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

神经元昼夜节律计时、输出和夹带的微观解剖机制

• 批准号: 10595056
• 负责人: ORIE T SHAFER
• 金额: $ 37.01万
• 依托单位: ADVANCED SCIENCE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595056
• 关键词: Address; Anatomy; Animals; Architecture; Behavioral; Brain; Cell model; Chronobiology; Circadian Rhythms; Complex; Consensus; Cues; Diffusion; Dorsal; Drosophila genus; Drosophila melanogaster; Ensure; Environment; Exhibits; Glutamates; Goals; Health; Hour; Human; Insecta; Lateral; Light; Mammals; Measures; Medial; Mediating; Microanatomy; Modeling; Modernization; Molecular; Morphology; Nervous System; Neurons; Neuropeptides; Organism; Output; Pacemakers; Paracrine Communication; Peptide Signal Sequences; Peptides; Physiological; Pigmentation physiologic function; Pigments; Play; Process; Property; Resolution; Role; Shapes; Signal Transduction; Site; Social Environment; Structure; Synapses; Temperature; Testing; Time; Work; cell type; cellular targeting; circadian; circadian pacemaker; fly; imaging modality; insight; neural; neural network; neurochemistry; neuromechanism; neuropeptide F; neurotransmission; new technology; operation; paracrine; presynaptic; release factor; sensory gating; sensory input; transmission process

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.

抽象的 昼夜节律时钟协调无数的分子、生理和行为过程，以确保内部 时间顺序和最佳每日时间。在动物中，主时钟位于大脑深处，它依赖于 复杂的神经网络，以确保强大的内部时间感，可以轻松与 24 小时同步 环境循环。人们越来越认识到，我们的主生物钟在现代环境下的运行 光和社会环境在很大程度上导致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同步的神经机制 因此，环境循环（即夹带）至关重要。我们理解的一个重大障碍 中央生物钟是其组成神经网络的复杂性，这一复杂性因以下事实而变得更加复杂： 含有时钟的神经元利用多种神经化学信号，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表达多种递质——包括肽辅酶 发射器 - 其中一些充当跨定义突触的本地信号，而其他则充当可扩散信号 远距离作用的信号。肽共释放虽然是神经系统的一个常见特征，但并非如此 很好理解。同样，时钟神经元如何利用局部信号和旁分泌信号来调节昼夜节律 计时和夹带仍然是个谜。在这里，我们建议研究关键的肽能时钟神经元 果蝇作为模型来研究从同一神经元释放的两种神经肽如何介导不同的神经肽 行为和生理功能，以支持强大的昼夜节律计时和夹带。我们的工作将 不仅有助于我们理解哺乳动物大脑的昼夜节律计时，而且还与 肽共释放的一般机制。