Cycling in a circadian circuit

在昼夜节律循环中骑自行车

• 批准号: 10021740
• 负责人: AMITA SEHGAL
• 金额: $ 4.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021740
• 关键词: Abdomen; Ablation; Activity Cycles; Address; Anatomy; Behavior; Behavioral; Biological Assay; Biology; Brain; Calcium; Cells; Circadian Rhythms; Clock protein; Corticotropin-Releasing Hormone; Cues; Data; Dependence; Dorsal; Drosophila genus; Drosophila melanogaster; Epilepsy; Exhibits; Functional disorder; Genetic; Glutamate Receptor; Glutamates; Goals; Hour; Human; Hypothalamic structure; Impaired cognition; Impairment; Lead; Maintenance; Measures; Mediating; Methods; Modeling; Molecular; Monitor; NF1 gene; Nervous system structure; Neurofibromatosis 1; Neurons; Neuropeptides; Neurophysiology - biologic function; Orthologous Gene; Output; Pathway interactions; Peptides; Periodicity; Physiology; Proteins; Regulation; Research; Rest; Role; Signal Transduction; Site; Sleep Disorders; Stroke; Testing; Time; Work; circadian; circadian pacemaker; experimental study; fly; insight; interest; molecular clock; mutant; nervous system disorder; neural circuit; neuronal circuitry; neurotransmitter release; public health relevance; receptor; relating to nervous system; response; shift work; therapy development; tool; transmission process; tumor growth

 DESCRIPTION (provided by applicant): Our overall goal is to determine how circadian rhythms of behavior are generated. In previous work on this project we identified and characterized molecular mechanisms of the endogenous circadian clock in Drosophila. We also initiated studies to identify the mechanisms that carry time of day cues from the clock and transmit them through the brain. Specifically, we identified output neurons that are required for rhythmic rest:activity and connect anatomically to central clock neurons. These output neurons include the Dorsal Neuron 1 (DN1) group, which contains a clock, and two non-clock clusters in the pars intercerebralis (PI), a region of neurosecretory cells equivalent to the mammalian hypothalamus. The two PI clusters that regulate circadian rhythms of rest:activity secretes the neuropeptides DH44 and SIFamide respectively. We found that DH44 is required for behavioral rhythms, but a role for SIFamide has not been determined yet. Interestingly, the DN1s have also been associated with the function or expression of known circadian output molecules, narrow abdomen and unpaired. In addition, our preliminary data indicate that another output molecule, Neurofibromatosis 1 (NF1), is required in DN1s for rest:activity rhythms. We also find that neural activity cycles with a 24 hour rhythm in DN1 and DH44 cells. Thus, we have started to place molecular components in the cellular substrates we identified, and develop assays to monitor the transmission of rhythmic signals through the network. We hypothesize that time-of-day cues generated in central clock cells are transmitted through DN1s to drive rhythmic activity in the PI, which then controls rest:activity rhythms through release of specific neuropeptides. We propose to: (1) Address the significance of rhythmic activity in the DN1s and determine which clock cells and output molecules are required for this rhythm. (2) Identify the upstream components in clock cells that drive rhythmic activity in the DH44 cells, and determine if DH44 acts rhythmically. (3) Address a role for SIFamide in rest:activity rhythms and identify other PI molecules relevant for rest:activity rhythms. Together these studies are expected to provide a comprehensive understanding of the molecular network and cellular circuit that generates a behavioral rhythm. Given known conservation of clock mechanisms and molecules from flies to humans, these studies will likely be relevant for our understanding of human rhythms, which are critical for normal behavior and physiology. These studies will also provide general insight into the maintenance and function of neural circuits, which are impaired in several neurological disorders.

 描述（由适用提供）：我们的总体目标是确定如何产生昼夜节律的节奏。在此项目的先前工作中，我们确定了果蝇中内源性昼夜节律时钟的分子机制。我们还启动了研究，以确定从时钟中携带时间提示并通过大脑传输的机制。具体而言，我们确定了节奏休息所需的输出神经元：活性并与中央时钟神经元连接。这些输出神经元包括背侧神经元1（DN1）组，其中包含一个时钟和两个非锁定簇（PARS Intercerbralis（PI），这是一个与哺乳动物下丘脑相等的神经分泌细胞区域。调节休息的昼夜节律的两个PI簇分别分泌神经肽DH44和西法酰胺。我们发现行为节奏需要DH44，但尚未确定米达胺的作用。有趣的是，DN1也与已知的昼夜节律分子，狭窄的腹部和未配对的功能或表达有关。此外，我们的初步数据表明DN1中需要另一个输出分子神经瘤病1（NF1）进行休息：活动节奏。我们还发现，DN1和DH44细胞中有24小时节奏的神经活动循环。这就是我们已经开始将分子成分放置在我们鉴定的细胞底物中，并开发测定以监视通过网络传播节奏信号的传播。我们假设在中央时钟细胞中产生的时间提示通过DN1传播，以驱动PI中的节奏活动， 然后控制休息：通过释放特定神经肽的活动节奏。我们建议：（1）解决DN1S节奏活性的重要性，并确定此节奏需要哪些时钟细胞和输出分子。 （2）确定在DH44细胞中驱动节奏活性的时钟细胞中的上游成分，并确定DH44是否有节奏。 （3）介绍了西佛胺在休息中的作用：活性节奏并识别与静止相关的其他PI分子：活性节奏。预计这些研究将对产生行为节奏的分子网络和细胞回路提供全面的理解。鉴于已知的时钟机制和分子从苍蝇到人类的分子，这些研究可能与我们对人类节奏的理解有关，这对于正常行为和生理至关重要。这些研究还将提供对神经元回路的维持和功能的一般见解，这些神经元电路受到了几种神经系统疾病的损害。