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

基本信息

批准号：
9749990
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
项目类别：
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/9749990
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 Injections 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 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 water maze

项目摘要

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.

调节记忆的活动依赖性细胞和分子事件项目概要活动调节信号通路，通过将有关突触输入的信息传递到细胞核和调节基因转录，在记忆中发挥至关重要的作用。了解这些过程将有利于提高记忆力的方法。尽管如此，我们对介导突触的分子机制的理解 - 令人惊讶的是，到核的信号传导仍然不完整。特别是突触定位的细节转录调节剂被转运到细胞核，激活转录机制，其目标对基因及其所服务的神经回路知之甚少，无法用于治疗应用程序。我们建议从一个以行为范式为特征的新角度来解决这一知识差距具有各种训练强度、激活或抑制基因转录的突变体、表观遗传分析和基因筛选。我们开发了一种小鼠训练模型，使我们能够独特地实现三个目标这些共同将显着促进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) 测试学习依赖性突触到细胞核运输的分子机制 b) 处理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，建立机制分析不同强度训练后分子和细胞变化的框架，并做出贡献各种记忆范例中依赖于的信号通路要求的概述海马体。目标 2 将定义转录激活因子之间的结合和组蛋白修饰变化的影响响应各种强度的训练和各种转录突变体，同时解决总体问题假设表观遗传修饰反映了其相应的特定转录机制解剖电路。我们将对转录辅助因子之间的结合进行详细分析，具体取决于关于它们的翻译后修饰。我们将使用突变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。目标 3 将表征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具体推动者经过不同强度的训练，并分析这些变化是如何影响的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力，特别是增强记忆力。鉴于明确的证据表明记忆强度对于维持健康至关重要，分子和神经连接突触与细胞核和基因靶标的学习依赖机制的电路剖析这些过程引起的应该会产生新的见解，指导提高记忆强度和人类健康。