RUI: Mapping physical networks to functional networks in SCN oscillation

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，下丘脑的视交叉上核，作为解决这个问题的模型系统。在大脑时钟中，个体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，整个大脑时钟，或者动物的行为和生理。该项目旨在揭示单个神经元是如何在一个网络中连接起来的，这个网络在大脑时钟中产生24小时的节奏，以及这个大脑主时钟如何向身体的其他部分提供定时信息。我们已经知道，每个神经元都有自己的内部时钟，它们在时间和空间上被组织成不同的簇，彼此之间有着稳定的相位关系。初步数据表明，大脑时钟包含相参的、高度组织化的细胞“环”。这是令人兴奋的：这是首次展示下丘脑核内的功能性网络地形。传统上，下丘脑被视为组织松散的神经元集合。在大脑的其他区域，如听觉或视觉皮层，神经元被组织成特定的三维空间结构，这对信息编码很重要。本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影响大脑时钟的网络和功能。在所有的工作中，生物学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促进时钟网络和功能。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。这些结果有助于发展表征SCN内相干结构的数学模型。第二项研究涉及使用组织清除方法来可视化SCN切片中观察到的环的结构。第三项研究旨在测试环在成人和发育期间以及具有改变昼夜节律突变的动物中的功能。在每一步中，环函数的数学模型正在与生物学工作并行发展，并用于发展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组织方面提供了一个新的分析水平，并扩展了对被广泛接受的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鲁棒性和弹性，这一假设在这里通过对突变型和野生型SCN的建模、模拟和生物学分析进行了验证。该奖项反映了美国国家科学基金会的法定使命，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。

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.