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

本RAISE项目由化学学部生命过程化学项目、物理学部生命系统物理项目、分子和细胞生物科学部细胞动力学与功能和分子生物物理集群、综合有机系统部门神经系统集群、新兴前沿部门、RAISE项目和综合活动办公室共同资助。该奖项将资助莱斯大学的Peter Wolynes、Margaret b张、Michael Diehl和Herbert Levine教授以及德克萨斯大学（UT） Health-Houston分校的M. Neal Waxham教授研究学习和记忆的分子机制。学习开始于神经元突触的变化，这些变化可以增强（或减弱）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。记忆和学习的初始事件包括钙浓度的暂时上升和一种叫做钙调蛋白的蛋白质的激活。下一步是钙调素依赖性酶激酶II （CaMKII）的激活。同时，肌动蛋白细胞骨架发生结构重排，导致脊柱间室增大。这些初始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。这个项目的重点是导致肌动蛋白细胞骨架变化的事件。该研究还解决了肌动蛋白细胞骨架中的这些结构变化如何用于维持记忆的问题。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。这些模型研究了在突触可塑性的初始步骤和开始之间架起时间尺度桥梁的分子变化。计算模型与最先进的结构和功能成像以及生化途径分析齐头并进。这项研究允许研究生和博士后获得亚细胞系统的计算机模拟和数学建模的专门训练。学生和研究员从分子水平开始了解大脑。理论和实验团队在这个问题上的合作加强了训练过程。该项目被整合到一个外展计划中，通过参与研究，向未被充分代表的群体中的本科生介绍科学。这个研究项目定量地描述了树突棘中参与形成记忆的动态“构造”重组的相关分子过程。它着重于使用计算机模拟和实验分析在分子和超分子尺度肌动蛋白细胞骨架。因此，这项研究直接有助于理解突触可塑性和学习记忆中的力学和结构的作用。明确地，假设是钙流入的短暂效应以camkii依赖的方式产生肌动蛋白结构空间模式的变化。这种变化可以通过朊病毒样蛋白的反馈回路来稳定。这些稳定的结构可能是一种“结构印痕”，它可以作为突触后神经元中维持增强的突触强度的长期储存库。对这一假设进行测试、修改和验证，可能有助于为研究大脑学习和记忆的第一阶段提供更精确的定量方法。

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.