NeuroNex: Enabling Identification and Impact of Synaptic Weight in Functional Networks

NeuroNex：实现功能网络中突触权重的识别和影响

• 批准号: 2014862
• 负责人: Kristen Harris
• 金额: $ 1750万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2014862&HistoricalAwards=false
• 关键词: NeuroNex; Enabling; Identification; Impact; Synaptic

Trillions of synapses connect billions of neurons in neural circuits that allow sensation, thought, action, learning, and memory. This NeuroNex Network involves the development of new approaches to determine the strength of connections between neurons—synaptic weight--in the brain. Understanding synaptic weight is crucial, yet even a clear definition remains elusive, despite more than a century of searching. This NeuroNex Network assembles world experts to study synapses from molecules to behavior, to answer this fundamental and ambitious question: What constitutes synaptic weight, and what role does it play in shaping neural circuits? Synaptic weight is hypothesized to involve the differential composition and co-occurrence of key proteins and subcellular resources. Multidisciplinary approaches are used to assess these features in well-defined states of neural circuits involving multiple cell types, brain regions, and diverse behaviors. Consistent predictors of synaptic state are mapped onto neural connectomes to enhance understanding of how synaptic weight influences circuit organization and function. New electron microscopy technologies developed and used in this project bridge gaps in image size and resolution needed to achieve deeper understanding of brain function and regulation from nanoscale to circuit levels. A long-lasting, far-reaching impact involves leveraging work from this NeuroNex Network with other BRAIN Initiative projects to enable acquisition and sharing of the new knowledge. Future applications, even beyond the brain, of the knowledge and tools developed here will give rise to data that address fundamental and novel principles of complex self-organizing systems. The NeuroNex Network also involves training the next generation, including through inter-laboratory and fellow exchanges.What constitutes synaptic weight, what role does it play in shaping neural circuits, and how does it change during growth and plasticity? Answers require a shift away from thinking about synapses as isolated entities. Synapses are not simply on or off one-bit machines; instead the information content stored in synapse size, as a proxy for weight, is much higher. Synaptic weight is controlled over broad temporal and spatial scales dynamically regulated by neural activity. New evidence points to subcellular resources (endoplasmic reticulum, mitochondria, endosomes, ribosomes) as brokers that drive synaptic efficacy and plasticity. This project seeks to understand how synapse composition and structure predict synaptic weight and function at a scale that reveals biological mechanisms at the subcellular level. A new 3D electron microscopy (EM) approach is developed using conical tilt tomography on the scanning EM operating in the transmission mode (tomoSEM). TomoSEM fills the current resolution-to-volume gap between methods of structural biology (high resolution, small volumes) and connectomics (relatively low resolution, larger volumes). TomoSEM eliminates major artifacts of other EM methods while reducing human effort and cost. The investigators comprise world experts in protein chemistry, cell biology, connectomics, and behavior. Experts in EM implement, validate, and deploy tomoSEM. Experts in image analysis, geometry, statistics, machine learning, and multilevel modeling create platforms to search data for hidden order. These strategies share international resources to overcome limits of accumulating data locally one synapse at a time. This project is co-funded by Emerging Frontiers in the Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

