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Distributed synaptic plasticity in fear conditioning

恐惧调节中的分布式突触可塑性

基本信息

批准号：
8392301
负责人：
FRED J HELMSTETTER
金额：
$ 34.62万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-20 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8392301
关键词：
Address Affect Age-Related Memory Disorders Amygdaloid structure Animals Anxiety Disorders Area Attention Biological Assay Biological Models Brain Cell physiology Data Disease Event Fright Funding Gene Expression Gene Proteins Goals Hippocampus (Brain)Learning MAP Kinase Gene Measures Mediating Memory Memory Disorders Memory impairment Modification Molecular Molecular Target Neurobiology Neurons Organism Pathway interactions Pharmaceutical Preparations Phobic anxiety disorder Phosphorylation Phosphotransferases Post-Traumatic Stress Disorders Process Protein Biosynthesis Protein Synthesis Inhibitors Proteins Protocols documentation Publishing Regulation Reporting Retrieval Rodent Rodent Model Role Series Signal Pathway Sirolimus Site Stimulus Structure Synapses Synaptic plasticity System Testing Therapeutic Time Training Transcript Translational Regulation Translations Ubiquitin Work base cognitive function conditioned fear experience improved inhibitor/antagonist insight long term memory mTOR protein memory recall memory retrieval multicatalytic endopeptidase complex neural circuit new therapeutic target prevent protein degradation relating to nervous system research study response synaptic function

项目摘要

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.

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。