DNA Recombination/Repair Mechanisms in Memory

描述（由申请人提供）：大脑是否具有产生遗传多样性的机制，可以支持记忆存储？这项提议旨在测试DNA重组/修复机制在大脑记忆存储中发挥特定作用的想法。基因重排可以在大脑中作为一种机制来产生经验依赖性蛋白质多样性，这可能有助于一生中获得的信息的存储。DNA重组可以作为转录上游的一种机制，调节一组对持久记忆储存很重要的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，而很可能是相互补充的。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，在神经元中介导这种过程的因素是什么，更重要的是，在学习过程中受到这种调节的基因是什么。在这个建议中，我们专注于巩固机制的条件性味觉厌恶（CTA），一种行为范式，其特征在于许多动物的能力，以避免某些物质后，经历了一个不愉快的或有害的躯体（内脏）反应。该提案的目的#1通过使用或基因敲低方法解决大鼠中杏仁核DNA重组机制在CTA巩固中的作用，这两种方法都靶向假定的重组效应酶Flap结构特异性内切酶-1（FEN-1）和DNA连接酶IV的功能。目的#2检查杏仁核基因组重排推定的DNA重组靶基因，如原钙粘蛋白p9。特别地，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。总的来说，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，表征参与此过程的特定因素的功能，并有助于证明特定基因靶点在记忆形成期间经历基因组重排。

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.