DNA Recombination/Repair Mechanisms in Memory

记忆中的 DNA 重组/修复机制

• 批准号: 7918871
• 负责人: SANDRA PENA DE ORTIZ
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918871
• 关键词: Address; Affect; Amygdaloid structure; Animals; Behavioral; Behavioral Paradigm; Binding; Biochemical; Bioinformatics; Biological Assay; Brain; Brain region; Complement; Control Groups; DNA; DNA Ligases; DNA Microarray Chip; DNA Restriction Enzymes; DNA Sequence Rearrangement; DNA ligase IV; Data; Down-Regulation; Enzymes; Epigenetic Process; Event; Flavoring; Gene Expression; Gene Expression Regulation; Gene Rearrangement; Gene Targeting; Genes; Genetic Recombination; Genetic Transcription; Genetic Variation; Genome; Genomics; Hippocampus (Brain); Information Storage; Infusion procedures; Injection of therapeutic agent; Laboratories; Learning; Ligase; Longevity; Lymphocyte; Mediating; Memory; Metabolism; Neurons; Nonhomologous DNA End Joining; Oligonucleotides; Peptide Signal Sequences; Play; Polymerase; Process; Proteins; RAG1 gene; RTH-1 Nuclease; Rattus; Reaction; Regulation; Reporting; Rodent; Role; Sampling; Site; Southern Blotting; Specificity; Structure; Surgical Flaps; Taste Perception; Techniques; Testing; Time; Training; V(D)J Recombination; Validation; Visceral; Work; cDNA Probes; caudate nucleus; conditioned fear; design; endonuclease; experience; gene discovery; inhibitor/antagonist; laser capture microdissection; long term memory; recombinational repair; research study; response

DESCRIPTION (provided by applicant): Does the brain possess a mechanism for generating genetic diversity that could support memory storage? This proposal aims to test the idea that DNA recombination/repair mechanisms play a specific part in memory storage in the brain. Gene rearrangements may be used in the brain as a mechanism to generate experience-dependent protein diversity that could contribute to the storage of information acquired throughout a lifetime. DNA recombination may serve as a mechanism upstream of transcription to regulate the expression and function of a specific set of genes important for long-lasting memory storage. Thus, epigenetic, transcriptional, and recombinational mechanisms of gene regulation in memory do not exclude one another, but most likely complement each other. At this point, the most intriguing questions related to the idea of gene recombination and memory formation in the brain are what are the factors that mediate such a process in neurons and, more importantly, what are the genes that are subjected to this kind of regulation in response to learning. In this proposal, we focus on consolidation mechanisms of conditioned taste aversion (CTA), a behavioral paradigm characterized by the ability of many animals to learn to avoid certain substances after experiencing an unpleasant or harmful somatic (visceral) reaction. Aim # 1 of this proposal addresses the role of amygdalar DNA recombination mechanisms in consolidation of CTA in rats by using or gene knockdown approaches, both targeting the function of putative recombination effector enzymes, Flap Structure-Specific Endonuclease-1 (FEN-1) and DNA ligase IV. AIM # 2 examines amygdalar genomic rearrangement of putative DNA recombination target genes, such as protocadherin p9. Particularly, experiments will determine if the protocadherin 09 gene undergoes CTArelated genomic rearrangement in amygdala neurons. Overall, these studies will establish that DNA recombination/repair processes are part of the initial mechanisms utilized by the brain for the long-lasting storage of information, characterize the function of specific factors involved in this processes, and help demonstrate that specific gene targets undergo genomic rearrangement during memory formation.

描述（由申请人提供）：大脑是否具有产生支持记忆存储的遗传多样性的机制？该提案旨在测试 DNA 重组/修复机制在大脑记忆存储中发挥特定作用的观点。基因重排可在大脑中用作产生依赖于经验的蛋白质多样性的机制，这有助于存储一生中获得的信息。 DNA重组可能作为转录上游的一种机制来调节对持久记忆存储很重要的一组特定基因的表达和功能。因此，记忆中基因调控的表观遗传、转录和重组机制并不相互排斥，而是很可能相互补充。在这一点上，与大脑中基因重组和记忆形成的想法相关的最有趣的问题是，在神经元中介导这一过程的因素是什么，更重要的是，哪些基因在学习反应中受到这种调节。在本提案中，我们重点关注条件性味觉厌恶（CTA）的巩固机制，这是一种行为范式，其特征是许多动物在经历不愉快或有害的躯体（内脏）反应后能够学会避免某些物质。该提案的目标#1通过使用或基因敲除方法解决了杏仁核 DNA 重组机制在大鼠 CTA 巩固中的作用，这两种方法都针对假定的重组效应酶、Flap 结构特异性核酸内切酶-1 (FEN-1) 和 DNA 连接酶 IV 的功能。 AIM # 2 检查假定的 DNA 重组目标基因（例如原钙粘蛋白 p9）的杏仁核基因组重排。特别是，实验将确定原钙粘蛋白 09 基因是否在杏仁核神经元中经历 CTA 相关的基因组重排。总体而言，这些研究将确定 DNA 重组/修复过程是大脑用于长期存储信息的初始机制的一部分，表征该过程中涉及的特定因素的功能，并有助于证明特定基因靶标在记忆形成过程中经历基因组重排。