Network Properties of Circadian Clock Modulation and Entrainment

我们的生物钟在生理、新陈代谢和行为方面协调内源生物节奏 必须每天调整，以保持与环境的同步，并产生最佳的定时节奏 产出。这种日常调节，即所谓的夹带，是通过大脑中枢的敏感度来实现的。 时钟神经元网络对外部和内部时间线索都有影响。后工业社会显著减少了 我们的昼夜节律系统用于携带的线索的可靠性。这种对我们的时钟提出的现代挑战 广泛存在的负面健康后果。大脑时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 大脑中昼夜计时的特性以及时间提示影响时钟中心的方式是 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。这个 这一竞争性续订应用的广泛目标是全面了解 黑腹果蝇的昼夜节律计时和携带，其昼夜节律系统具有很高的特征 具有与哺乳动物时钟网络相同的保守的分子、解剖和生理特征。 在这个定义明确的时钟中心内，我们将调查高度保守的外部和内部时间提示 产生全网时钟调制并控制睡眠。我们的三个具体目标的目的是阐明： 1)胆碱能和GABA能传入时钟神经元网络的机制基础及其作用 在睡眠控制和昼夜计时和携带中发挥作用，2)神经生理学机制，通过 时钟网络的各种时钟神经元类别相互调制以产生一致的昼夜节律 3)光温网络整合的解剖学和神经生理学基础 来自外围感官感受器的信号。这项建议的统一目标是增进我们对 昼夜节律计时和大脑中的缠绕。这项工作的结果最终将告知 制定和实施干预措施，旨在减轻严重不良代谢和 现代社会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.