The Generation of Multi-Phasic Circadian Output

多相昼夜节律输出的生成

• 批准号: 10618652
• 负责人: Paul H Taghert
• 金额: $ 39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618652
• 关键词: Behavior; Biological Models; Brain; Cell Communication; Cells; Dedications; Diabetes Mellitus; Drosophila genus; Functional disorder; Generations; Goals; Hormones; Laboratory Study; Malignant Neoplasms; Mental Depression; Mental disorders; Metabolic Diseases; Modeling; Molecular; Neuroendocrinology; Neurons; Neuropeptides; Output; Pacemakers; Periodicity; Phase; Physiology; Research; Series; Signal Pathway; Signal Transduction; Sleep; Stereotyping; System; Temperature; Testing; Time; Tissues; Work; circadian; circadian pacemaker; fly; mind control; molecular clock; neural circuit; neuromechanism; neurophysiology; nodal myocyte; programs; transmission process

PROJECT SUMMARY/ ABSTRACT The purpose of an internal circadian clock is to generate a series of phases - time markers across the day and night by which different aspects of physiology and behavior (e.g., sleep, hormone release, temperature elevations) may be aligned to local time for optimal efficiency. We know a great deal about the molecular mechanisms of the clock (the timekeeping system) and how it is sensitive to local time. We know much less about circadian output, and specifically how the clock generates multiple phases across the entire solar day. Such phases are used by other clock cells, and by non-clock bearing downstream cells and circuits. Our laboratory studies circadian neurophysiology and the overall goal of this project is to understand the generation and usage of different circadian phasic outputs. The work is performed in the model system Drosophila. It builds on observations and a model we created from our past studies of the neural circuit in the Drosophila brain that controls daily locomotor behavior. In the fly brain, ~150 dedicated circadian pacemaker neurons direct daily rhythmic physiology and behavior. These 150 pacemakers are highly synchronized: they all tell the same time. Our model features the cell-intrinsic molecular clock in all pacemakers directing a morning phase of heightened neuronal activity. Yet, different subsets of pacemakers are not all active in the morning, but at different and stereotyped times of the day and night. The diversity of active periods (circadian phases) is generated primarily by cell interactions (especially neuropeptide modulation) and together these activity periods represent the multi-phasic outputs of the pacemaker system. Overall, this research program aims to extend and test this model by providing a cell- and molecular-level understanding for how circadian phase information is transmitted beyond the pacemaker system and received by downstream target circuits. Our work in Drosophila will likely inform our understanding of circadian output in the mammalian brain, and will also be relevant more generally to the mechanisms of neural circuit modulation by neuropeptides.

项目总结/摘要 内部生物钟的目的是产生一系列的相位-时间标记， 生理和行为的不同方面（例如，睡眠，荷尔蒙释放， 温度升高）可以与本地时间对准以获得最佳效率。我们知道很多关于 时钟的分子机制（计时系统）以及它如何对当地时间敏感。我们知道 更不用说昼夜节律输出，特别是时钟如何在整个过程中产生多个相位。 太阳日这样的相位由其他时钟单元使用，并且由非时钟承载下游单元使用， 电路.我们的实验室研究昼夜神经生理学，这个项目的总体目标是了解 不同昼夜节律相位输出的产生和使用。工作是在模型系统中完成的 果蝇它建立在观察和我们从过去的神经回路研究中创建的模型基础上， 控制日常运动行为的果蝇大脑在果蝇大脑中，约150个专用的昼夜节律 起搏神经元指导日常节律生理和行为。这150个心脏起搏器 synchronized：它们都在同一时间发出声音。我们的模型的特点是细胞内在的分子钟在所有 心脏起搏器引导神经元活动的早晨阶段。然而，不同的起搏器子集 并不都是在早上活动，而是在白天和晚上不同的固定时间活动。之多样 活跃期（昼夜节律阶段）主要由细胞相互作用（特别是神经肽）产生 调制），并且这些活动周期一起表示起搏器系统的多相输出。 总的来说，这项研究计划的目的是通过提供一个细胞和分子水平， 了解昼夜节律相位信息如何传输到起搏器系统之外， 由下游目标电路接收。我们在果蝇中的工作可能会帮助我们理解 哺乳动物大脑中的昼夜节律输出，也将更普遍地与 通过神经肽调节神经回路。