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Exploring epigenetic regulation of memory extinction

探索记忆消退的表观遗传调控

基本信息

批准号：
9979028
负责人：
TIMOTHY JOSEPH JAROME
金额：
$ 41.91万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST 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：
2020-05-05 至 2023-05-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979028
关键词：
Adult Affect Anxiety Disorders Behavior Behavioral Behavioral Paradigm Binding Sites Bioinformatics Brain Brain region Cells Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Control Animal CpG dinucleotide Cues DNA Data Development Dorsal Enhancers Enzymes Epigenetic Process Equilibrium Event Exposure to Extinction (Psychology)Fright Gene Expression Genes Genetic Genetic Transcription Goals Grant Hippocampus (Brain)Impairment Knock-out Knockout Mice Lead Learning Medial Mediating Memory Mental Health Mental disorders Methylation Modification Molecular Mus Mutant Strains Mice NPAS4 gene Neurons Pharmacology Phenotype Population Post-Traumatic Stress Disorders Prefrontal Cortex Process Proteins Protocols documentation Quantitative Reverse Transcriptase PCR Reporting Research Personnel Role Site Synaptic plasticity System Technology Testing Therapeutic Time base bisulfite sequencing demethylation design epigenetic regulation experience fear memory genome-wide insight learning extinction memory consolidation memory process methylome mouse model new therapeutic target next generation sequencing novel postnatal postnatal development promoter public health relevance pyrosequencing recruit relating to nervous system response success therapeutic effectiveness tool transcription factor transcriptome sequencing treatment strategy whole genome

项目摘要

TITLE: EXPLORING EPIGENETIC REGULATION OF MEMORY EXTINCTION PROJECT SUMMARY The broad goal of this proposal is to understand how fear memories are extinguished in the brain. Extinction learning, in which continued exposure to cues associated with an aversive event result in reduced responding to these cues, has been proposed as a way to modify or erase fear memories. However, the molecular mechanisms that control the extinction process remain poorly defined, limiting the therapeutic potential of this behavioral process. Recent evidence suggests that extinction learning requires the functions of neuronal activity induced transcription factors including EGR1 and DNA demethylation enzyme TET1 in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DHPC), though it is unknown how these two mechanisms regulate the extinction process. Our recent study indicated that EGR1 recruits TET1 to remove methylation marks on brain DNA during early postnatal development, though whether such a relationship exists during learning-dependent synaptic plasticity in the adult brain remains equivocal. The purpose of this grant is to explore how these two proteins interact to control memory extinction processes with two specific aims. In Aim 1, the investigators will determine the epigenetic roles of EGR1 and TET1 in the mPFC and DHPC during the extinction of fear memory using a combination of behavioral paradigms in genetic knockout mouse models with whole-genome next generation sequencing approaches. In Aim 2, using targeted CRISPR-dCas9 manipulations in the mPFC and DHPC, the investigators will determine the epigenetic role of EGR1-dependent recruitment of TET1 to the memory permissive gene Npas4 during memory extinction. Collectively, the success of this project will provide novel insights into our understanding of the epigenetic role of Egr1/Tet1 and Npas4 genes during extinction consolidation and significantly broaden our understanding of the mechanisms underlying memory extinction, which could potentially lead to new treatment therapeutic strategies for the treatment fear memories associated with a variety of psychiatric disorders.

标题：探索记忆消退的表生调节项目摘要这项计划的主要目标是了解恐惧记忆是如何在大脑中消失的。灭绝学习，即持续暴露于与厌恶事件相关的线索，导致对这些线索的反应减少，已被提出作为修改或消除恐惧记忆的一种方法。然而，控制灭绝过程的分子机制仍然不清楚，限制了这种行为过程的治疗潜力。最近的证据表明，消退学习需要内侧前额叶皮层（mPFC）和背海马（DHPC）的神经元活动诱导转录因子EGR 1和DNA去甲基化酶TET 1的作用，但这两种机制如何调控消退过程尚不清楚。我们最近的研究表明，EGR 1在出生后早期发育过程中招募TET 1来去除大脑DNA上的甲基化标记，尽管这种关系是否存在于成人大脑中学习依赖的突触可塑性中仍然不明确。该资助的目的是探索这两种蛋白质如何相互作用以控制记忆消退过程，有两个具体目标。在目标1中，研究人员将确定EGR 1和TET 1在恐惧记忆消退期间在mPFC和DHPC中的表观遗传作用，使用遗传敲除小鼠模型中的行为范式与全基因组下一代测序方法的组合。在目标2中，在mPFC和DHPC中使用靶向CRISPR-dCas 9操作，研究人员将确定在记忆消退期间TET 1依赖于EGR 1的募集到记忆允许基因Npas 4的表观遗传作用。总的来说，该项目的成功将为我们理解Egr 1/Tet 1和Npas 4基因在消退巩固过程中的表观遗传作用提供新的见解，并显着拓宽我们对记忆消退机制的理解，这可能会导致新的治疗策略，用于治疗与各种精神疾病相关的恐惧记忆。