Molecular and Neural Mechanisms of Temperature Preference Rhythm in Drosophila

人的体温在清醒时升高，在睡眠时降低。这个 体温节律是生物钟的强健输出，是维持体温的基础 动态平衡，例如产生新陈代谢能量和睡眠，以及引入外周时钟 哺乳动物。然而，调控BTR的机制在很大程度上是未知的。因此，有一个迫切的需要 以确定调控BTR的分子机制。 果蝇是外温类动物，它们的体温接近环境温度；因此，苍蝇 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)，其中苍蝇的偏好温度在 白天减少，夜间减少。因此，TPR产生每日的体温节律。Fly TPR分享了许多 哺乳动物btr的特征。在目前的赠款期限内，我们建立了利尿剂激素31受体 (DH31R)，一个果蝇降钙素受体家族蛋白，介导TPR，我们证明了最接近的 DH31R的小鼠同源基因，即降钙素受体(Calcr)，对于小鼠正常的BTR是必不可少的。重要的是，两者 TPR和BTR以不同于运动活动节律的方式调节，DH31R和Calcr都不是 调节运动活动节律。综上所述，我们的发现表明DH31R/Calcr是一种古老而特异的 Btr的调解人。因此，了解Fly TPR将提供对分子和神经的基本见解 在哺乳动物中控制BTR的机制。 这项建议的目的是确定TPR的分子和神经机制。我们最近的研究 提示DH31通过DH31R作用于时钟神经元，调节TPR。虽然DH31主要激活 DH31R、DH31还可以激活运动活动所需的色素分散因子受体(PDFR) 节律，在体外处于适度的水平。由于PDFR在日间TPR中不起主要作用，我们预计 DH31R和PDFR在不同的细胞中表达。除了关键的配体-受体的鉴定 相互作用，我们最近发现主时钟细胞，背部时钟神经元2(DN2)，控制TPR，但不 运动活动节律。这一提议的中心假设：DN2有时间调节的接触 通过DN1ps和控制DH31的节律性表达，激活PDFR阴性DN1ps中的DH31R， 导致了TPR。在目标1中，我们将阐明DN1p和DN2s之间的物理和功能关系 控制TPR。在目标2中，我们将确定在DN1ps中设定节律性DH31表达的机制。在AIM 3，我们将确定DH31R表达神经元控制TPR的机制。这个项目将 有助于对Fly TPR的机械性理解。这项研究的结果最终应该提供一个 对哺乳动物btr的新的机制理解。

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.