Distributed synaptic plasticity in fear conditioning

描述(申请人提供)：正常长期记忆(LTM)的形成需要改变神经元中的基因表达和蛋白质合成。这些变化对突触功能的改变是至关重要的，并在训练后经历一个依赖于时间的巩固过程。最近的证据有力地表明，当一个稳定的LTM后来被回忆起来并进入活跃状态时，这种记忆的神经底物需要一段时间的“再巩固”，这取决于最初记忆形成中涉及的一些相同的细胞过程。本项目探讨了两个细胞过程在记忆的形成和稳定中的重要性：由哺乳动物雷帕霉素靶标(MTOR)途径控制的蛋白质翻译和通过泛素-蛋白小体系统控制的蛋白质降解。我们在啮齿动物中使用巴甫洛夫恐惧条件反射作为一个已建立的模型系统，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。利用定量蛋白质分析，我们将测量LTM形成和提取过程中多个行为相关脑区mTOR和相关分子靶点的活性，并检验关于这一翻译控制途径在学习中的作用的一系列具体假说。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合成与其靶向降解之间的相互作用。这些结果应该会为记忆的神经生物学和作为学习基础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症的重要新靶点。 公共卫生相关性：这个项目解决了关于长期记忆的形成和存储的基本神经生物学问题。这里要解决的细胞机制在整个动物研究中很少受到关注，可能形成重要的新疗法的基础，用于治疗记忆障碍、年龄相关性记忆损伤以及影响突触可塑性和认知功能的疾病。更好地了解恐惧记忆是如何储存的，也将改进对创伤后应激障碍和恐惧症等焦虑症的治疗方法。

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.