Molecular and Neural Mechanisms of Temperature Preference Rhythm in Drosophila

果蝇温度偏好节律的分子和神经机制

• 批准号: 10439942
• 负责人: Fumika Hamada
• 金额: $ 20.79万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439942
• 关键词: Antibodies; Behavior; Behavioral; Body Temperature; Brain; Calcitonin Receptor; Calcium; Cells; Circadian Rhythms; Cyclic AMP; Data; Diuretics; Dorsal; Drosophila genus; Exhibits; Fc Receptor; Genetic; Goals; Grant; Homeostasis; Homologous Gene; Hormones; Human; Human body; Image; In Vitro; Infrastructure; Jet Lag Syndrome; Knockout Mice; Lead; Ligands; Mammals; Measurement; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolism; Molecular; Monitor; Motor Activity; Mus; Neurons; Outcome; Outcome Study; Output; Periodicity; Peripheral; Physiology; Pigments; Play; Protein Family; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Role; Sleep; Sleep Disorders; Sleep disturbances; Synapses; Temperature; Testing; Time; Wakefulness; circadian; circadian pacemaker; expectation; experimental study; fly; high resolution imaging; insight; knock-down; mutant; neural circuit; neuromechanism; novel; preference; receptor; reconstitution; shift work

Human body temperature increases during wakefulness and decreases during sleep. The body temperature rhythm (BTR) is a robust output of the circadian clock and is fundamental for maintaining homeostasis, such as generating metabolic energy and sleep, as well as entraining peripheral clocks in mammals. However, the mechanisms that regulate BTR are largely unknown. Therefore, there is a crucial need to identify the molecular mechanisms that regulate BTR. Drosophila are ectotherms, and their body temperatures are close to ambient temperature; therefore, flies select a preferred environmental temperature to set their body temperature. We identified a novel circadian output, the temperature preference rhythm (TPR), in which the preferred temperature in flies increases during the day and decreases at night. TPR thereby produces a daily body temperature rhythm. Fly TPR shares many features with mammalian BTR. During the current grant term, we established that Diuretic hormone 31 receptor (DH31R), a Drosophila calcitonin receptor family protein, mediates TPR, and we demonstrated that the closest mouse homolog of DH31R, calcitonin receptor (Calcr), is essential for normal BTR in mice. Importantly, both TPR and BTR are regulated in a distinct manner from locomotor activity rhythms, and neither DH31R nor Calcr regulate locomotor activity rhythms. Together, our findings suggest that DH31R/Calcr is an ancient and specific mediator of BTR. Thus, understanding fly TPR will provide fundamental insights into the molecular and neural mechanisms that control BTR in mammals. The goal of this proposal is to determine the molecular and neural mechanisms of TPR. Our recent study suggests that DH31 acts on clock neurons via DH31R to regulate TPR. Although DH31 primarily activates DH31R, DH31 can also activate the Pigment dispersing factor receptor (PDFR), required for locomotor activity rhythms, at a modest level in vitro. Because PDFR does not play a major role in daytime TPR, we expect that DH31R and PDFR are expressed in different cells. In addition to the identification of crucial ligand-receptor interactions, we recently found that master clock cells, the dorsal clock neurons 2 (DN2s), control TPR but not locomotor activity rhythms. The central hypothesis of this proposal: DN2s have temporally-regulated contacts with DN1ps and control rhythmic expression of DH31, which activates DH31R in PDFR-negative DN1ps, resulting in TPR. In Aim 1, we will elucidate the physical and functional relationship between DN1ps and DN2s to control TPR. In Aim 2, we will determine the mechanism that sets rhythmic DH31 expression in DN1ps. In Aim 3, we will determine the mechanism by which DH31R-expressing neurons control TPR. This project will contribute to a mechanistic understanding of fly TPR. The outcomes of this study should ultimately provide a novel mechanistic understanding of the mammalian BTR.

人的体温在清醒时升高，在睡眠时降低。的 体温节律（BTR）是生物钟的强大输出，是维持体温的基础 体内平衡，如产生代谢能量和睡眠，以及夹带外周时钟， 哺乳动物然而，调节BTR的机制在很大程度上是未知的。因此，迫切需要 以确定调节BTR的分子机制。 果蝇是外温动物，它们的体温接近环境温度;因此， 选择一个首选的环境温度来设置他们的体温。我们发现了一种新的昼夜节律 输出，温度偏好节律（TPR），其中苍蝇的首选温度在 白天和晚上减少。TPR由此产生每日体温节律。飞TPR分享许多 哺乳动物BTR的特征。在本研究期间，我们确定利尿激素31受体 （DH 31 R），果蝇降钙素受体家族蛋白，介导TPR，我们证明，最接近的 DH 31 R的小鼠同源物降钙素受体（Calcr）对于小鼠中的正常BTR是必需的。重要的是，两者 TPR和BTR的调节方式与自发活动节律不同， 调节运动活动节奏。总之，我们的研究结果表明，DH 31 R/Calcr是一种古老而特异的基因， BTR的中介。因此，了解苍蝇TPR将提供基本的见解，分子和神经 控制哺乳动物BTR的机制。 本研究的目的是确定TPR的分子和神经机制。我们最近的研究 提示DH 31通过DH 31 R作用于时钟神经元，调节TPR。虽然DH 31主要激活 DH 31 R，DH 31还可以激活运动活动所需的色素分散因子受体（PDFR） 节奏，在体外的适度水平。由于PDFR在日间TPR中不起主要作用，我们预计， DH 31 R和PDFR在不同的细胞中表达。除了鉴定关键的配体-受体外， 我们最近发现，主时钟细胞，背时钟神经元2（DN 2），控制TPR，但不 自发活动节律。该建议的核心假设：DN 2具有时间调节的接触 与DN 1 ps和控制DH 31的节律性表达，其激活PDFR阴性DN 1 ps中的DH 31 R， 导致TPR。在目的1中，我们将阐明DN 1 ps和DN 2s之间的物理和功能关系 控制TPR。在目标2中，我们将确定在DN 1 ps中设置节律性DH 31表达的机制。在Aim中 3.我们将确定表达DH 31 R的神经元控制TPR的机制。该项目将 有助于从机理上理解飞行TPR。这项研究的结果最终将提供一个 对哺乳动物BTR的新机制理解。