Modeling the Molecular Networks that Underlie the Formation and Consolidation of Memory

模拟记忆形成和巩固的分子网络

• 批准号: 10083237
• 负责人: John H Byrne
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083237
• 关键词: ATF2 gene; Affect; Animal Model; Aplysia; Biological; Brain-Derived Neurotrophic Factor; CCAAT-Enhancer-Binding Proteins; CREB1 gene; CREBBP gene; Cell model; Chemosensitization; Cluster Analysis; Coffin-Lowry syndrome; Cognition Disorders; Computer Models; Cyclic AMP-Dependent Protein Kinases; Data; Development; Feedback; Gene Mutation; Genetic Transcription; Grant; Growth Factor; Hippocampus (Brain); Histone Acetylation; Impaired cognition; Impairment; Intervention; Intuition; Laboratories; Lead; Learning; Lesion; Long-Term Potentiation; MAP Kinase Gene; Maps; Memory; Memory impairment; Methodology; Methods; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Mutation; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phosphorylation; Phosphotransferases; Play; Process; Protocols documentation; Regulation; Rett Syndrome; Ribosomal Protein S6 Kinase; Ribosomes; Role; Rubinstein-Taybi Syndrome; Serotonin; Signal Pathway; Stimulus; Synapses; Synaptic plasticity; System; Testing; Training; Transcriptional Regulation; Transforming Growth Factor beta; United States National Institutes of Health; Up-Regulation; Wood material; conditioning; design; enhancing factor; extracellular; innovation; insight; long term memory; memory consolidation; molecular modeling; molecular site; mouse model; novel; p38 Mitogen Activated Protein Kinase; predictive modeling; research study; simulation; transcription factor; treatment strategy

Molecular processes that underlie the induction and consolidation of long-term memory (LTM) are the subjects of intensive research, and studies are providing a wealth of empirical data that relate aspects of memory to specific intracellular signaling pathways. For example, empirical studies are elucidating the roles played by extracellular factors (e.g. growth factors), kinase activity, and transcriptional regulation in induction and consolidation of memory. Due in part to the complexity and nonlinear features of these molecular pathways, it is difficult to develop an intuitive understanding of the ways in which these pathways respond to stimulus protocols or pharmacological manipulations or are affected by single-site molecular lesions. To provide a better understanding of the processes underlying LTM, the present proposal will develop quantitative models of the molecular pathways that underlie two well-characterized models of LTM: i) long-term synaptic facilitation (LTF) and ii) long-term synaptic potentiation (LTP). Parameters will be constrained by empirical data. Parameter sensitivity analysis and a novel cluster analysis will assess model robustness. Aim 1 will extend our model for LTF, which describes the regulation of transcription by PKA and ERK via phosphorylation of the transcription factors CREB1 and CREB2. The extended model will include components of additional intra- and extracellular feedback loops (e.g., TGFβ, and ApNT), an additional transcription factor (C/EBP), ribosomal s6 kinase (RSK) and p38 MAP kinase. In Aim 2, this model will be used to predict stimulus protocols, as well as pharmacological treatments, that enhance LTF and that rescue impaired LTF. Aim 3 will extend our current model of LTP, which describes roles of several kinase pathways (e.g., MAPK, PKA, PKC, and CAMKII) and histone acetylation. The model will incorporate a recently delineated BDNF positive-feedback loop, which leads to activation of ERK, phosphorylation of CREB1, and induction of transcription necessary for the consolidation of LTP. We will simulate stimulus protocols and drug effects to predict treatments that could rescue impaired memory mechanisms in Rett syndrome, which is caused by mutations that alter the activity of the transcription factor MeCP2, and that can rescue impaired mechanisms in Rubinstein-Taybi syndrome, which is caused by mutations in CREB binding protein. This proposed approach of using models to predict novel learning paradigms and/or drug treatments that restore normal plasticity, is an innovative methodology that could ultimately lead to the development of new strategies for the treatment of cognitive disorders.

长期记忆（LTM）诱导和巩固的分子过程是主题 深入的研究，并且研究提供了大量的经验数据，将记忆的各个方面与 特定的细胞内信号传导途径。例如，实证研究正在阐明 细胞外因子（例如生长因子）、激酶活性以及诱导和转录调控 巩固记忆。部分由于这些分子途径的复杂性和非线性特征， 很难对这些途径对刺激的反应方式产生直观的理解 方案或药理学操作或受到单位点分子损伤的影响。为了提供更好的 为了理解 LTM 的基本过程，本提案将开发 LTM 的定量模型 两种充分表征的 LTM 模型的分子途径： i) 长期突触促进 (LTF) ii) 长时程突触增强（LTP）。参数将受到经验数据的约束。范围 敏感性分析和新颖的聚类分析将评估模型的稳健性。目标 1 将我们的模型扩展为 LTF，描述了 PKA 和 ERK 通过转录磷酸化对转录的调节 因子 CREB1 和 CREB2。扩展模型将包括额外的细胞内和细胞外组件 反馈环（例如 TGFβ 和 ApNT）、附加转录因子 (C/EBP)、核糖体 s6 激酶 (RSK) 和 p38 MAP 激酶。在目标 2 中，该模型将用于预测刺激方案以及药理学 治疗，增强 LTF 并挽救受损的 LTF。目标 3 将扩展我们当前的 LTP 模型，即 描述了多种激酶途径（例如 MAPK、PKA、PKC 和 CAMKII）和组蛋白乙酰化的作用。这 模型将包含最近描述的 BDNF 正反馈回路，这会导致 ERK 的激活， CREB1 的磷酸化，以及 LTP 巩固所必需的转录诱导。我们将 模拟刺激方案和药物效果来预测可以挽救受损记忆的治疗方法 雷特综合征的机制，该综合征是由改变转录因子活性的突变引起的 MeCP2，可以挽救由突变引起的 Rubinstein-Taybi 综合征的受损机制 在CREB结合蛋白中。这种使用模型来预测新的学习范式和/或 恢复正常可塑性的药物治疗是一种创新方法，最终可能导致 开发治疗认知障碍的新策略。