Cycling in a circadian circuit

在昼夜节律循环中骑自行车

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：我们的总体目标是确定行为的昼夜节律是如何产生的。在该项目的先前工作中，我们确定并表征了果蝇内源生物钟的分子机制。我们还启动了研究来确定其机制。具体来说，我们确定了有节奏的休息：活动所需的输出神经元，并在解剖学上连接到中央时钟神经元，这些输出神经元包括背神经元。 1 (DN1) 组，包含一个时钟和两个位于脑间部 (PI) 的非时钟簇，该区域是相当于哺乳动物下丘脑的神经分泌细胞区域，这两个 PI 簇负责调节休息的昼夜节律：活动分泌我们发现DH44是行为节律所必需的，但SIFamide的作用尚未确定。也与已知的昼夜节律输出分子、窄腹和不配对的功能或表达有关。此外，我们的初步数据表明，另一种输出分子神经纤维瘤病 1 (NF1) 是 DN1 中休息：活动节律所必需的。发现 DN1 和 DH44 细胞中的神经活动周期具有 24 小时节律，因此，我们开始将分子成分放入我们确定的细胞基质中，并开发检测方法来监测节律信号的传递。我们勇敢地说，中央时钟细胞生成的时间线索通过 DN1 传输，以驱动 PI 中的节律活动，然后通过释放特定神经肽来控制休息：节律活动我们建议：（1）解决 DN1 中节律活动的重要性，并确定该节律需要哪些时钟细胞和输出分子（2）识别 DN1 中的上游成分。驱动 DH44 细胞节律活动的时钟细胞，并确定 DH44 是否有节律地发挥作用 (3) 确定 SIFamide 在休息：活动节律中的作用，并识别与休息：活动节律相关的其他 PI 分子。鉴于已知的从果蝇到人类的时钟机制和分子的保守性，这些研究预计将提供对产生行为节律的分子网络和细胞回路的全面了解，这些研究可能与我们对人类节律的理解相关，这至关重要。这些研究还将提供对神经回路的维护和功能的一般见解，神经回路在几种神经系统疾病中受到损害。