Modeling Circadian Clock Mechanisms from Synapse to Gene

大脑的生物钟控制着荷尔蒙的产生和睡眠/醒来行为的日常节奏。例如，由于时差或夜班工作造成的这些节奏的中断，对数百万美国人的健康有影响。这个项目的主要目标是从数学上了解时钟的电活动在昼夜计时中所起的作用，特别是时钟对外部光/暗周期的反应方式。这个项目将通过发现细胞膜和基因之间信息流的原理来为大脑倡议做出贡献。这些新发现的原理将有助于开发大脑过程的数学模型，如长期记忆形成和控制神经元的生存和死亡。该项目还将通过开发能够处理差异很大的时间尺度的计算机模拟方法，对昼夜节律以外的数学生物学领域产生影响。通过这个项目，研究人员将指导数学和神经科学相结合的跨学科研究的研究生和本科生，并将与城市学者协会合作，参与对服务不足的城市社区的教育推广。该项目的主要目标是创建一个数学框架，以了解基因表达的动态变化如何影响神经元的电特性，并最终影响动物行为。昼夜节律提供了这些不同组织水平之间相互作用的最明显的例子之一，节律基因的表达导致了神经活动、生理和行为的日常节律。长期以来，哺乳动物生物钟的主要输出信号一直被认为是视交叉上核(SCN)内神经元放电速率的简单昼夜差异。最近的发现挑战了这一理论，并证明了很大一部分SCN神经元在整个昼夜周期中表现出一组更复杂、更违反直觉的电状态转换。通过对时钟核内关键细胞类型的数据驱动的数学建模、模拟和动态系统分析，该项目将加深对SCN电状态的日常变化以及它们在哺乳动物生物钟中所起的功能作用的理解。此外，该项目将通过推导两种细胞类型及其突触的基于电导的膜兴奋性数学模型来确定两种不同类别的SCN神经元的活动模式是起源于细胞水平还是电路水平。SCN活动模式在整个昼夜周期中发生的转变将通过开发一个多尺度的昼夜计时模型来解释，该模型将SCN神经元内分子时钟的详细模型与这些膜兴奋性模型联系起来。

The brain's circadian clock controls daily rhythms in hormone production and sleep/wake behavior. Disruptions of these rhythms, due to jet lag or night-shift work for example, have health implications for millions of Americans. The primary goal of this project is to gain a mathematical understanding of the role that the clock's electrical activity plays in circadian timekeeping, in particular the way the clock responds to the external light/dark cycle. This project will contribute to the BRAIN Initiative by discovering principles about the flow of information between the cell membrane and genes. These newly discovered principles will aid in the development of mathematical models of brain processes such as long-term memory formation and the control of neuronal survival and death. This project will also impact areas of mathematical biology beyond circadian rhythms through its development of computer simulation methods that are capable of handling widely disparate time scales. Through this project, the investigator will mentor graduate and undergraduate students in interdisciplinary research at the interface of mathematics and neuroscience, and will participate in educational outreach to under-served urban communities in collaboration with the Urban Scholar Society.The primary goal of this project is to create a mathematical framework for understanding how dynamic changes in gene expression affect the electrical properties of neurons and ultimately animal behavior. Circadian rhythms offer one of the clearest examples of the interplay between these different levels of organization, with rhythmic gene expression leading to daily rhythms in neural activity, physiology, and behavior. The main output signal of the master circadian clock in mammals has long been believed to be a simple day/night difference in the firing rate of neurons within the suprachiasmatic nucleus (SCN). Recent findings challenge this theory, and demonstrate that a substantial portion of SCN neurons exhibit a more complex and counterintuitive set of electrical state transitions throughout the day/night cycle. Through data-driven mathematical modeling, simulation, and dynamical systems analysis of the key cell types within the clock nucleus, this project will develop an understanding of the daily transitions in the SCN's electrical state and the functional roles they play in the mammalian circadian clock. In addition, this project will determine whether the activity patterns of two distinct classes of SCN neurons originate at the cellular or the circuit level by deriving conductance-based mathematical models of membrane excitability for both cell types and their synapses. The transitions in SCN activity patterns that occur throughout the day/night cycle will be explained by developing a multi-scale model of circadian timekeeping that links detailed models of the molecular clocks inside SCN neurons to these models of membrane excitability.