Network Properties of Circadian Clock Modulation and Entrainment

我们的生物钟协调生理、代谢和行为中的内源性生物节律， 必须每天进行调整，以保持与环境的同步，并产生最佳的时间节奏 产出这种日常调整，被称为夹带，是通过大脑中枢神经系统的敏感性来实现的。 时钟神经元网络的外部和内部的时间线索。后工业社会大大减少了 我们的昼夜节律系统用于夹带的线索的可靠性。这种对我们时钟的现代挑战 广泛的负面健康后果。大脑生物钟中心的复杂性是一个重要的障碍， 全面了解昼夜节律系统的日常调节。了解网络 大脑中昼夜节律计时的特性以及时间线索对生物钟中心的影响方式， 如果我们要解决昼夜节律失调和功能障碍的显著负面影响，这一点至关重要。的 这种竞争性更新应用程序的广泛目标是全面了解 黑腹果蝇的昼夜节律计时和夹带，其昼夜节律系统具有高度 保守的分子，解剖和生理特征，它与哺乳动物的时钟网络共享。 在这个定义明确的时钟中心，我们将调查如何高度保守的外部和内部时间线索 产生网络范围的时钟调制和控制睡眠。我们三个具体目标的目标是阐明： 1)胆碱能和γ-氨基丁酸能输入到时钟神经元网络的机制基础及其作用 在睡眠控制和昼夜节律计时和诱导中发挥作用，2）神经生理机制， 时钟网络的各种时钟神经元类彼此调制以产生连贯的昼夜节律 节律; 3）光温网络整合的解剖学和神经生理学基础 来自外周感受器的线索这一建议的统一目标是促进我们对以下问题的理解： 昼夜节律计时和大脑中的夹带。这项工作的结果将最终告知 制定和实施干预措施，旨在减轻显著不利的代谢和 现代社会中昼夜节律紊乱的心理影响。

Our circadian clocks orchestrate endogenous biological rhythms in physiology, metabolism, and behavior that must be adjusted every day to maintain synchrony with the environment and produce optimally timed rhythmic outputs. This daily adjustment, known as entrainment, is achieved through a sensitivity of the brain's central clock neuron network to both external and internal time cues. Postindustrial society has significantly reduced the reliability of the cues that our circadian system uses for entrainment. This modern challenge to our clocks has wide-spread negative health consequences. The complexity of the brain's clock center is a significant barrier to a comprehensive understanding of the daily adjustment of the circadian system. Understanding the network properties of circadian timekeeping in the brain and the ways in which time cues impinge upon clock centers is critical if we are to address the significantly negative effects of circadian misalignment and dysfunction. The broad goal of this competing renewal application is a comprehensive understanding of the network properties of circadian timekeeping and entrainment in Drosophila melanogaster, whose circadian system features highly conserved molecular, anatomical, and physiological features that it shares with mammalian clock networks. Within this well-defined clock center, we will investigate how highly conserved external and internal time cues produce network-wide clock modulation and control sleep. The goals of our three specific aims are to elucidate: 1) the mechanistic basis of cholinergic and GABAergic inputs into the clock neuron network and the roles they play in sleep control and circadian timekeeping and entrainment, 2) the neurophysiological mechanisms by which the various clock neuron classes of the clock network modulate one another to produce coherent circadian rhythms, and 3) the anatomical and neurophysiological basis of the network integration of light and temperature cues from peripheral sensory receptors. The unifying goal of this proposal is to advance our understanding of circadian timekeeping and entrainment in the brain. The results of this work will ultimately inform the development and implementation of interventions designed to alleviate the significantly adverse metabolic and psychological effects of circadian dysfunction in the modern world.