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: 9239107
• 负责人: GLEB P SHUMYATSKY
• 金额: $ 38.31万
• 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/9239107
• 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; Time; 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

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.

活性依赖的细胞和分子事件调节记忆 项目摘要 活动调节的信号通路，通过将有关突触输入的信息传递到核和 调控基因转录，在记忆中起着至关重要的作用。了解这些过程将使 改善记忆力的方法。尽管如此，我们对调节突触的分子机制的理解- 令人惊讶的是，到核的信号仍然不完整。特别是，如何在突触上本地化的细节 转录调节剂被运送到细胞核，激活转录机器，它们的目标 人们对它们所服务的基因和神经回路知之甚少，无法利用它们进行治疗。 申请。我们建议从一个以行为范式为特征的新角度来解决这个知识鸿沟 有不同的训练强度，激活或抑制基因转录的突变体，表观遗传分析，和基因 放映。我们已经在鼠标中开发了一个培训模型，该模型将我们独特地定位为解决三个目标 这些都将极大地促进对依赖学习的基本生物学的理解 细胞内信号。 目标1将：a)测试学习依赖型突触到核转运的分子机制 不同强度的训练后的海马体，以及b)满足转录的潜在要求 使用抑制或激活转录的突变体的活性。拟议工作的完成将确定 介导基因转录训练反应的信号通路，建立了 分析不同强度训练后分子和细胞变化的框架 不同记忆范例中信号通路要求的概述 海马体。 目标2将定义转录激活物和组蛋白修饰变化之间的结合的影响 在应对各种强度的训练和各种转录突变体的同时解决总体 表观遗传修饰反映其相应的转录机制的假说 解剖回路。我们将对转录辅助因子之间的结合进行详细的分析 关于他们的翻译后修饰。我们将使用突变的转录抑制物和激活剂来定义 它们在表观遗传修饰中的作用。 目标3将表征可诱导转录辅活化子的特定基因靶点，表观遗传学变化 他们的特定推动者以不同的力量进行训练，并分析这些变化是如何影响的 突变的转录抑制物和激活剂。我们将详细研究这些新的基因靶点在 尤其是在增强记忆力方面。 给出明确的证据表明记忆强度对健康维护至关重要，分子和神经 连接突触与核和基因靶点的学习依赖机制的电路剖析 由这些过程引起的应该产生新的见解，指导改善记忆强度和 人类健康。