The cellular memory of early life adversity

早年逆境的细胞记忆

基本信息

批准号：
10556395
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/10556395
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 DNMT3a Development Early identification Eligibility Determination Epigenetic Process Equilibrium Exhibits Exons Frequencies Fright Gene Expression Genes Genetic Transcription Genome Genome Stability Genomic Segment Heterogeneity Hippocampus Individual Ion Channel 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 Stress and Coping Synapses Testing Translating Translations Work behavioral response combinatorial dentate gyrus digital early life adversity epigenome epigenomics mRNA Stability maladaptive behavior methylome neuronal excitability novel pharmacologic 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.

抽象的妊娠期和产后早期的不良经历，因为它们会在以后产生心理病理后果生命，对受影响的个人和社会来说是一个重大负担。我们在以下位置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状态，可能控制基因表达，这两种状态之间的随机平衡会因早期生命而改变。我们将测试神经元亚群的逆境，导致神经元功能异常。假设逆境激活中关键“开关”的甲基化状态发生永久性变化神经元代表了早期生活中逆境引起的表观遗传的“细胞记忆”。变化增加了神经元的兴奋性，使它们在招募过程中永久符合招募条件这反过来又增加了神经回路对新奇/压力刺激的反应能力。除了理论上的影响（编码环境）之外，还会出现夸大的恐惧反应/焦虑。通过二元表观遗传开关的影响），我们的工作具有转化意义。基于甲基化的开关（由于其亚稳定性），与其他表观遗传上更稳定的开关相比基因组，为他们的选择性操作提供了机会，以减轻 ELA 的不利影响。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Serotonin-1A receptor, a psychiatric disease risk factor, influences offspring immunity via sex-dependent genetic nurture.

DOI：
10.1016/j.isci.2022.105595
发表时间：
2022-12-22
期刊：
ISCIENCE
影响因子：
5.8
作者：
Chen, Rosa J.;Nabila, Anika;Phalke, Swati;Castro, Danny Flores;Toth, Judit Gal;Bergin, Paul;Bastiaans, Jeroen;Stuhlmann, Heidi;Pernis, Alessandra B.;Toth, Miklos
通讯作者：
Toth, Miklos