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

项目概述：喂食和饮水是维持能量和营养的基本行为 液体动态平衡。不能保持能量平衡会导致肥胖或营养不良 液体平衡失调会导致脱水或高血压。控制的神经回路 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神经通路上重叠 口渴，而喂食和喝水的强烈相互依存使人们很难理清 各自的电路。为了解决这个长期存在的问题，这个项目采用了一种新的方法， 使用Brattleboro大鼠梳理高血糖素样多肽-1(GLP-1)系统的各个方面， 控制喂食和饮水。Brattleboro大鼠是一种研究广泛的中枢性糖尿病啮齿动物模型 起源于一群长埃文斯大鼠的尿崩症。自然产生的单核苷酸 这些大鼠的突变导致不能分泌的加压素前体，导致严重的 多尿症。为了弥补多尿，Brattleboro大鼠喝了大约五倍于 由野生型产仔食用，没有观察到任何与取食有关的表型。一系列 我们实验室的研究表明，至少部分多饮与饱腹感信号中断有关。 具体地说，舔舔微结构分析揭示了与改变的 饱腹症和其他研究表明Brattleboro大鼠改变了与液体摄入相关的GLP-1 信号，但完整的摄食相关的GLP-1反应。此外，Brattleboro老鼠似乎有 GLP-1前体在后脑的表达差异及其与野生型的比较 一窝产仔。利用这些液体摄入量的差异，在食物没有差异的情况下 进气，这个项目使用各种方法来更好地阐明负责控制的电路 喝水，特别是与满足口渴有关，并将它们与负责的回路分开 用于食物摄取。因此，通过测试野生型和Brattleboro鼠之间的差异，我们可以 识别GLP-1系统中控制饮酒的回路和细胞群，并将它们分开 与那些控制其他功能的动物不同，比如进食。因此，这些数据将导致更多 完全了解控制液体和食物摄取饱足感的回路，并提供目标 能量和体液动态平衡紊乱的治疗。

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.