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

RAISE：树突棘力学生物学和记忆形成过程

• 批准号: 1743392
• 负责人: Peter Wolynes
• 金额: $ 99.68万
• 依托单位: William Marsh Rice University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1743392&HistoricalAwards=false
• 关键词: RAISE; Dendritic; spine; mechano; biology

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.

该RAISE项目由化学部生命过程计划的化学，物理部生命系统计划的物理，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学集群，综合有机系统部的神经系统集群，新兴前沿部，RAISE计划和综合活动办公室。该奖项资助了莱斯大学的彼得·沃林斯教授、玛格丽特·张教授、迈克尔·迪尔教授和赫伯特·莱文教授以及M。Neal瓦克瑟姆在德克萨斯大学休斯顿分校研究学习和记忆的分子机制。学习的开始始于神经元突触的变化，这些变化可以加强（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升高和一种称为钙调蛋白的蛋白质的激活。下一步是激活钙调蛋白依赖性酶，激酶II（CaMKII）。 与此同时，肌动蛋白细胞骨架发生结构重排，导致脊柱室扩大。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。本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。国家的最先进的计算建模是用来回答这些问题。建模应用于分子和超分子尺度。这些模型检查了在突触可塑性的初始步骤和开始之间的时间尺度上架起桥梁的分子变化。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。该研究允许研究生和博士后研究员获得亚细胞系统的计算机模拟和数学建模的专门培训。学生和研究员从分子水平开始了解大脑。 在这个问题上合作的理论家和实验家团队加强了培训过程。该项目是一个外展计划，旨在通过参与研究，将来自代表性不足群体的本科生引入科学领域。该研究项目定量描述了参与形成记忆的树突棘内动态“构造”重组的相关分子过程。 它侧重于肌动蛋白细胞骨架使用计算机模拟和实验分析在分子和超分子尺度。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。解释，假设是从钙流入的瞬时效应创建，在CaMKII依赖的方式，在肌动蛋白结构的空间图案的变化。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“结构印迹”，然后作为长期储存器，用于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指明一条更复杂的定量方法。

项目成果

Insights from graph theory on the morphologies of actomyosin networks with multilinkers

• DOI: 10.1103/physreve.102.062420
• 发表时间: 2020-12-23
• 期刊: PHYSICAL REVIEW E
• 影响因子: 2.4
• 作者: Eliaz, Yossi;Nedelec, Francois;Cheung, Margaret S.
• 通讯作者: Cheung, Margaret S.

Vectorial channeling as a mechanism for translational control by functional prions and condensates

• DOI: 10.1073/pnas.2115904118
• 发表时间: 2021-11-23
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Gu, Xinyu;Schafer, Nicholas P.;Wolynes, Peter G.
• 通讯作者: Wolynes, Peter G.

Assemblies of calcium/calmodulin-dependent kinase II with actin and their dynamic regulation by calmodulin in dendritic spines

• DOI: 10.1073/pnas.1911452116
• 发表时间: 2019-09-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Wang，Qian;Chen，Mingchen;Cheung，Margaret S.
• 通讯作者: Cheung，Margaret S.

The role of the Arp2/3 complex in shaping the dynamics and structures of branched actomyosin networks

• DOI: 10.1073/pnas.1922494117
• 发表时间: 2020-05-19
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Liman, James;Bueno, Carlos;Cheung, Margaret S.
• 通讯作者: Cheung, Margaret S.

Exploring the F-actin/CPEB3 interaction and its possible role in the molecular mechanism of long-term memory

• DOI: 10.1073/pnas.2012964117
• 发表时间: 2020-09-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Gu, Xinyu;Schafer, Nicholas P.;Wolynes, Peter G.
• 通讯作者: Wolynes, Peter G.