RUI: Mapping physical networks to functional networks in SCN oscillation

RUI：在SCN振荡中将物理网络映射到功能网络

• 批准号: 1749500
• 负责人: Rae Silver
• 金额: $ 145万
• 依托单位: Barnard College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1749500&HistoricalAwards=false
• 关键词: RUI; Mapping; physical; networks; functional

A broad goal of Neuroscience is to understand how the structure of the brain gives rise to its functions. The present project uses the brain's master circadian clock, the suprachiasmatic nucleus in the hypothalamus, as a model system to tackle this problem. In the brain clock, the way individual elements interact can be studied at multiple levels; for example, clock genes, clock neurons, the brain clock as a whole, or the behavior and physiology of the animal. The project aims to reveal new information about how individual neurons are connected in a network that produces a 24-hour rhythm in the brain clock, and how this master brain clock provides timing information to the rest of the body. It already is known that individual neurons, each with internal clocks of their own, are organized in time and space into distinct clusters bearing stable phase relationships to each other. Preliminary data indicate that the brain clock contains phase-coherent, and highly organized, "rings" of cells. This is exciting: it is the first demonstration of functional network topography within a hypothalamic nucleus. Classically, the hypothalamus is viewed as loosely organized collections of neurons. In other brain regions, such as the auditory or the visual cortex, neurons are organized in specific 3-dimensional spatial formations that are important for information coding. The goal of this study is to understand information coding in the suprachiasmatic nucleus, and how the newly discovered rings contribute to the brain clock's network and function. In all the work, research in both the biological and mathematical aspects of the studies engages women undergraduate students interested in Neuroscience and in Applied Mathematics.The suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock in the brain. The goal of this project is to gain insight into information coding in the SCN and to elucidate how ring-like arrangements among cells in the SCN contribute to the clock's network and function. The first study establishes the orientation of the rings by using coronal, sagittal, and horizontal slices of the SCN in vivo. The results contribute to the development of mathematical models that characterize coherent structures within the SCN. The second study involves use of tissue clearing methods to visualize the structures of the rings observed in SCN slices. The third study serves to test the function of the rings both in adults and during development and in animals with mutations that alter circadian rhythmicity. At each step, mathematical models of ring functions are being developed in parallel with the biological work, and used to develop ideas on how to further understanding of the ring structures. The results from these studies provide a new level of analysis to previously established aspects of SCN organization and extend the understanding of the widely-accepted core/shell structure of the SCN. A unifying hypothesis is that this multi-scale organization provides robustness and resilience to the circadian oscillatory system, a hypothesis tested here via modeling, simulation, and biological analyses of mutant and wild type SCN.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.

神经科学的一个广泛目标是了解大脑的结构如何产生其功能。目前的项目使用大脑的主生物钟，即下丘脑的视交叉上核，作为解决这个问题的模型系统。在脑钟中，各个元素相互作用的方式可以在多个层面上进行研究。例如，时钟基因、时钟神经元、整个脑时钟或动物的行为和生理机能。该项目旨在揭示关于各个神经元如何在脑时钟中产生 24 小时节律的网络中连接的新信息，以及这个主脑时钟如何向身体其他部分提供计时信息。众所周知，每个神经元都有自己的内部时钟，在时间和空间上被组织成不同的簇，彼此之间具有稳定的相位关系。初步数据表明，大脑时钟包含相位一致且高度组织的细胞“环”。这是令人兴奋的：这是下丘脑核内功能网络拓扑的首次演示。传统上，下丘脑被视为组织松散的神经元集合。在其他大脑区域，例如听觉或视觉皮层，神经元以特定的 3 维空间形式组织，这对于信息编码很重要。这项研究的目的是了解视交叉上核的信息编码，以及新发现的环如何对脑钟的网络和功能做出贡献。在所有工作中，生物和数学方面的研究都吸引了对神经科学和应用数学感兴趣的女本科生。下丘脑的视交叉上核（SCN）是大脑中的主时钟。 该项目的目标是深入了解 SCN 中的信息编码，并阐明 SCN 中细胞之间的环状排列如何影响时钟的网络和功能。第一项研究通过体内 SCN 的冠状、矢状和水平切片确定了环的方向。这些结果有助于描述 SCN 内相干结构的数学模型的发展。第二项研究涉及使用组织透明化方法来可视化 SCN 切片中观察到的环结构。第三项研究旨在测试环在成人和发育过程中以及在具有改变昼夜节律的突变的动物中的功能。在每一步中，环函数的数学模型都与生物学工作并行开发，并用于开发如何进一步理解环结构的想法。这些研究的结果为先前建立的 SCN 组织方面提供了新的分析水平，并扩展了对广泛接受的 SCN 核/壳结构的理解。一个统一的假设是，这种多尺度组织为昼夜节律振荡系统提供了稳健性和弹性，该假设通过突变型和野生型 SCN 的建模、模拟和生物学分析进行了检验。该奖项反映了 NSF 的法定使命，并被认为是值得的通过使用基金会的智力优势和更广泛的影响审查标准进行评估来获得支持。

项目成果

Editorial: Development of Circadian Clock Functions

社论：昼夜节律时钟功能的发展

• DOI: 10.3389/fnins.2021.735007
• 发表时间: 2021
• 期刊: Frontiers in Neuroscience
• 影响因子: 4.3
• 作者: Myung J;Nakamura TJ;Jones JR;Silver R;Ono D
• 通讯作者: Ono D

Connectome of the Suprachiasmatic Nucleus: New Evidence of the Core-Shell Relationship

视交叉上核的连接组：核壳关系的新证据

• DOI: 10.1523/eneuro.0205-18.2018
• 发表时间: 2018-09
• 期刊: eneuro
• 影响因子: 3.4
• 作者: Varadarajan S;Tajiri M;Jain R;Holt R;Ahmed Q;LeSauter J;Silver R
• 通讯作者: Silver R

Elevated zinc transporter ZnT3 in the dentate gyrus of mast cell‐deficient mice

肥大细胞缺陷小鼠齿状回锌转运蛋白 ZnT3 升高

• DOI: 10.1111/ejn.14575
• 发表时间: 2020-03-01
• 期刊: European Journal of Neuroscience
• 影响因子: 3.4
• 作者: Amen Wiqas;J. LeSauter;A. Taub;R. Austin;R. Silver
• 通讯作者: R. Silver

Evolutionary Kuramoto dynamics

仓本进化动力学

• DOI: 10.1098/rspb.2022.0999
• 发表时间: 2022-11-09
• 期刊: Proceedings of the Royal Society B: Biological Sciences
• 作者: Tripp, Elizabeth A.;Fu, Feng;Pauls, Scott D.
• 通讯作者: Pauls, Scott D.

Circadian rhythmicity and the community of clockworkers

• DOI: 10.1111/ejn.14626
• 发表时间: 2019-12-09
• 期刊: European Journal of Neuroscience
• 影响因子: 3.4
• 作者: K. Gamble;R. Silver
• 通讯作者: R. Silver