Brain Recombination Processes in Learning and Memory

学习和记忆中的大脑重组过程

• 批准号: 6766392
• 负责人: SANDRA PENA DE ORTIZ
• 金额: $ 22.56万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766392
• 关键词: DNA repair; amygdala; behavior test; behavioral /social science research tag; brain; cytosine analog; gene expression; genetic recombination; genetic regulation; hippocampus; inhibitor /antagonist; laboratory rat; learning; memory; microarray technology; molecular psychobiology; neural plasticity; neurogenetics; neuropsychology; neuroregulation

The overall goal of this proposal is to assess the importance of DNA recombination and DNA repair processes in brain plasticity and complex behaviors. Long-term memory is known to require the production of new proteins in the brain via the regulation of gene transcription and translation mechanisms. Additionally, several reports have postulated the idea that regulation of gene expression and function by DNA recombination mechanisms may also be involved in learning and memory processes. DNA repair mechanisms are tightly associated to recombination processes, such as those utilized in the immune system, which involve DNA cutting, repair, and rejoining (or ligation) mechanisms. Our preliminary studies with a drug that blocks the repair and rejoining of DNA, known as ara-CTP, strongly implicate these processes in the formation of long-term memory in the brain. The experiments proposed here will test specific hypotheses regarding the functional significance of DNA recombination and repair mechanisms in learning and memory processes of the brain. In Specific Aim 1 we hypothesize that ara-CTP impairs memory formation in hippocampal and amygdala dependent behavioral tasks. Just prior to training, ara-CTP, its precursor agent ara-C, or control solution, are injected directly into the brain of rats in order to reach important learning and memory structures. Learning and long-term memory is assessed in rats. Biochemical processes subserving the effects of ara-CTP will also be studied. In Specific Aim 2 we explore the hypothesis that blockade of memory by ara-C is due to an impairment in the regulation of genes important for learning and memory that might be directly or indirectly regulated by DNA recombination in the brain. For these studies we combine the behavioral experiments with gene expression profiling with microarrays. Results from this work will provide fundamental knowledge concerning how the brain stores information, which may help understand the pathophysiology of neurodegenerative and psychiatric diseases, such as Alzheimer's disease and post-traumatic stress syndrome.

该提案的总体目标是评估DNA重组和DNA修复过程在大脑可塑性和复杂行为中的重要性。已知长期记忆需要通过调节基因转录和翻译机制来产生大脑中的新蛋白质。此外，一些报告假定了以下想法：通过DNA重组机制调节基因表达和功能也可能参与学习和记忆过程。 DNA修复机制与重组过程紧密相关，例如免疫系统中使用的，涉及DNA切割，修复和重新加入（或连接）机制。我们使用一种阻止DNA的修复和重新结合的药物的初步研究（称为ARA-CTP）强烈暗示了这些过程在大脑中长期记忆的形成中。这里提出的实验将检验有关DNA重组和修复机制在大脑学习和记忆过程中的功能意义的特定假设。在特定目标1中，我们假设ARA-CTP会损害海马和杏仁核依赖性行为任务中的记忆形成。在训练之前，将ARA-CTP（其前体剂ARA-C或对照溶液）直接注入大鼠大脑中，以达到重要的学习和记忆结构。在大鼠中评估学习和长期记忆。还将研究为ARA-CTP效应的生化过程。在特定目标2中，我们探讨了以下假设：ARA-C对记忆的阻滞是由于调节对学习和记忆重要的基因的损害，这可能直接或间接地受到大脑中DNA重组的调节。对于这些研究，我们将行为实验与基因表达分析与微阵列结合在一起。这项工作的结果将提供有关大脑如何存储信息的基本知识，这可能有助于了解神经退行性和精神病的病理生理，例如阿尔茨海默氏病和创伤后应激综合征。