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.

项目摘要/摘要 有迅速积累的证据表明昼夜节律的睡眠，活动和喂养铅的破坏 有害健康后果。虽然昼夜节律的机制得到了很好的研究，但这种关系 在一天的时间提示和诸如饥饿之类的稳态驱动器之间，人们了解得很糟糕。整合 带有营养提示的昼夜节律发生在大脑中的核心时钟细胞下游。 多个行为电路的交点。该提案利用了果蝇的遗传 模型以检查昼夜节信号与进食电路集成到的机制 与喂养行为协调运动节律。果蝇pars Intercerbralis（PI），一个类似物 哺乳动物下丘脑是一个肽吉尼亚的中心，可以接受日期和营养状态 信息。根据已发布和初步发现，PI可能会从 通过神经肽信号以及产生胆碱能的抑制性输入的核心时钟神经元 味道中间神经元。该提议的中心假设是每个肽吉尼亚PI种群 （DH44+，类似胰岛素的肽产生，Sifamide+和Tacotie）接收一组独特的输入，然后必须 集成在PI中以协调行为输出，并且这种整合通过PI内分泌发生 神经肽信号传导。因此，PI种群可能会调节休息：活动节奏和喂养行为 取决于营养状态，以允许对急性环境线索的反应。在这一指导阶段 申请人将表征中央大脑时钟（AIM 1）和Hugin+的连通性 味觉中间神经元（目标2）到PI并检查这些电路中的每个电路如何调节进食和 休息：活动行为（目标1和2）。在该项目的独立阶段，申请人将使用获得的技能 在指导阶段，研究饥饿如何覆盖PI神经元生理和行为的时钟控制 （AIM 3）以及PI内连接性在协调运动节奏和喂养行为中的作用（AIM 4）。到 追求这些目标，申请人将使用包括RNAi和CRISPR在内的遗传工具的组合， 生理测定法，包括电生理学和钙成像，以及运动的行为测定 节奏和喂养。该项目的成功完成将在两级方面提供重要的进步 神经回路和行为。首先，它将开始阐明相交电路如何使用 神经调节性肽。事实证明，神经调节信号传导在哺乳动物系统中很难研究，并且 这项工作可以提供洞察力，这些见解适用于哺乳动物中神经肽区域的研究，尤其是 在下丘脑中。其次，它将促进对昼夜节律和 在电路和行为水平上喂食。不仅了解电路如何塑造行为，还了解如何塑造行为 诸如改变的喂养模式之类的行为反馈到大脑很重要 改善人类健康。