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: 10317000
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317000
• 关键词: ATF2 gene; Affect; Animal Model; Aplysia; 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）的诱导和巩固的分子过程是主题 深入的研究，研究提供了丰富的经验数据，将记忆的各个方面与 特定的细胞内信号通路。例如，实证研究正在阐明 细胞外因子（例如生长因子）、激酶活性和诱导中的转录调节， 记忆的巩固。部分由于这些分子途径的复杂性和非线性特征， 很难对这些通路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单部位分子损伤影响。提供更好的 为了了解LTM的基本过程，本提案将开发LTM的定量模型。 作为LTM的两种良好表征模型的基础的分子途径：i）长期突触促进（LTF） 和ii）长时程突触增强（LTP）。参数将受到经验数据的约束。参数 敏感性分析和新的聚类分析将评估模型的稳健性。Aim 1将扩展我们的模型， LTF，其描述PKA和ERK通过转录的磷酸化来调节转录， CREB 1和CREB 2。扩展模型将包括额外的细胞内和细胞外的成分， 反馈回路（例如，TGFβ和ApNT）、一种额外的转录因子（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和挽救受损的LTF。目标3将扩展我们目前的LTP模型， 描述了几种激酶途径的作用（例如，MAPK、PKA、PKC和CAMK II）和组蛋白乙酰化。的 模型将纳入一个最近描绘的BDNF正反馈回路，这导致ERK的激活， CREB 1的磷酸化，以及诱导LTP巩固所必需的转录。我们将 模拟刺激方案和药物效应，以预测可以挽救受损记忆的治疗方法 Rett综合征的机制，这是由改变转录因子活性的突变引起的， MeCP 2，它可以挽救Rubinstein-Taybi综合征中受损的机制，这是由突变引起的 CREB结合蛋白所提出的使用模型来预测新的学习范式和/或 药物治疗，恢复正常的可塑性，是一种创新的方法，最终可能导致 开发治疗认知障碍的新策略。