Integration of circadian and homeostatic signals in a peptidergic circuit in Drosophila

果蝇肽能回路中昼夜节律和稳态信号的整合

• 批准号: 10523627
• 负责人: Annika Fitzpatrick Barber
• 金额: $ 4.53万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523627
• 关键词: Acute; Back; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Calcium; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cues; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Feeding Patterns; Feeding behaviors; Genetic; Genetic Models; Goals; Health; Homeostasis; Human; Hunger; Hypothalamic structure; Image; Interneurons; Intervention; Lead; Mammals; Mentors; Neurons; Neuropeptides; Nutritional; Organism; Output; Peptides; Phase; Physiological; Physiology; Population; Publishing; RNA Interference; Rest; Role; Shapes; Signal Transduction; Source; Starvation; System; Time; Work; analog; base; cholinergic; circadian; circadian pacemaker; environmental change; feeding; improved; insight; insulin-like peptide; neural circuit; neuroregulation; paracrine; response; skills; sleep pattern; tool

Project Summary/ Abstract There is rapidly accumulating evidence that disruptions of circadian patterns of sleep, activity and feeding lead to deleterious health consequences. While circadian clock mechanisms are well-studied, the relationship between time-of-day cues and homeostatic drives such as hunger are poorly understood. The integration of circadian information with nutritional cues occurs downstream of the core clock cells in the brain at the intersection of multiple behavioral circuits. This proposal exploits the Drosophila melanogaster genetic model to examine the mechanism by which circadian signals integrate with feeding circuitry to coordinate locomotor rhythms with feeding behavior. The Drosophila pars intercerebralis (PI), an analog of the mammalian hypothalamus, is a peptidergic center that receives both time-of-day and nutritional state information. Based on published and preliminary findings, it is likely that that the PI receives excitatory input from core clock neurons via neuropeptide signals, as well as inhibitory inputs from cholinergic Hugin-producing gustatory interneurons. The central hypothesis of this proposal is that each of the peptidergic PI populations (DH44+, insulin-like peptide producing, SIFamide+ and Taotie) receives a unique set of inputs, which must then be integrated within the PI to coordinate behavioral outputs, and that this integration occurs via intra-PI paracrine neuropeptide signaling. Thus, PI populations likely modulate both rest:activity rhythms and feeding behavior depending on nutritional state to allow responses to acute environmental cues. In the mentored phase of this project the applicant will characterize the connectivity from the central brain clock (Aim 1) and the hugin+ gustatory interneurons (Aim 2) to the PI and examine how each of these circuits modulates feeding and rest:activity behavior (Aims 1 and 2). In the independent phase of this project the applicant will use skills gained in the mentored phase to investigate how starvation overrides clock control of PI neuron physiology and behavior (Aim 3) and the role of intra-PI connectivity in coordinating locomotor rhythms and feeding behavior (Aim 4). To pursue these aims the applicant will use a combination of genetic tools including RNAi and CRISPR, physiological assays including electrophysiology and calcium imaging, and behavioral assays for locomotor rhythms and feeding. Successful completion of this project will offer important advances at both the level of neural circuitry and behavior. First, it will begin to elucidate how intersecting circuits communicate using neuromodulatory peptides. Neuromodulatory signaling has proven difficult to study in mammalian systems, and this work can offer insights that will be applicable to studies of neuropeptidergic regions in mammals, particularly in the hypothalamus. Second, it will advance understanding of the complex interplay of circadian rhythms and feeding both at the circuit and behavioral levels. Understanding not only how circuitry shapes behavior, but how behavior such as altered feeding patterns feeds back to the brain is important for developing interventions to improve human health.

项目总结/摘要 越来越多的证据表明，睡眠、活动和进食的昼夜节律模式的破坏， 有害健康的后果。虽然生物钟机制已经得到了很好的研究， 一天中的时间线索和自我平衡驱动（如饥饿）之间的关系尚不清楚。的整合 具有营养线索的昼夜节律信息发生在大脑中的核心时钟细胞的下游， 多个行为回路的交叉点。这项提议利用了黑腹果蝇的基因 模型来研究昼夜节律信号与进食电路整合的机制， 协调运动节奏和进食行为。果蝇大脑间部（PI），一种类似物 哺乳动物的下丘脑是一个肽能中心，接收一天中的时间和营养状态 信息.根据已发表的和初步的调查结果，PI很可能接收到来自 核心时钟神经元通过神经肽信号，以及抑制输入胆碱能Hugin产生 味觉中间神经元该建议的中心假设是，每个肽能PI群体 (DH44+，胰岛素样肽产生，SIFamide+和饕餮）接收一组独特的输入，然后必须 在PI内整合以协调行为输出，并且这种整合通过PI内旁分泌发生 神经肽信号因此，PI种群可能调节休息：活动节律和进食行为 这取决于营养状况，以允许对急性环境线索作出反应。在这个指导阶段， 项目申请人将表征从中枢脑时钟（目标1）和hugin+的连接 味觉中间神经元（目标2）的PI，并检查这些电路如何调节喂养和 休息：活动行为（目标1和2）。在这个项目的独立阶段，申请人将使用获得的技能 在指导阶段，研究饥饿如何超越PI神经元生理和行为的时钟控制 (Aim 3）和PI内连接在协调运动节律和摄食行为中的作用（目的4）。到 为了实现这些目标，申请人将使用包括RNAi和CRISPR在内的遗传工具的组合， 包括电生理学和钙成像在内的生理学测定，以及用于运动的行为测定。 节奏和进食该项目的成功完成将在以下两个方面取得重要进展： 神经回路和行为首先，它将开始阐明交叉电路如何使用 神经调节肽神经调节信号已被证明难以在哺乳动物系统中进行研究， 这项工作可以提供的见解，将适用于研究哺乳动物的神经肽能区域，特别是 在下丘脑第二，它将促进对昼夜节律复杂相互作用的理解， 在电路和行为层面上都有进食。不仅要了解电路如何塑造行为， 行为，如改变喂养模式反馈到大脑是重要的发展干预， 改善人类健康。