Network Properties of Circadian Clock Modulation and Entrainment

摘要 生物钟协调生理、代谢和行为中的内源性每日节律， 必须进行调整（即，夹带）到环境循环以保持适当定时的输出。后 工业环境显著降低了昼夜节律系统 依赖于夹带，这对人类健康产生了广泛的负面影响。 了解大脑中昼夜节律计时的网络特性以及时间 如果我们要解决昼夜节律失调的不利影响， 功能障碍大脑生物钟中心的复杂性是我们理解大脑的一个重要障碍。 昼夜节律系统的日常调整。因此，在相对“简单”的时钟神经元网络中工作， 丰富并告知我们对哺乳动物大脑中昼夜节律计时和夹带的理解。 这一竞争更新申请的目标是继续一个富有成效和有影响力的研究计划 关于果蝇昼夜节律计时和夹带的网络特性， 尽管它相对简单，但它具有分子，解剖学和生理学特征， 与哺乳动物的时钟网络非常相似。在苍蝇的时钟神经元网络中，我们将 确定内源性昼夜节律计时是如何由网络结构的支持， 大脑的时钟中心，以及特定的神经通路和神经递质如何介导夹带， 环境循环。我们的三个具体目标的目标是阐明：1）性质和计时 生物钟神经元网络的突触和调节连接的功能，2.）如何 CCNN整合光输入来诱导昼夜节律，以及3）不依赖于自身的神经元如何 表达分子钟参与时钟神经元网络以支持内源性计时。 这项研究计划的统一目标是促进我们对昼夜节律计时的理解， 在大脑中的夹带。这项工作的结果将为今后的干预措施提供参考， 后工业环境中昼夜节律功能障碍对健康的不利影响。

Abstract Circadian clocks orchestrate endogenous daily rhythms in physiology, metabolism, and behavior that must be adjusted (i.e., entrained) to environmental cycles to maintain properly timed outputs. Post- industrial environments have significantly reduced the reliability of the time cues that the circadian system relies upon for entrainment and this has had widespread and negative consequences for human health. Understanding the network properties of circadian timekeeping in the brain and the ways in which time cues impinge upon it is required if we are to address the adverse effects of circadian misalignment and dysfunction. The complexity of the brain’s clock center is a significant barrier to our understanding of the daily adjustment of the circadian system. Work in relatively “simple” clock neuron networks can therefore enrich and inform our understanding of circadian timekeeping and entrainment in the mammalian brain. The goal of this competing renewal application is to continue a productive and impactful research program on the network properties of circadian timekeeping and entrainment in Drosophila melanogaster, which, despite its relative simplicity, shares molecular, anatomical, and physiological features that are remarkably similar to those of mammalian clock networks. Within the fly’s clock neuron network, we will determine how endogenous circadian timekeeping is supported by the network structure of the of the brain’s clock center and how specific neural pathways and neurotransmitters mediate entrainment to environmental cycles. The goals of our three specific aims are to elucidate: 1) the nature and timekeeping functions of the synaptic and modulatory connections of the circadian clock neuron network, 2.) how the CCNN integrates light input to entrain circadian rhythms, and 3) how neurons that do not themselves express molecular clocks participate in the clock neuron network to support endogenous timekeeping. The unifying goal of this research program is to advance our understanding of circadian timekeeping and entrainment in the brain. The results of this work will inform future interventions for the alleviation of the adverse health effects of circadian dysfunction in post-industrial environments.