Parsing the central control of thirst and hunger using a rat model of diabetes insipidus

使用尿崩症大鼠模型解析口渴和饥饿的中枢控制

• 批准号: 10508858
• 负责人: Derek Daniels
• 金额: $ 50.05万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508858
• 关键词: Address; Agonist; Area; Behavior; Behavior Control; Body Fluids; Brain; Brattleboro Rats; Cardiovascular system; Cell Separation; Cells; Central Diabetes Insipidus; Consumption; Data; Dehydration; Diabetes Insipidus; Diabetes Mellitus; Disease; Diuresis; Eating; Failure; Feeding behaviors; Fluid Balance; GLP-I receptor; Genotype; Health; Homeostasis; Hunger; Hypertension; Intake; Laboratories; Lead; Ligands; Liquid substance; Long-Evans Rats; Maintenance; Malnutrition; Modeling; Motivation; Mutation; Neural Pathways; Nucleotides; Obesity; Pathway interactions; Phenotype; Polydipsia; Polyuria; Population; Rattus; Residual state; Rodent Model; Satiation; Series; Signal Transduction; Site; Source; System; Testing; Thirst; Time; Tracer; Vasopressins; Water; Water consumption; antagonist; base; behavioral pharmacology; brain behavior; diabetic rat; drinking; energy balance; feeding; glucagon-like peptide 1; hindbrain; motivated behavior; neural circuit; neuroregulation; novel strategies; preoptic nucleus; preproglucagons; prevent; receptor binding; relating to nervous system; response; restoration

Project Summary: Feeding and drinking are essential behaviors for the maintenance of energy and fluid homeostasis. Failure to maintain energy balance causes obesity or malnutrition and perturbations in fluid balance cause dehydration or hypertension. The neural circuits that control hunger and thirst have been well studied but overlapping neural pathways in the control of hunger or of thirst, and the strong interdependence of feeding and drinking has made it difficult to untangle the respective circuits. To address this long-standing problem, this project takes a novel approach that uses the Brattleboro rat to tease apart aspects of the glucagon-like peptide-1 (GLP-1) system that control feeding and drinking. The Brattleboro rat is a well-studied rodent model of central diabetes insipidus that originated in a colony of Long Evans rats. A naturally occurring single nucleotide mutation in these rats results in a vasopressin precursor that cannot be secreted, causing severe polyuria. To compensate for the polyuria, Brattleboro rats drink approximately five times that consumed by wild-type littermates, without any observed feeding-related phenotype. A series of studies in our laboratory suggest that at least part of the polydipsia involves disrupted satiety signals. Specifically, licking microstructure analyses revealed differences that are consistent with altered satiation and additional studies suggest that Brattleboro rats have altered fluid intake-relevant GLP-1 signaling, but intact feeding-related GLP-1 responses. Moreover, Brattleboro rats appear to have different GLP-1 precursor expression in the hindbrain when compared with that of wild type littermates. Taking advantage of these differences in fluid intake, in the absence of differences in food intake, this project uses a variety of approaches to better elucidate circuits responsible for the control of drinking, especially relevant for satiation of thirst, and to separate these from circuits responsible for food intake. Accordingly, by testing for differences between wild-type and Brattleboro rats, we can identify circuits and populations of cells in the GLP-1 system that control drinking and separate them from those that control other functions such as feeding. As such, these data will lead to a more complete understanding of the circuits that control fluid and food intake satiety and provide targets for treatments of disordered energy and fluid homeostasis.

项目概述：进食和饮水是维持能量的基本行为， 体液平衡不能保持能量平衡会导致肥胖或营养不良， 体液平衡的紊乱引起脱水或高血压。神经回路控制 饥饿和口渴已经得到了很好的研究，但在控制饥饿或口渴的重叠神经通路中， 口渴，以及喂养和饮用的强烈相互依赖性使得很难解开 各自的电路。为了解决这个长期存在的问题，该项目采用了一种新颖的方法， 使用布拉特伯勒大鼠梳理胰高血糖素样肽-1（GLP-1）系统的各个方面， 控制饮食。布拉特伯勒大鼠是一种经过充分研究的中枢性糖尿病啮齿动物模型 尿崩症，起源于一个殖民地的朗埃文斯大鼠。天然存在的单核苷酸 这些大鼠的突变导致不能分泌的加压素前体，引起严重的 多尿。为了补偿多尿，布拉特伯勒大鼠喝大约五倍于 被野生型同窝仔消耗，没有观察到任何喂养相关的表型。一系列 我们实验室的研究表明，至少部分烦渴涉及饱腹感信号的中断。 具体来说，舔微观结构分析显示，差异是一致的改变， 饱食和其他研究表明，Brattleboro大鼠的液体摄入相关GLP-1 信号，但完整的喂养相关的GLP-1反应。此外，布拉特伯勒大鼠似乎有 与野生型相比，后脑中GLP-1前体表达不同 同窝出生的利用这些液体摄入量的差异，在没有食物差异的情况下， 摄入量，该项目使用各种方法，以更好地阐明负责控制电路 饮酒，特别是与口渴的饱足有关，并将这些与负责的电路分开 用于食物摄入。因此，通过测试野生型和Brattleboro大鼠之间的差异，我们可以 确定GLP-1系统中控制饮酒的细胞回路和细胞群，并将它们分离 控制其他功能如进食的神经元。因此，这些数据将导致更多 完全了解控制液体和食物摄入饱腹感的回路，并提供目标 治疗紊乱的能量和流体稳态。