Modeling Gene Regulation Essential for Long-Term Synaptic Plasticity

对长期突触可塑性至关重要的基因调控建模

• 批准号: 6995172
• 负责人: John H Byrne
• 金额: $ 24.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6995172
• 关键词: behavioral /social science research tag; cAMP response element binding protein; chemical stimulation; computational neuroscience; electrostimulus; genetic regulation; genetic transcription; long term memory; long term potentiation; mathematical model; model design /development; neural plasticity; neurogenetics; phosphorylation; protein kinase; transcription factor

This project will develop a framework based on mathematical modeling that a) describes the mechanism by which synaptic plasticity emerges from molecular processes regulating gene transcription, and b) tests mechanistic hypotheses, such as proposed roles of specific protein kinases. The project builds upon our previous model describing aspects of the gene and protein network responsible for long-term synaptic facilitation (LTF) and the formation of long-term memory (LTM) in the mollusk Aplysia. This model is based on transcriptional regulation by Ca2+/cAMP response element - binding protein (CREB, termed ApCREBI in Aplysia) and related transcription factors. We will extend this model to incorporate additional elements of gene regulation recently demonstrated to be essential for LTF. In addition, we will develop an analogous model to simulate biochemical events underlying the induction of late long-term synaptic potentiation (L-LTP) in vertebrates. Both LTF and L-LTP are thought to play essential roles in the formation of LTM, and LTF induction and L-LTP induction exhibit mechanistic similarities, such as dependence on MAP kinase activation. Therefore, a modeling framework that can simulate aspects of both LTF and L-LTP induction is likely to significantly increase the understanding of learning mechanisms. The LTF model variant will incorporate additional transcriptional regulators essential for LTF, such as ApCREB2, and ApC/EBP. Bifurcation analysis and pre-programmed integrations will identify key control parameters which are plausible sites of physiological regulation and which, when varied, have important effects on the dynamics of the model. We will then use the model to simulate the results of experimental protocols in which alterations are made in the activity of the transcriptional regulators listed above. A minimal set of variations in key control parameters will be identified that allows simulation of data from these protocols. This approach is likely to help identify the key mechanisms that determine the amount of LTF induced by different training protocols. The L-LTP model variant will be used to simulate three common stimulus protocols that induce hippocampal L-LTP. These protocols are high-frequency (tetanic) stimulation, theta-burst stimulation, and stimulation by forskolin. Parameters will be optimized to fit experimental time courses of nuclear [Ca2+] and of kinase and transcription factor activities. The model will then be used to test the hypothesis that CREB kinases other than protein kinase A, such as ribosomal S6 kinase 2, are primarily responsible for CREB phosphorylation and LTP induction. Preliminary model development and simulations predict that L-LTP induction by a low-frequency burst stimulus protocol does not depend on nuclear CaM kinase activation and consequent CREB phosphorylation.

该项目将基于数学模型开发一个框架，该框架a）描述了从调节基因转录的分子过程中出现突触可塑性的机制，b）检验机械假设，例如特定蛋白激酶的提议作用。该项目建立在我们以前的模型基础上，描述了负责长期突触促进（LTF）的基因和蛋白质网络的各个方面以及长期形成 Mollusk Aplysia中的内存（LTM）。该模型基于Ca2+/CAMP响应元件 - 结合蛋白（CREB，称为Apcrebi在Aplysia中）和相关转录因子的转录调控。我们将扩展该模型，以结合最近证明对LTF至关重要的基因调节的其他要素。此外，我们将开发一个类似模型，以模拟脊椎动物中长期长期突触增强（L-LTP）诱导的基础的生化事件。 LTF和L-LTP都被认为在LTM的形成中起着重要作用，LTF诱导和L-LTP诱导表现出机械的相似性，例如对MAP激酶激活的依赖性。因此，可以模拟LTF和L-LTP诱导方面的建模框架可能会显着增加对学习机制的理解。 LTF模型变体将结合LTF所必需的其他转录调节剂，例如APCREB2和APC/EBP。分叉分析和预编程的集成将识别关键控制参数 生理调节的合理位点，并且在变化时会对模型的动力学产生重要影响。然后，我们将使用该模型来模拟实验方案的结果，在这些方案中，在上面列出的转录调节器的活动中进行了更改。将确定关键控制参数的最小变化集，以允许从这些协议中模拟数据。这种方法可能有助于确定确定不同培训方案引起的LTF量的关键机制。 L-LTP模型变体将用于模拟诱导海马L-LTP的三种常见刺激方案。这些方案是高频刺激，theta-burst刺激和福斯科林刺激。将优化参数以适合核[Ca2+]以及激酶和转录因子活性的实验时间课程。然后，该模型将用于测试 假设蛋白激酶A以外的CREB激酶（例如核糖体S6激酶2）主要负责CREB磷酸化和LTP诱导。初步模型的开发和模拟预测，低频爆发刺激方案的L-LTP诱导不取决于核CAM激酶激活和随之而来的CREB磷酸化。