Activity-Dependent Cellular and Molecular Events Regulating Memory

活动依赖性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细胞核， 调节基因转录，在记忆中起着重要作用。了解这些过程将有利于 提高记忆力的方法。尽管如此，我们对调节突触的分子机制的理解- 到细胞核的信号传导仍然令人惊讶地不完全。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，它们的靶点 基因和它们所服务的神经回路知之甚少，无法用于治疗 应用.我们建议从一个新的角度来解决这一知识差距，其特点是行为范式 通过各种训练强度，激活或抑制基因转录的突变体，表观遗传分析和基因 筛选我们已经开发了一种小鼠训练模型，该模型使我们能够实现三个目标 这将大大促进对学习依赖的基础生物学的理解， 胞内信号传导 目的1将：a）测试学习依赖性突触到核转运的分子机制， 和B）解决转录的潜在需求， 使用抑制或激活转录的突变体的活性。完成拟议的工作将确定 在基因转录中介导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， 概述了各种记忆范式中的信号通路要求，这些范式依赖于 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 在应对各种强度的训练和各种转录突变体的同时， 假设表观遗传修饰反映了转录机制，其相应的 解剖电路我们将根据转录辅因子之间的结合进行详细的分析， 它们的翻译后修饰。我们将使用突变的转录抑制因子和激活因子来定义 它们在表观遗传修饰中的作用 目的3将表征诱导型转录辅激活因子的特异性基因靶点， 他们的具体推动者在不同强度的训练后，并分析这些变化是如何影响， 突变体转录抑制剂和激活剂。我们将详细研究这些新的基因靶点的作用， 记忆，特别是增强记忆力。 鉴于明确的证据表明，记忆强度是至关重要的健康维护，分子和神经， 学习依赖机制的电路解剖，将突触连接到细胞核和基因靶点 由这些过程引起的应该产生新的见解，指导改善记忆力的策略， 人体健康

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.