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DNA Methylation in Memory Formation

记忆形成中的 DNA 甲基化

基本信息

批准号：
8272530
负责人：
John David Sweatt
金额：
$ 36.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-03 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8272530
关键词：
AMPA Receptors Acute Adult Affect Alleles Animals Anterior Area Attention Behavior Behavior Therapy Behavioral Biochemical Brain region Brain-Derived Neurotrophic Factor Calcineurin Cells Chemicals Chromatin Chromatin Structure CpG Islands DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Process Development Dissection Functional disorder Gene Expression Genes Genetic Transcription Goals Hippocampus (Brain)Histones Immediate-Early Genes Immunohistochemistry Infusion procedures Laboratories Lasers Lead Learning Memory Memory impairment Methods Methylation Molecular Nervous system structure Neurons Neurosciences Pattern Pharmaceutical Preparations Play Post-Translational Protein Processing Prefrontal Cortex Preparation Process Production Property Regulation Research Role Signal Transduction Slice Synaptic plasticity System Testing Thinking Transcriptional Regulation Work base behavior change calmodulin-dependent protein kinase II cingulate cortex drug development experience fascinate histone modification in vivo inhibitor/antagonist long term memory memory encoding neurobehavioral novel synaptic function

项目摘要

DESCRIPTION (provided by applicant): The biochemical signaling mechanisms underlying the sustenance and perpetuation of long-lasting, experience-dependent functional change in the CNS remain mysterious. Although several appealing potential mechanisms in this context have been identified, including CaMKII autophosphorylation, PKM-zeta production, and AMPA receptor auto-regulation, transcription-regulating mechanisms have received little attention to date. This Project will investigate the hypothesis that a potent transcription-regulating mechanism, altered DNA methylation, might serve as a lasting signal in the hippocampus and cortex to subserve persisting alterations in gene expression, cellular properties, and circuit function. We will test this idea by executing two Specific Aims that test important predictions of the concept. In Specific Aim 1 we will test the hypothesis that DNA methylation controls arc gene expression and hippocampal place field stability in vivo. Prior results have demonstrated that application of a variety of DNMT inhibitors, and conditional deletion of the DNMT 1 and 3A genes, leads to deficits in hippocampal LTP and deficits in hippocampus-dependent long-term contextual learning. However, it is not known how the deficits in hippocampal plasticity lead to memory deficits in the behaving animal. In this Aim we will investigate the role of DNA methylation at the cellular and systems level by investigating experience-driven long-term and short-term changes in DNA methylation in specific hippocampal neuronal subtypes using both immunohistochemistry and laser-capture dissection. In additional studies we will investigate the capacity of DNA methylation to regulate hippocampal arc gene expression, and by investigating the capacity of DNA methylation to control the formation and stabilization of hippocampal place cell firing patterns. In Specific Aim 2 we will test the hypothesis that DNA methylation controls the storage of remote memory in the anterior cingulate cortex. Recent work from several laboratories has demonstrated that remote, i.e. very long-lasting, contextual memories are consolidated and stored in the anterior cingulate cortex. It is intriguing to consider that lasting changes in DNA methylation might contribute to stabilization of remote memory in the cortex, and in this Aim we will test whether remote memory formation is associated with altered DNA methylation in the anterior cingulate cortex, and whether disrupting cortical DNA methylation leads to remote memory destabilization.

描述（由申请人提供）：中枢神经系统中持久的、依赖于经验的功能变化的维持和延续的生化信号传导机制仍然是神秘的。尽管在这方面已经确定了一些有吸引力的潜在机制，包括 CaMKII 自磷酸化、PKM-zeta 产生和 AMPA 受体自动调节，但转录调节机制迄今为止很少受到关注。该项目将研究这样的假设：一种有效的转录调节机制，即改变的 DNA 甲基化，可能作为海马体和皮质中的持久信号，以促进基因表达、细胞特性和回路功能的持续改变。我们将通过执行两个特定目标来测试这个想法，以测试该概念的重要预测。在具体目标 1 中，我们将检验 DNA 甲基化在体内控制 arc 基因表达和海马位置场稳定性的假设。先前的结果表明，应用多种 DNMT 抑制剂以及有条件删除 DNMT 1 和 3A 基因，会导致海马 LTP 缺陷和海马依赖性长期情境学习缺陷。然而，目前尚不清楚海马可塑性缺陷如何导致行为动物的记忆缺陷。在这个目标中，我们将使用免疫组织化学和激光捕获解剖来研究特定海马神经元亚型中 DNA 甲基化的经验驱动的长期和短期变化，从而研究 DNA 甲基化在细胞和系统水平上的作用。在其他研究中，我们将研究 DNA 甲基化调节海马弧基因表达的能力，并通过研究 DNA 甲基化控制海马位置细胞放电模式的形成和稳定的能力。在具体目标 2 中，我们将检验 DNA 甲基化控制前扣带皮层远程记忆存储的假设。几个实验室最近的工作表明，遥远的（即非常持久的）情境记忆被巩固并存储在前扣带皮层中。有趣的是，DNA 甲基化的持久变化可能有助于皮质中远程记忆的稳定，在这个目标中，我们将测试远程记忆的形成是否与前扣带皮层 DNA 甲基化的改变有关，以及破坏皮质 DNA 甲基化是否会导致远程记忆不稳定。