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。这些变化对于突触功能的改变至关重要，并且在训练后通过时间依赖性巩固过程进行。最近的证据有力地表明，当一个稳定的LTM后来被召回并进入活跃状态时，这种记忆的神经基质需要一段时间的“重新巩固”，这取决于最初记忆形成中所涉及的一些相同的细胞过程。 该项目探讨了两个细胞过程在记忆形成和稳定性中的重要性：由哺乳动物雷帕霉素靶点（mTOR）途径控制的蛋白质翻译，以及通过遍在蛋白-蛋白体系统的蛋白质降解。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，其中几个大脑结构的记忆形成和存储的关键已被确定。使用定量蛋白质测定，我们将测量mTOR和相关分子靶点在多个行为相关的大脑部位的活动，在形成和检索的LTM和测试一系列特定的假设，这个翻译控制途径在学习中的作用。 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。 这些结果将为记忆的神经生物学和学习的分子基础提供重要的新见解。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。 公共卫生相关性：这个项目解决了关于长期记忆的形成和储存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，可能会成为记忆障碍，年龄相关记忆障碍和影响突触可塑性和认知功能的疾病的重要新治疗方法的基础。更好地了解恐惧记忆是如何储存的也将改善治疗焦虑症的方法，如创伤后应激障碍和恐惧症。

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.