Epigenetic priming of response to future stressors

项目摘要 早期生活逆境（ELA）是抑郁，焦虑，自杀和其他疾病的最强终身风险因素之一。 精神障碍，特别是在以后的生活中面临额外的压力事件后。ELA使个人敏感 成年后的压力源导致抑郁发作的可能性增加了一倍 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， 归因于情绪和焦虑障碍，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的神经生物学影响， 我以前发现，ELA导致VTA的终身转录组学变化，包括独特的转录 这与我们观察到的潜在行为变化相似。基因表达 由表观遗传机制调节，最近显示，染色质景观继续 在ELA对应激敏感性影响最大的时期成熟。染色质动态 对发育和环境线索作出反应，充当细胞中分子记忆的底物， 促进适应性基因表达对重复刺激的反应，这种现象称为表观遗传启动。在 这个生物行为研究奖创新新科学家（大脑）的建议，我将测试概念上的 ELA改变染色质景观的成熟，引发细胞类型中的染色质的创新假设， 作为对未来刺激的高度反应性的生物机制的特定方式。在目标1中，我们将应用切割- 边缘测序方法和计算分析，以了解染色质景观如何成熟 在正常的出生后发育与细胞特异性，如何ELA改变这些轨迹，以及是否 这些变化是为了加强对未来压力的反应。在目标2中，我们将开发新的表观基因组 编辑工具，我们将在体外测试并应用于体内，以了解 对未来刺激的敏感机制。虽然我们基于CRISPR/dCas9的表观基因组引发方法需要 一定程度的风险创新，它被有希望的初步数据所平衡，我们提供了替代方法 这将减轻这个高风险高回报实验的失败。拟议的研究将确定 神经表观遗传机制，通过发育大脑可塑性编码逆境，并赋予 对未来压力的敏感性。该提案与NIMH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。 ELA归因的精神疾病和潜在的干预关键窗口。咨询理事会成立 通过这个大脑奖，将最佳地支持将我们的发现转化为发展的最终目标 新的治疗方法，以减轻儿童逆境对不良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.