Epigenetic priming of response to future stressors

项目总结 早期生活逆境(ELA)是导致抑郁、焦虑、自杀和其他疾病的最强烈的终生危险因素之一 精神障碍，特别是在以后的生活中面临额外的压力事件之后。ELA使个人变得敏感 并使成年后应激源导致抑郁发作的可能性增加一倍 或者焦虑。然而，这种压力敏感性或启动的神经生物学基础几乎完全保持不变。 未被开发的。临床和临床前研究表明腹侧被盖区(VTA)在ELA中的作用。 可归因于情绪和焦虑障碍，并且ELA改变了VTA的发展过程及其在 对压力源和奖励的反应。使用小鼠模型研究ELA对神经生物学的影响， 我之前发现ELA会导致VTA终生转录变化，包括独特的转录 对成人应激源的反应，这与我们观察到的潜在行为变化是平行的。基因表达是 受到表观遗传机制的调节，最近的研究表明染色质景观继续 在ELA对压力敏感性的影响最大的时候，出生后就成熟了。染色质动态变化 对发育和环境提示作出反应，作为细胞中分子记忆的底物，以及 促进对重复刺激的适应性基因表达反应，这一现象被称为表观启动。在……里面 这项生物行为研究奖创新新科学家(大脑)的提议，我将从概念上进行测试 创新的假说认为，ELA改变了染色质景观的成熟，在一种细胞类型中启动了染色质- 作为对未来刺激反应增强的生物学机制的特定方式。在目标1中，我们将应用切割- 边排序方法和计算分析以了解染色质景观是如何成熟的 在具有细胞特异性的正常出生后发育中，ELA如何改变这些轨迹，以及 这样的变化会增强对未来应激源的反应。在目标2中，我们将开发新的表观基因组 编辑工具来启动目标基因组位置，我们将在体外进行测试，并在体内应用以了解 对未来刺激敏感的机制。而我们基于CRISPR/dCas9的表观基因组启动方法需要 一定程度的风险创新，它与有希望的初步数据相平衡，我们提供替代方法 这将缓解这一高风险、高回报实验的失败。拟议的研究将确定 发育大脑可塑性编码逆境和赋予逆境的神经表观遗传机制 对未来应激源的敏感性。这项建议与NIMH检查心理健康的战略目标直接相关 疾病在整个生命周期中的轨迹。了解ELA如何改变大脑发育的过程 表观基因组水平有可能改变我们对神经发育起源的理解 可归因于ELA的精神疾病和潜在的干预关键窗口。咨询委员会成立 通过这个大脑奖将以最佳方式支持将我们的研究成果转化为发展的最终目标 提供新的治疗方法，以减轻童年逆境对不利心理健康结果的影响。

PROJECT SUMMARY Early life adversity (ELA) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. ELA sensitizes individuals to future stressors and doubles the likelihood that a stressor in adulthood will result in an episode of depression or anxiety. However, the neurobiological basis of this stress sensitivity, or priming, remains almost entirely unexplored. Clinical and preclinical studies demonstrate a role for the ventral tegmental area (VTA) in ELA- attributable mood and anxiety disorders, and that ELA alters the course of VTA development and its function in response to both stressors and rewards. Using a mouse model to investigate the neurobiological impact of ELA, I previously found that ELA leads to lifelong transcriptomic changes in VTA including unique transcriptional response to adult stressors, which parallels latent behavioral changes we have observed. Gene expression is regulated by epigenetic mechanisms, and it was recently shown that the chromatin landscape continues to mature postnatally during a time when ELA has the greatest impact on stress sensitivity. Chromatin dynamically responds to developmental and environmental cues, acts as a substrate of molecular memory in cells, and facilitates adaptive gene expression response to recurring stimuli, a phenomenon termed epigenetic priming. In this Biobehavioral Research Awards for Innovative New Scientists (BRAINS) proposal, I will test the conceptually innovative hypothesis that ELA alters maturation of the chromatin landscape, priming chromatin in a cell-type- specific manner as a biological mechanism of heightened reactivity to future stimuli. In Aim 1 we will apply cutting- edge sequencing approaches and computational analyses to understand how the chromatin landscape matures across normal postnatal development with cellular specificity, how ELA alters these trajectories, and whether such changes are engaged in enhanced response to future stressors. In Aim 2 we will develop novel epigenome editing tools to prime targeted genomic locations, which we will test in vitro and apply in vivo to understand mechanisms of sensitivity to future stimuli. While our CRISPR/dCas9-based epigenome priming approach entails a degree of risky innovation, it is balanced by promising preliminary data and we provide alternative approaches that would mitigate failure of this high-risk high-reward experiment. The proposed research will identify the neuroepigenetic mechanisms through which developmental brain plasticity encodes adversity and confers sensitivity to future stressors. This proposal is directly relevant to the NIMH Strategic Goal to examine mental illness trajectories across the lifespan. Understanding how ELA alters the course of brain development at the level of the epigenome has the potential to transform our understanding of the neurodevelopmental origins of ELA-attributable mental illness and potential critical windows for intervention. The Advisory Council formed through this BRAINS Award will optimally support the ultimate goal of translating our findings into development of novel treatments to mitigate the impact of childhood adversity on adverse mental health outcomes.