Brain Recombination Processes in Learning and Memory

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。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紧密相关，例如免疫系统中使用的重组过程，其涉及DNA切割，修复和重新连接（或连接）机制。我们对一种阻止DNA修复和重新连接的药物（称为ara-CTP）的初步研究强烈暗示这些过程与大脑长期记忆的形成有关。本文提出的实验将检验关于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特定假设。在具体目标1中，我们假设ara-CTP损害海马和杏仁核依赖性行为任务中的记忆形成。就在训练之前，将ara-CTP、其前体药物ara-C或对照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。在大鼠中评估学习和长期记忆。生化过程subserving ara-CTP的影响也将进行研究。在具体目标2中，我们探讨了一个假设，即阿糖胞苷对记忆的阻断是由于对学习和记忆重要的基因的调节受损，这些基因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，我们联合收割机了行为实验与基因表达谱与微阵列。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.