Distributed synaptic plasticity in fear conditioning

描述（由申请人提供）：正常长期记忆（LTM）的形成需要神经元中基因表达和蛋白质合成的改变。这些变化对突触功能的改变至关重要，并在训练后经历一个时间依赖性的巩固过程。最近的证据有力地表明，当一个稳定的LTM后来被回忆并进入活跃状态时，这种记忆的神经基质需要一段时间的“再巩固”，这取决于一些与初始记忆形成有关的细胞过程。该项目解决了两个细胞过程在记忆形成和稳定中的重要性：由哺乳动物雷帕霉素靶蛋白（mTOR）途径控制的蛋白质翻译，以及通过泛素-蛋白体系统控制的蛋白质降解。我们在啮齿类动物中使用巴甫洛夫恐惧条件反射作为一个建立的模型系统，在这个模型系统中，已经确定了几个对记忆形成和存储至关重要的大脑结构。通过定量蛋白分析，我们将测量在LTM形成和恢复过程中多个与行为相关的大脑部位的mTOR和相关分子靶点的活性，并测试一系列关于这一翻译控制途径在学习中的作用的具体假设。我们还将评估蛋白质降解在记忆形成和稳定性中的重要性，并开始分析新突触蛋白的活性依赖性合成与其靶向降解之间的相互作用。这些结果应该为记忆的神经生物学和学习背后的分子事件提供重要的新见解。这些发现可能有助于确定治疗记忆和焦虑障碍的重要新治疗靶点。

DESCRIPTION (provided by applicant): The formation of normal long-term memory (LTM) requires alterations in gene expression and protein synthesis in neurons. These changes are critical for modifications in synaptic function and proceed through a time dependent consolidation process after training. Recent evidence strongly suggests that when a stable LTM is later recalled and moves into an active state, the neural substrate for this memory requires a period of "reconsolidation" that depends on some of the same cellular processes involved in initial memory formation. This project addresses the importance of two cellular processes in the formation and stability of memory: protein translation controlled by the mammalian target of rapamycin (mTOR) pathway, and protein degradation through the ubiquitin-proteosome system. We use Pavlovian fear conditioning in rodents as an established model system in which several brain structures critical for memory formation and storage have been identified. Using quantitative protein assays we will measure the activity of mTOR and related molecular targets at multiple behaviorally relevant brain sites during the formation and retrieval of LTM and test a series of specific hypotheses about the role of this translational control pathway in learning. We will also assess the importance of protein degradation in the formation and stability of memory and begin to analyze the interactions between activity dependent synthesis of new synaptic protein and its targeted degradation. The results should provide important new insights regarding the neurobiology of memory and the molecular events that underlie learning. These finding may help to identify important new therapeutic targets in the treatment of memory and anxiety disorders. PUBLIC HEALTH RELEVANCE: This project addresses basic neurobiological questions about the formation and storage of long-term memory. The cellular mechanisms to be addressed here are and have little attention in whole animal studies and may form the basis for important new treatments for memory disorders, age related memory impairment, and diseases that affect synaptic plasticity and cognitive function. A better understanding of how fear memory is stored will also improve therapeutic approaches to anxiety disorders such as PTSD and phobias.