RAISE: Dendritic spine mechano-biology and the process of memory formation

该RAINE项目由化学系的生命过程化学计划、物理系的生命系统物理计划、分子和细胞生物科学部的细胞动力学和功能以及分子生物物理组、综合组织系统司的神经系统组、新兴前沿部门、RAISE计划和综合活动办公室共同资助。该奖项资助莱斯大学的Peter Wolynes、Margaret Cheung、Michael Diehl和Herbert Levine教授以及德克萨斯大学(UT)休斯顿分校的M.Neal Waxham教授研究学习和记忆的分子机制。学习的启动始于神经元突触的变化，这些变化可以加强(或削弱)突触的反应。这个过程被称为突触可塑性。产生学习的刺激导致突触后树突棘的结构变化。记忆和学习的最初事件包括短暂的钙浓度上升和一种名为钙调蛋白的蛋白质的激活。下一步是激活钙调蛋白依赖的酶，激酶II(CaMKII)。同时，肌动蛋白细胞骨架发生结构重排，导致脊柱间隙扩大。这些最初的事件如何导致肌动蛋白细胞骨架的重塑在很大程度上是未知的。这个项目主要关注导致肌动蛋白细胞骨架变化的事件。这项研究还解决了肌动蛋白细胞骨架的这些结构变化是如何用来维持记忆的问题。最先进的计算模型被用来回答这些问题。建模应用于分子和超分子尺度。这些模型检测了连接突触可塑性初始步骤和开始之间的时间尺度的分子变化。计算建模与最先进的结构和功能成像以及生化途径分析齐头并进。这项研究使研究生和博士后研究员能够获得亚细胞系统的计算机模拟和数学建模方面的专门培训。学生和研究员从分子水平开始了解大脑。在这个问题上合作工作的理论家和实验者团队加强了培训过程。这个项目被整合到一个推广项目中，通过参与研究将来自代表性不足群体的本科生介绍给科学。这个研究项目定量地描述了树突内动态的构造重组所涉及的相关分子过程，这些重组涉及形成记忆。它使用计算机模拟和实验分析在分子和超分子尺度上重点研究肌动蛋白细胞骨架。因此，这项研究直接有助于理解力学和结构在突触可塑性和学习记忆中的作用。明确地说，假设是钙离子内流的瞬时效应以CaMKII依赖的方式改变了肌动蛋白结构的空间模式。这样的变化可以通过类普里子蛋白的反馈环来稳定下来。这些稳定的结构可能是一种结构印记，然后作为长期的储存库，维持突触后神经元中增强的突触强度。测试、修改和验证这一假设可能有助于为大脑学习和记忆的第一阶段提供一种更复杂的量化方法。

This RAISE project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry, the Physics of Living Systems Program in the Division of Physics, the Cellular Dynamics and Function and the Molecular Biophysics Clusters in the Division of Molecular and Cellular Biosciences, the Neural Systems Cluster in the Division of Integrative Organismal Systems, the Division of Emerging Frontiers, the RAISE Program and the Office of Integrative Activities. This award is funding Professors Peter Wolynes, Margaret Cheung, Michael Diehl and Herbert Levine at Rice University and M. Neal Waxham at University of Texas (UT) Health-Houston to investigate the molecular mechanisms of learning and memory. The initiation of learning begins with changes at neuronal synapses that can strengthen (or weaken) the response of the synapse. This process is termed synaptic plasticity. Stimuli that produce learning lead to structural changes of the post-synaptic dendritic spine. The initial events of memory and learning include a temporary rise in calcium concentrations and activation of a protein called calmodulin. The next step is activation of calmodulin-dependent enzyme, kinase II (CaMKII). At the same time, structural rearrangements occur in the actin cytoskeleton leading to an enlargement of the spine compartment. How these initial events lead to remodeling of the actin cytoskeleton is largely unknown. This project focuses on the events that lead to the changes in actin cytoskeleton. The research also addresses the question of how these structural changes in the actin cytoskeleton are used to maintain memory. State-of-the-art computational modeling is used to answer these questions. Modeling is applied at molecular and supra-molecular scales. The models examine molecular changes that bridge the time scales between the initial steps and start of synaptic plasticity. The computational modeling goes hand in hand with state-of-the-art structural and functional imaging and biochemical pathway analyses. The research allows graduate students and postdoctoral fellows to acquire specialized training in computer simulations and mathematical modeling of a subcellular system. The students and fellows acquire an understanding of the brain starting from a molecular level. The team of theoreticians and experimentalists working cooperatively on this problem strengthens the training process. This project is integrated into an outreach program to introduce undergraduate students from underrepresented groups to science by participating in the research.This research project quantitatively characterizes the relevant molecular processes involved in the dynamical "tectonic" reorganization inside a dendritic spine involved in forming memories. It focuses on the actin cytoskeleton using computer simulations and experimental analyses at both molecular and supra-molecular scales. This study therefore contributes directly to understanding the role of mechanics and structure in synaptic plasticity and learning and memory. Explicitly, the hypothesis is that the transient effects from calcium influx create, in a CaMKII-dependent manner, changes in the spatial patterning of the actin structure. Such changes may be be stabilized by feedback loops with prion-like proteins. These stabilized structures may be a type of "structural engram" which then serves as long-term reservoir for maintaining enhanced synaptic strength in the postsynaptic neuron. Testing, modifying, and verifying this hypothesis may help point the way towards a more quantitatively-sophisticated approach to the first stages of learning and memory in the brain.