Modeling Gene Regulation Essential for Long-Term Plasticity

描述(申请人提供)：学习和记忆是人类认知的基石，认知缺陷与许多大脑疾病有关。最近，将认知功能与特定分子联系起来已经成为可能。这些分子包括CREB转录因子家族，它们对长期(LT)突触可塑性和记忆至关重要。CREB信号通路的改变与损害认知的疾病有关，如Rubinstein-Taybi综合征、神经纤维瘤病和Coffin-Lowry综合征。这些信号通路的许多分子细节是已知的。然而，这些元素如何定量解释正常和病理细胞行为的方式还没有被很好地理解，因为信号级联被嵌入到包括广泛的串扰和负反馈和正反馈循环的生化和遗传网络中。为了解决这个问题，本提案概述了对CREB信号通路及其在记忆中的作用进行建模和模拟的计算研究。记忆的两个特征良好的神经元关联将被建模：长时促进(LTF)和长时程增强(LTP)。建议的模型将使用微分方程式来模拟分子过程，并将受到经验数据的约束。目的1将验证这一假设，即LTF的诱导和巩固的动力学是由PKA和ERK激酶级联的动力学以及CREB调控的转录中的反馈环控制的。模拟将检验训练方案的有效性，并预测优化学习的方案。目的2验证LTF和LTP具有共同的分子机制和动力学的假设。模拟将识别控制参数，这些参数可能对应于增强学习和认知的药理控制点。模拟还将探索由于影响CREB活性的突变造成的LT可塑性损害，例如Rubinstein-Taybi综合征。最后，这些模型将被用来预测改善CREB相关记忆缺陷的治疗方法，从而帮助恢复正常的可塑性、学习和记忆。

DESCRIPTION (provided by applicant): Learning and memory are cornerstones of human cognition, and cognitive defects are associated with many brain disorders. It has recently become possible to relate cognitive function to specific molecules. These molecules include the CREB family of transcription factors, which are essential for long-term (LT) synaptic plasticity and memory. Alterations in CREB signaling pathways are associated with diseases that impair cognition, such as Rubinstein-Taybi syndrome, neurofibromatosis, and Coffin-Lowry syndrome. Many of the molecular details of these signaling pathways are known. However, the ways in which these elements quantitatively account for normal and pathological cellular behavior are not well understood because the signaling cascades are embedded in a biochemical and genetic network that includes extensive cross talk and negative and positive feedback loops. To address this issue, the present proposal outlines computational studies that model and simulate CREB signaling pathways and their role in memory. Two well characterized neuronal correlates of memory will be modeled: long-term facilitation (LTF) and long-term potentiation (LTP). The proposed models will use differential equations to simulate molecular processes and will be constrained by empirical data. Aim 1 will test the hypothesis that the dynamics for the induction and consolidation of LTF are governed by the dynamics of the PKA and ERK kinase cascades and by feedback loops within CREB regulated transcription. Simulations will examine the efficacy of training protocols and predict protocols that optimize learning. Aim 2 will test the hypothesis that LTF and LTP share molecular mechanisms and dynamics. Simulations will identify control parameters, which may correspond to pharmacological control points for enhancing learning and cognition. Simulations also will explore LT plasticity impairment due to mutations that affect CREB activity, such as Rubinstein-Taybi syndrome. Finally, the models will be used to predict treatments for ameliorating CREB-related memory deficits and thereby help restore normal plasticity, learning and memory.