Micro-Anatomical Mechanisms of Neuronal Circadian Timekeeping, Output, and Entrainment

摘要 生物钟协调无数的分子、生理和行为过程，以确保内部 时间顺序和最佳的日常时间安排。在动物中，主时钟位于大脑的深处，它依赖于 在复杂的神经网络上，以确保强大的内部时间感，可以容易地与24小时同步 环境循环。越来越多的人一致认为，在现代社会下，我们的生物钟的运行 光和社会环境极大地加剧了一系列令人不安的健康挑战。理解 昼夜节律计时和主起搏器与心脏起搏器同步的神经机制 因此，环境周期(即夹带)至关重要。一个严重的障碍是我们理解 中央生物钟是其组成神经网络的复杂性，这种复杂性因以下事实而变得更加复杂 含有时钟的神经元使用多种神经化学信号，这些信号通过不同的信号机制发挥作用。 哺乳动物和昆虫的关键时钟神经元都表达多种递质--包括多肽协同传递-- 传递体--其中一些作为局部信号穿过已定义的突触，而另一些则起扩散作用 作用于远距离的信号。多肽共释放，虽然是神经系统的一个共同特征，但不是 很好理解。同样，时钟神经元如何利用局部和旁分泌信号来调节昼夜节律 计时和携带仍然是个谜。在这里，我们建议研究关键的肽能时钟神经元在 以果蝇为模型研究从同一神经元释放的两种神经肽如何介导不同的 行为和生理功能，以支持强大的昼夜节律计时和携带。我们的工作将 不仅有助于我们理解哺乳动物大脑中的昼夜节律，而且还将与 一般情况下，多肽共释放的机制。

Abstract Circadian clocks orchestrate myriad molecular, physiological, and behavioral processes to insure internal temporal order and optimal daily timing. In animals, the master clock resides deep within the brain where it relies on complex neural networks to ensure a robust internal sense of time that can readily synchronize with 24-h environmental cycle. There is growing consensus that the operation of our master circadian clock under modern light and social environments contributes significantly to a troubling array of health challenges. Understanding the neural mechanisms underlying circadian timekeeping and the synchronization of the master pacemaker with environmental cycles (i.e., entrainment) is therefore critical. A significant barrier to our understanding of the central circadian clock is the complexity of its constituent neural networks, a complexity compounded by the fact that clock-containing neurons employ multiple neurochemical signals that act via distinct signaling mechanisms. Critical clock neurons in both mammals and insects express multiple transmitters – including peptide co- transmitters - some of which function as local signals across defined synapses while others act as diffusible signals that act over large distances. Peptide co-release, though a common feature of nervous systems, is not well understood. Likewise, how clock neurons employ both local and paracrine signals to mediate circadian timekeeping and entrainment remains enigmatic. Here we propose to study key peptidergic clock neurons in Drosophila as a model to examine how two neuropeptides released from the same neuron can mediate distinct behavioral and physiological functions to support robust circadian timekeeping and entrainment. Our work will not only inform our understanding of circadian timekeeping in the mammalian brain but will also be relevant to the mechanism of peptide co-release generally.