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: 10200913
• 负责人: Annika Fitzpatrick Barber
• 金额: $ 24.05万
• 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/10200913
• 关键词: Ablation; Acetylcholine; Acute; Back; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Calcium; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Complex; Cues; Diuretics; Drosophila genus; Drosophila melanogaster; Eating; Electrophysiology (science); Feeding Patterns; Feeding behaviors; Genetic; Genetic Models; Goals; Habits; Health; Homeostasis; Hormones; Human; Hunger; Hypothalamic structure; Image; Insulin Resistance; Interneurons; Intervention; Lead; Locomotion; Mammals; Measures; Mediating; Mentors; Modeling; Neurons; Neuropeptide Receptor; Neuropeptides; Nutritional; Obesity; Organism; Output; Pattern; Peptides; Periodicity; Phase; Physiological; Physiology; Population; Publishing; RNA Interference; Rest; Role; Shapes; Signal Transduction; Source; Starvation; Stress; System; Testing; Time; Work; analog; base; calcium indicator; cholinergic; circadian; circadian pacemaker; circadian regulation; environmental change; feeding; food restriction; genetic approach; improved; insight; insulin-like peptide; knock-down; locomotor control; neural circuit; neuropeptide F; neuropeptide F receptor; neuroregulation; paracrine; receptor expression; reduced food intake; response; sensor; skills; sleep pattern; tool

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, I propose that the PI receives excitatory input from core clock neurons via neuropeptide signals, as well as inhibitory inputs from cholinergic Hugin-producing gustatory interneurons. I hypothesize 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 I 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 I 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 I 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.

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会导致有害的健康后果。虽然生物钟机制已得到充分研究，但人们对一天中的时间线索与饥饿等稳态驱动之间的关系知之甚少。昼夜节律信息与营养线索的整合发生在大脑中多个行为回路交叉点的核心时钟细胞的下游。该提案利用果蝇遗传模型来研究昼夜节律信号与进食回路整合以协调运动节律与进食行为的机制。果蝇脑间部 (PI) 类似于哺乳动物下丘脑，是一个肽能中心，负责接收时间和营养状态信息。根据已发表的初步研究结果，我提出 PI 通过神经肽信号接收来自核心时钟神经元的兴奋性输入，以及来自产生胆碱能 Hugin 的味觉中间神经元的抑制性输入。我假设每个肽能 PI 群体（DH44+、胰岛素样肽产生、SIFamide+ 和饕餮）接收一组独特的输入，然后必须将其整合到 PI 内以协调行为输出，并且这种整合通过 PI 内旁分泌神经肽信号传导发生。因此，PI群体可能会根据营养状态调节休息：活动节律和进食行为，以对急性环境线索做出反应。在该项目的指导阶段，我将描述从中央大脑时钟（目标 1）和 Hugin+ 味觉中间神经元（目标 2）到 PI 的连接，并检查这些回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，我将利用在指导阶段获得的技能来研究饥饿如何超越 PI 神经元生理和行为的时钟控制（目标 3）以及 PI 内连接在协调运动节律和进食行为中的作用（目标 4）。为了实现这些目标，我将结合使用 RNAi 和 CRISPR 等遗传工具、电生理学和钙成像等生理测定以及运动节律和进食行为测定。该项目的成功完成将在神经回路和行为层面取得重要进展。首先，它将开始阐明交叉电路如何使用神经调节肽进行通信。事实证明，神经调节信号传导在哺乳动物系统中很难研究，这项工作可以提供适用于哺乳动物神经肽能区域（特别是下丘脑）研究的见解。其次，它将增进对昼夜节律和饮食在回路和行为层面上复杂相互作用的理解。不仅了解电路如何塑造行为，而且了解改变进食模式等行为如何反馈到大脑对于制定改善人类健康的干预措施也很重要。