数万亿的突触连接着神经回路中数十亿的神经元，这些神经回路允许感觉，思想，行动，学习和记忆。NeuroNex网络涉及新方法的开发，以确定大脑中神经元之间的连接强度-突触重量。了解突触的重量是至关重要的，然而，尽管经过了世纪的探索，甚至连一个明确的定义都仍然难以捉摸。这个NeuroNex网络聚集了世界各地的专家来研究从分子到行为的突触，以回答这个基本而雄心勃勃的问题：什么构成了突触重量，它在塑造神经回路中扮演什么角色？突触重量被假设为涉及关键蛋白质和亚细胞资源的差异组成和共存。多学科的方法被用来评估这些功能在明确定义的状态的神经回路，涉及多种细胞类型，大脑区域，和不同的行为。突触状态的一致预测映射到神经连接体，以增强对突触权重如何影响电路组织和功能的理解。该项目中开发和使用的新电子显微镜技术弥补了图像尺寸和分辨率方面的差距，以更深入地了解从纳米级到电路级的大脑功能和调节。一个持久的，深远的影响涉及利用这个NeuroNex网络与其他BRAIN倡议项目的工作，使新知识的获取和共享。未来的应用，甚至超越大脑，这里开发的知识和工具将产生解决复杂自组织系统的基本和新颖原理的数据。NeuroNex网络还涉及训练下一代，包括通过实验室间和同行交流。什么构成突触重量，它在塑造神经回路中扮演什么角色，以及它在生长和可塑性过程中如何变化？答案需要从将突触视为孤立实体的思维转变。突触并不是简单的开或关一位机器;相反，作为权重的代理，突触大小中存储的信息内容要高得多。突触重量控制在广泛的时间和空间尺度上动态调节神经活动。新证据表明亚细胞资源（内质网、线粒体、核内体、核糖体）是驱动突触功效和可塑性的经纪人。该项目旨在了解突触的组成和结构如何预测突触的重量和功能，揭示亚细胞水平的生物学机制。一种新的三维电子显微镜（EM）的方法，开发使用圆锥倾斜层析成像的扫描EM操作在透射模式（tomoSEM）。TomoSEM填补了目前结构生物学（高分辨率，小体积）和连接组学（相对低分辨率，大体积）方法之间的分辨率-体积差距。TomoSEM消除了其他EM方法的主要伪影，同时减少了人力和成本。研究人员包括蛋白质化学、细胞生物学、连接组学和行为学方面的世界专家。EM专家实施、验证和部署tomoSEM。图像分析、几何学、统计学、机器学习和多级建模领域的专家创建平台来搜索数据中的隐藏顺序。这些策略共享国际资源，以克服一次一个突触地在本地积累数据的限制。该项目由生物科学理事会的新兴前沿共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Actin chromobody imaging reveals sub-organellar actin dynamics.

肌动蛋白染色体成像揭示了亚轨道肌动蛋白动力学。

• DOI: 10.1038/s41592-020-0926-5
• 发表时间: 2020-09
• 期刊: Nature methods
• 影响因子: 48
• 作者: Schiavon CR;Zhang T;Zhao B;Moore AS;Wales P;Andrade LR;Wu M;Sung TC;Dayn Y;Feng JW;Quintero OA;Shadel GS;Grosse R;Manor U
• 通讯作者: Manor U

Local shape descriptors for neuron segmentation.

• DOI: 10.1038/s41592-022-01711-z
• 发表时间: 2023-03
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Sheridan, Arlo;Nguyen, Tri M. M.;Deb, Diptodip;Lee, Wei-Chung Allen;Saalfeld, Stephan;Turaga, Srinivas C. C.;Manor, Uri;Funke, Jan
• 通讯作者: Funke, Jan

Connectomic comparison of mouse and human cortex

• DOI: 10.1126/science.abo0924
• 发表时间: 2022-07-08
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Loomba, Sahil;Straehle, Jakob;Helmstaedter, Moritz
• 通讯作者: Helmstaedter, Moritz

An ultrastructural connectomic analysis of a higher‐order thalamocortical circuit in the mouse

小鼠高阶丘脑皮质回路的超微结构连接组学分析

• DOI: 10.1111/ejn.15092
• 发表时间: 2021
• 期刊: European Journal of Neuroscience
• 影响因子: 3.4
• 作者: Sampathkumar, Vandana;Miller‐Hansen, Andrew;Murray Sherman, S.;Kasthuri, Narayanan
• 通讯作者: Kasthuri, Narayanan

A pathoconnectome of early neurodegeneration: Network changes in retinal degeneration.

• DOI: 10.1016/j.exer.2020.108196
• 发表时间: 2020-10
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Pfeiffer RL;Anderson JR;Dahal J;Garcia JC;Yang JH;Sigulinsky CL;Rapp K;Emrich DP;Watt CB;Johnstun HA;Houser AR;Marc RE;Jones BW
• 通讯作者: Jones BW