Modeling Circadian Clock Mechanisms from Synapse to Gene

模拟从突触到基因的昼夜节律时钟机制

• 批准号: 1412877
• 负责人: Casey Diekman
• 金额: $ 23.39万
• 依托单位: New Jersey Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1412877&HistoricalAwards=false
• 关键词: Modeling; Circadian; Clock; Mechanisms; Synapse

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.

大脑的生物钟控制着激素产生和睡眠/觉醒行为的日常节奏。例如，由于时差或夜班工作而导致的这些节奏的中断对数百万美国人的健康产生了影响。该项目的主要目标是从数学上理解时钟的电活动在昼夜节律计时中的作用，特别是时钟对外部光/暗周期的响应方式。该项目将通过发现细胞膜和基因之间信息流动的原理为BRAIN Initiative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，例如长期记忆形成和神经元存活和死亡的控制。该项目还将通过开发能够处理广泛不同时间尺度的计算机模拟方法，影响生物节律以外的数学生物学领域。通过这个项目，研究人员将指导研究生和本科生在数学和神经科学的接口跨学科研究，并将参与教育推广活动，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清晰的例子之一，有节奏的基因表达导致神经活动，生理学和行为的日常节奏。长期以来，哺乳动物主生物钟的主要输出信号被认为是视交叉上核（SCN）内神经元放电频率的简单昼夜差异。最近的研究结果挑战了这一理论，并表明很大一部分SCN神经元在整个昼夜周期中表现出一组更复杂且违反直觉的电状态转变。通过数据驱动的数学建模，模拟和动态系统分析的关键细胞类型内的时钟核，该项目将开发的SCN的电气状态的日常转换的理解和功能的作用，他们在哺乳动物的生物钟。 此外，该项目将通过推导细胞类型及其突触的膜兴奋性的基于电导的数学模型来确定两种不同类别的SCN神经元的活动模式是否起源于细胞或电路水平。SCN活动模式的转变，发生在整个白天/夜晚的周期将被解释通过开发一个多尺度模型的昼夜节律计时，链接详细的模型SCN神经元内的分子时钟，这些模型的膜兴奋性。