DNA Methylation in Memory Formation

记忆形成中的 DNA 甲基化

基本信息

批准号：
8645746
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/8645746
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）：在中枢神经系统中，长期持久的，依赖经验的功能变化的生化信号传导机制仍然神秘。尽管在这种情况下已经确定了几种吸引人的潜在机制，包括CAMKII自磷酸化，PKM-ZETA产生和AMPA受体自动调节，但到目前为止，转录调节机制几乎没有受到关注。该项目将调查以下假设：有效的转录调节机制改变了DNA甲基化，可以作为海马和皮层中的持久信号，以持续持续改变基因表达，细胞性质和电路功能。我们将通过执行两个特定目标来测试该概念的重要预测来测试这个想法。在特定目标1中，我们将检验以下假设：DNA甲基化控制体内的ARC基因表达和海马位置场稳定性。先前的结果表明，多种DNMT抑制剂的应用以及DNMT 1和3A基因的有条件缺失导致海马LTP的缺陷以及海马依赖性长期上下文学习的缺陷。但是，尚不清楚海马可塑性中的缺陷如何导致行为动物的记忆缺陷。在此目标中，我们将使用免疫组织化学和激光捕获夹夹来研究特定海马神经元亚型中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甲基化的能力来控制海马放置细胞发射模式的形成和稳定。在特定的目标2中，我们将测试以下假设：DNA甲基化控制远程扣带回皮层中的遥控器的存储。来自几个实验室的最新工作表明，远程，即非常持久的上下文记忆是合并并存储在前扣带回皮层中的。考虑到DNA甲基化的持久变化可能有助于皮质中遥远的内存稳定，这一点很有趣，在此目的中，我们将测试远程记忆形成是否与前扣带回皮层中的DNA甲基化改变有关，以及破坏皮层DNA甲基化是否导致远程存储器的远程记忆型。