Brain Recombination Processes in Learning and Memory

本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。众所周知，长期记忆需要通过基因转录和翻译机制的调节在大脑中产生新的蛋白质。此外，一些报告已经假设，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密切相关，例如免疫系统中使用的重组过程涉及DNA切割、修复和重新连接（或结扎）机制。我们初步研究了一种阻断DNA修复和重新连接的药物，称为ara-CTP，它强烈暗示了这些过程与大脑长期记忆的形成有关。这里提出的实验将测试关于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具体假设。在具体目标1中，我们假设ara-CTP损害海马和杏仁核依赖的行为任务的记忆形成。在训练之前，将ara-CTP及其前体剂ara-C或控制溶液直接注射到大鼠的大脑中，以达到重要的学习和记忆结构。对大鼠的学习和长期记忆进行了评估。还将研究为ara-CTP作用服务的生化过程。在Specific Aim 2中，我们探讨了ara-C对记忆的阻断是由于对学习和记忆重要基因的调节受损，这可能是由大脑中的DNA重组直接或间接调节的。在这些研究中，我们将行为实验与基因表达谱与微阵列相结合。这项工作的结果将提供关于大脑如何存储信息的基础知识，这可能有助于理解神经退行性疾病和精神疾病的病理生理学，如阿尔茨海默病和创伤后应激综合征。

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.