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: 10414063
• 负责人: Annika Fitzpatrick Barber
• 金额: $ 23.59万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414063
• 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.

有迅速积累的证据表明，昼夜节律的睡眠，活动和喂养的破坏会导致有害的健康后果。虽然昼夜节律的机制得到了充分研究，但对饥饿等静止驱动器（例如饥饿之类的驱动器）之间的关系知之甚少。在多个行为回路的交点上，昼夜节律信息与营养线索的整合发生在大脑中核心时钟细胞的下游。该建议利用了果蝇的遗传模型来检查昼夜节信号与进食电路集成以与喂养行为相协调的运动节奏的机制。果蝇的脑膜间脑脑间（PI）是哺乳动物下丘脑的类似物，是一个替代性中心，同时接收日期和营养状态信息。根据已发表和初步的发现，我建议PI通过神经肽信号从核心时钟神经元获得兴奋性输入，以及产生胆碱能产生的糖果中神经元的抑制性输入。我假设每种肽GIC的PI种群（DH44+，胰岛素样产生的肽，Sifamide+和Tacotie）都会收到一组独特的输入，然后必须将其集成到PI中以协调行为的行为输出，并且该整合通过内型帕托里抗激素神经神经肽信号出现。因此，PI种群可能同时调节休息：活动节奏和喂养行为，具体取决于营养状态，以允许对急性环境线索的反应。在该项目的指导阶段，我将表征中央大脑时钟（AIM 1）和Hugin+味觉中间神经元（AIM 2）到PI的连通性，并检查这些电路中的每个电路如何调节喂食和休息：活动行为：活动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进食行为中的作用（AIM 4）。为了追求这些目标，我将使用包括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测定以及运动节律和喂养的行为测定。该项目的成功完成将在神经电路和行为的水平上提供重要的进步。首先，它将开始阐明使用神经调节肽的相交电路如何通信。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，它将提高人们对昼夜节律的复杂相互作用的理解，并在电路和行为水平上喂食。不仅了解电路如何塑造行为，而且了解诸如改变的喂养模式之类的行为如何回馈大脑，这对于制定干预措施以改善人类健康至关重要。