Epigenetic and cellular markers of stress sensitization by early life stress in mice

小鼠早期生活应激引起的应激敏化的表观遗传和细胞标记

• 批准号: 9894064
• 负责人: Catherine Jensen Pena
• 金额: $ 24.9万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894064
• 关键词: Address; Adult; Affinity; Animals; Appearance; Architecture; Award; Behavior; Behavioral; Bioinformatics; Brain; Brain region; Cell Nucleus; Cells; ChIP-seq; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Data Set; Deposition; Enzymes; Epigenetic Process; Female; Future; Genetic Transcription; Goals; Human; Individual; Institutes; Knock-out; Knowledge; Label; Life; Life Experience; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Mentors; Molecular; Molecular Biology; Mus; Neurosciences; Nucleic Acid Regulatory Sequences; Nucleus Accumbens; Pathway interactions; Pattern; Pharmacogenetics; Phase; Prefrontal Cortex; Research; Research Personnel; Resolution; Rewards; Risk; Risk Factors; Stress; Stressful Event; Sum; Symptoms; Syndrome; Techniques; Testing; Time; Training; Transcription Alteration; Transgenic Mice; Transgenic Organisms; Universities; Ventral Tegmental Area; Work; XCL1 gene; behavior test; behavioral response; chromatin immunoprecipitation; confocal imaging; depressive symptoms; design; designer receptors exclusively activated by designer drugs; developmental plasticity; early experience; early life stress; early onset; epigenetic regulation; epigenome; experience; genome sequencing; genome-wide; histone modification; insight; lifetime risk; male; mouse model; new therapeutic target; novel; pediatric trauma; post-doctoral training; postnatal; programs; recruit; response; reward circuitry; sex; skills; transcriptome sequencing; whole genome

Modified Project Summary/Abstract Section This project will be continued at Princeton University in the Princeton Neuroscience Institute. Early life stress (ELS) is one of the strongest lifetime risk factors for developing depression and other psychiatric disorders, particularly after facing additional stressful events in adulthood. However, relatively little is known about how the developing brain encodes experience of ELS to increase sensitivity to additional stress. To address this, we have established a translationally relevant “two-hit” mouse model of early life and adult stress, wherein stress during a specific postnatal sensitive window increases the likelihood that stress in adulthood will lead to depressive-like behaviors. This proposal will examine whether changes in transcription, epigenetic regulation, and cellular microcircuit reactivation are induced by ELS experience, and whether these changes directly contribute to stress-sensitized depression-like behaviors. In Aims 1 and 3, we will investigate changes in transcription and “priming” of the epigenetic landscape using a variety of cutting-edge techniques including RNA sequencing, chromatin immunoprecipitation, and ATAC-sequencing. In Aim 2, we will ask whether cells in mesocorticolimbic reward-related brain regions activated by ELS are reactivated by adult stress, using activity dependent transgenic mice (ArcCreERT2). In Aim 3 we will then combine these approaches using a novel transgenic cross (ArcCreERT2 x R26-CAGLSL- Sun1-sfGFP-myc) to examine, for the first time, changes in epigenetic priming specifically within nuclei isolated from ELS-activated cells. We will then use pharmacogenetic inhibition to assess the necessity of cells initially activated by ELS for subsequent stress sensitization and depression-like behavior. In addition, we will use CRISPR constructs to knock out Setd7, an enzyme that establishes epigenetic priming by H3K4me1 deposition. This will allow us to test the functional relevance of this mark for the stress sensitization effects of ELS. In sum, the research proposed in this Pathway to Independence Award will reveal both separate and potentially interactive molecular and cellular mechanisms of long-lasting ELS-induced stress sensitization and enhanced vulnerability to depression and psychiatric disease.

修改后的项目摘要/摘要部分 该项目将在普林斯顿大学的普林斯顿神经科学研究所继续进行。早期生活压力（ELS）是一生中罹患抑郁症和其他精神疾病的最强风险因素之一，尤其是在成年后面临额外的压力事件之后。然而，对于发育中的大脑如何编码 ELS 体验以提高对额外压力的敏感性，人们知之甚少。为了解决这个问题，我们建立了一种与翻译相关的早期生活和成年压力的“双重打击”小鼠模型，其中特定的产后敏感窗口期间的压力增加了成年期压力导致抑郁样行为的可能性。该提案将研究转录、表观遗传调控和细胞微电路重新激活的变化是否是由 ELS 经历引起的，以及这些变化是否直接导致应激敏感的抑郁样行为。在目标 1 和 3 中，我们将使用各种尖端技术（包括 RNA 测序、染色质免疫沉淀和 ATAC 测序）研究转录的变化和表观遗传景观的“启动”。在目标 2 中，我们将使用活动依赖性转基因小鼠 (ArcCreERT2) 来询问由 ELS 激活的中皮质边缘奖赏相关大脑区域中的细胞是否会因成年压力而重新激活。在目标 3 中，我们将使用新型转基因杂交 (ArcCreERT2 x R26-CAGLSL-Sun1-sfGFP-myc) 结合这些方法，首次检查从 ELS 激活细胞分离的细胞核内表观遗传引发的变化。然后，我们将使用药物遗传学抑制来评估最初被 ELS 激活的细胞对于随后的应激敏化和抑郁样行为的必要性。此外，我们将使用 CRISPR 构建体敲除 Setd7，这是一种通过 H3K4me1 沉积建立表观遗传启动的酶。这将使我们能够测试该标记与 ELS 压力敏化效应的功能相关性。总之，独立之路奖中提出的研究将揭示长期 ELS 诱导的压力敏化以及对抑郁和精神疾病的脆弱性增强的独立和潜在相互作用的分子和细胞机制。