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受试者 密集研究和研究提供了大量的经验数据，这些数据将记忆的方面与 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），激酶活性和转录调节诱导和 记忆的合并。部分归因于这些分子途径的复杂性和非线性特征 难以发展对这些途径对刺激的响应方式的直观理解 方案或药理操作或受单位分子病变的影响。提供更好的 了解LTM的过程，本提案将开发针对该过程的定量模型 LTM的两个良好特征模型的分子途径：i）长期突触设施（LTF） ii）长期突触势（LTP）。参数将受经验数据的约束。范围 灵敏度分析和新的聚类分析将评估模型鲁棒性。 AIM 1将扩展我们的模型 LTF，描述了通过转录的磷酸化对PKA和ERK的转录调节 因素CREB1和CREB2。扩展模型将包括其他细胞内和细胞外组件 反馈回路（例如TGFβ和APNT），另一种转录因子（C/EBP），核糖体S6激酶（RSK） 和p38 MAP激酶。在AIM 2中，该模型将用于预测刺激方案以及药物 治疗方法，增强了LTF和救助LTF的救助。 AIM 3将扩展我们当前的LTP模型，该模型 描述了几种激酶途径（例如MAPK，PKA，PKC和CAMKII）和组蛋白乙酰化的作用。 模型将结合一个最近划定的BDNF阳性反馈回路，这导致ERK激活， CREB1的磷酸化以及LTP合并所需的转录诱导。我们将 模拟刺激方案和药物效应，以预测可能挽救记忆力受损的治疗方法 RETT综合征的机制，这是由改变转录因子活性的突变引起的 MECP2，这可以挽救鲁宾斯坦 - 塔比综合症中的机制受损的机制，这是由突变引起的 在CREB结合蛋白中。这种建议的方法是使用模型来预测新颖的学习范例和/或 恢复正常可塑性的药物治疗是一种创新的方法，最终可能导致 制定治疗认知障碍的新策略。