提高认识，如何早期生活 经验影响情绪和认知结果。 总之，在对原始文件进行审查的指导下，重新提交的更新提案确定了FRAG 作为异常脑回路发展的一个新来源，预示着对精神疾病的脆弱性; 将FRAG整合到现有的框架中，并提供了新的，年龄和性别特异性的预测标志物， 易患精神疾病，因此，基于实验的，预防性的变革路径 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.