Activity-Dependent Cellular and Molecular Events Regulating Memory

调节记忆的活动依赖性细胞和分子事件

• 批准号: 9357732
• 负责人: GLEB P SHUMYATSKY
• 金额: $ 38.75万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357732
• 关键词: Address; Affect; Agonist; Anatomy; Behavioral Paradigm; Binding; Biology; CREB1 gene; Cell Nucleus; Clinical; Complex; Data; Dependence; Disease; Dissection; Dominant-Negative Mutation; Epigenetic Process; Event; Exhibits; FGF1 gene; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Transcription; Health; Hippocampus (Brain); Histone Acetylation; Human; Injection of therapeutic agent; Knowledge; Lead; Learning; Maintenance; Mediating; Memory; Memory Loss; Messenger RNA; Microtubules; Modeling; Modification; Molecular; Molecular Analysis; Molecular Probes; Mus; Neurobiology; Nuclear Translocation; Pathway interactions; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Protocols documentation; Psyche structure; RNA Interference; Regulation; Role; Shock; Signal Pathway; Signal Transduction; Synapses; System; Testing; Therapeutic; Training; Transcription Coactivator; Transcriptional Regulation; Water; Work; cofactor; combat; conditioned fear; dentate gyrus; experience; gain of function; healthy aging; histone modification; improved; inhibitor/antagonist; insight; long term memory; loss of function; mutant; neural circuit; neurocognitive disorder; novel; nucleocytoplasmic transport; object recognition; promoter; receptor; response; screening; social; strength training; transcription factor

Activity-dependent Cellular and Molecular Events Regulating Memory Project Summary Activity-regulated signaling pathways, by transmitting information regarding synaptic inputs to the nucleus and regulating gene transcription, play a vital role in memory. Knowing these processes would benefit the approaches to improve memory. Still, our understanding of the molecular mechanisms that mediate synapse- to-nucleus signaling remains surprisingly incomplete. In particular, details of how synaptically localized transcriptional modulators are transported to the nucleus, activate the transcriptional machinery, their target genes and the neural circuits they serve on are too poorly understood to be harnessed for therapeutic applications. We propose to address this knowledge gap from a new angle that features a behavioral paradigm with various training strength, mutants that activate or inhibit gene transcription, epigenetic analysis, and gene screening. We have developed a training model in the mouse that uniquely positions us to address three aims that together will markedly advance understanding of the fundamental biology of learning-dependent intracellular signaling. Aim 1 will: a) test the molecular mechanism of learning-dependent synapse-to-nucleus transport in the hippocampus following various strength of training, and b) address potential requirements for transcriptional activity using mutants that inhibit or activate transcription. Accomplishment of the proposed work will define the signaling pathways that mediate training responses in gene transcription, establishing the mechanistic framework for analysis of molecular and cellular changes following various strength of training, and contributing an overview of signaling pathway requirements in various memory paradigms that are dependent on the hippocampus. Aim 2 will define the impact of binding between transcriptional activators and changes in histone modifications in response to various strength of training and various transcriptional mutants while addressing the overall hypothesis that epigenetic modifications reflect the transcriptional machinery specific to their corresponding anatomic circuits. We will conduct a detailed analysis of binding between transcriptional cofactors depending on their posttranslational modifications. We will use mutant transcriptional inhibitors and activators to define their role in epigenetic modifications. Aim 3 will characterize specific gene targets of inducible transcriptional coactivators, epigenetic changes on their specific promoters following training with various strength and analyze how these changes affected by mutant transcriptional inhibitors and activators. We will examine in detail the role of these novel gene targets in memory and in particular in enhancement of memory strength. Given unequivocal evidence that memory strength is critical for healthy maintenance, molecular and neural circuitry dissection of learning-dependent mechanisms connecting synapses to the nucleus and gene targets induced by these processes should yield new insights that guide strategies for improving memory strength and human health.

依赖活性的细胞和分子事件调节记忆 项目摘要 通过将有关突触输入的信息传输到细胞核和 调节基因转录，在记忆中起着至关重要的作用。知道这些过程将使 改善记忆的方法。尽管如此，我们对介导突触的分子机制的理解 - 核心信号仍然令人惊讶地不完整。特别是，详细介绍了如何局限 转录调节剂被运输到核，激活转录机制，其目标 他们所使用的基因及其神经回路太鲜为人知，无法利用治疗 申请。我们建议从具有行为范式的新角度来解决这个知识差距 具有各种训练强度，激活或抑制基因转录，表观遗传分析和基因的突变体 筛选。我们已经在鼠标中开发了一种培训模型，该模型唯一地定位了我们解决三个目标 这将显着提高对学习依赖的基本生物学的理解 细胞内信号传导。 目标1将：a）测试在学习中学习依赖于学习的突触到核转运的分子机制 海马遵循各种训练力量，b）解决转录的潜在要求 使用抑制或激活转录的突变体的活性。提议的工作的完成将定义 信号通路介导基因转录中的训练反应，建立机理 分析各种训练强度后分子和细胞变化的框架，并有助于 在各种内存范式中的信号通路要求的概述，取决于 海马。 AIM 2将定义转录激活剂之间结合的影响和组蛋白修饰的变化 响应各种训练和各种转录突变体的力量，同时解决总体 表观遗传修饰反映了其相应的转录机械的假设 解剖电路。我们将对转录辅因子之间的结合进行详细的分析 在他们的翻译后修饰上。我们将使用突变的转录抑制剂和激活剂来定义 它们在表观遗传修饰中的作用。 AIM 3将表征可诱导转录共激活因子的特定基因靶标，表观遗传变化 他们的特定促进者在训练方面具有各种力量，并分析了这些变化如何影响 突变转录抑制剂和激活剂。我们将详细研究这些新基因靶标在 记忆，尤其是增强记忆力的力量。 鉴于明确的证据表明记忆力对于健康维持，分子和神经至关重要 将突触与细胞核和基因靶标连接的学习依赖性机制的电路解剖 这些过程引起的应产生新见解，以指导提高记忆力和 人类健康。