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

基本信息

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
项目类别：
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

项目摘要

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普林斯顿神经科学研究所继续进行，早期生活压力（ELS）是导致抑郁症和其他精神疾病的最强烈的终生风险因素之一，特别是在成年后面临额外的压力事件之后。了解大脑如何编码 ELS 体验以提高对额外压力的敏感性为了解决这个问题，我们建立了一种与早期生命和成年压力相关的“两次打击”小鼠模型，然而，在特定的出生后敏感窗口发育期间，压力会增加。成年期的压力可能会导致该提案将研究转录、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压力敏感的抑郁样行为。使用各种尖端技术（包括 RNA 测序、染色质免疫沉淀和 ATAC 测序）研究转录和表观遗传景观“启动”的变化。在目标 2 中，我们将询问是否。使用活动依赖性转基因小鼠 (ArcCreERT2)，由 ELS 激活的中皮质边缘奖赏相关大脑区域中的细胞被成年应激重新激活。在目标 3 中，我们将使用新型转基因杂交 (ArcCreERT2 x R26-CAGLSL-Sun1-sfGFP) 结合这些方法。 -myc）首次检查从 ELS 激活细胞中分离出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。评估最初被 ELS 激活的细胞对于随后的应激敏感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。总之，独立之路奖中提出的研究将揭示持久的独立和潜在相互作用的分子和细胞机制。 ELS 诱导的压力敏感性和增加对抑郁症和精神疾病的脆弱性。