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The cellular memory of early life adversity

早年逆境的细胞记忆

基本信息

批准号：
10338187
负责人：
Miklos Toth
金额：
$ 52.26万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338187
关键词：
3&apos Untranslated Regions Address Adverse effects Adverse event Affect Alternative Splicing Anxiety Area Behavior Behavior Control Behavioral Brain Cell Adhesion Molecules Cell model Cells Chemosensitization Code Communities Cues DNA Methylation DNA Modification Methylases Development Early identification Eligibility Determination Epigenetic Process Equilibrium Exhibits Exons Frequencies Fright Gene Expression Genes Genetic Transcription Genome Genomic Segment Heterogeneity Hippocampus (Brain)Individual Ion Channel Lead Learning Length Life Life Experience Limbic System Link Membrane Memory Messenger RNA Methylation Modeling Nature Neurons Population Pregnancy Protein Isoforms RNA Splicing Reaction Regulator Genes Rest Series Signal Transduction Societies Stimulus Stress Synapses Testing Translating Translations Work base behavioral pharmacology behavioral response combinatorial dentate gyrus digital early life adversity epigenome epigenomics mRNA Stability maladaptive behavior methylome novel postnatal recruit response

项目摘要

Abstract Gestational and early postnatal adverse experiences, because of their psychopathological consequences later in life, represent a significant burden for the affected individual and society. We identified an epigenetic motif at two thousand genomic regions in neurons that, via dynamic switching between methylated and unmethylated states, may control gene expression. The stochastic balance between the two states is altered by early life adversity in a subpopulation of neurons, resulting in abnormal neuronal functioning. We will test the hypothesis that permanent changes in the methylation state of key “switches” in the adversity-activated neurons represent the “cellular memory” of early life adverse experiences. Adversity-induced epigenetic changes increase the excitability of neurons, making them permanently eligible for recruitment during behavioral tasks. This in turn, increases the responsiveness of the circuit to novel/stressful stimuli, manifested as exaggerated fear reaction/anxiety later in life. Besides of the theoretical implications (coding environmental effects via binary epigenetic switches), our work has translational significance. The sensitivity of DNA methylation based switches (due to their metastability), compared to the rest of the epigenetically more stable genome, provides an opportunity for their selective manipulation to mitigate the adverse effects of ELA.

摘要怀孕和产后早期的不良经历，因为他们的精神病理后果，生命，对受影响的个人和社会构成重大负担。我们发现了一个表观遗传基序，神经元中的两千个基因组区域，通过甲基化和非甲基化之间的动态切换，可以控制基因的表达。这两种状态之间的随机平衡被早期生活所改变逆境中的神经元亚群，导致异常的神经元功能。我们将测试假设在逆境激活的细胞中关键“开关”甲基化状态的永久变化神经元代表了生命早期不良经历的“细胞记忆”。逆境诱导的表观遗传这些变化增加了神经元的兴奋性，使它们永久地符合招募条件，行为任务这反过来又增加了电路对新的/压力刺激的反应性，表现为在以后的生活中被夸大的恐惧反应/焦虑。除了理论上的影响（编码环境通过二元表观遗传开关的影响），我们的工作具有翻译意义。DNA的敏感性基于甲基化的开关（由于它们的亚稳定性），与表观遗传学上更稳定的其余开关相比，基因组，提供了一个机会，他们的选择性操纵，以减轻不利影响的ELA。