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一种新型的胰高血糖素样肽-1 受体表达的小鼠模型:对大脑的观察。

A novel mouse model of glucagon-like peptide-1 receptor expression: A look at the brain.

机构信息

Department of Biomedical Sciences and Center for Brain Repair, Florida State University College of Medicine, Tallahassee, Florida, USA.

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

出版信息

J Comp Neurol. 2020 Oct;528(14):2445-2470. doi: 10.1002/cne.24905. Epub 2020 Mar 29.

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a number of functions to maintain energy homeostasis and contribute to motivated behavior, both peripherally and within the central nervous system (CNS). These functions, which include insulin secretion, gastric emptying, satiety, and the hedonic aspects of food and drug intake, are primarily mediated through stimulation of the GLP-1 receptor. While this receptor plays an important role in a variety of physiological outcomes, data regarding its CNS expression has been primarily limited to regional receptor binding and single-label transcript expression studies. We thus developed a bacterial artificial chromosome transgenic mouse, in which expression of a red fluorescent protein (mApple) is driven by the GLP-1R promoter. Using this reporter mouse, we characterized the regional and cellular expression patterns of GLP-1R expressing cells in the CNS, using double-label immunohistochemistry and in situ hybridization. GLP-1R-expressing cells were enriched in several key brain regions and circuits, including the lateral septum, hypothalamus, amygdala, bed nucleus of the stria terminalis, hippocampus, ventral midbrain, periaqueductal gray, and cerebral cortex. In most regions, GLP-1R primarily colocalized with GABAergic neurons, except within some regions such as the hippocampus, where it was co-expressed in glutamatergic neurons. GLP-1R-mApple cells were highly co-expressed with 5-HT3 receptor-containing neurons within the cortex and striatum, as well as with dopamine receptor- and calbindin-expressing cells within the lateral septum, the brain region in which GLP-1R is most highly expressed. In this manuscript, we provide detailed images of GLP-1R-mApple expression and distribution within the brain and characterization of these neurons.

摘要

胰高血糖素样肽-1 (GLP-1) 是一种肠促胰岛素激素,具有多种功能,可维持能量稳态,并有助于外周和中枢神经系统 (CNS) 中的动机行为。这些功能包括胰岛素分泌、胃排空、饱腹感以及食物和药物摄入的愉悦方面,主要通过刺激 GLP-1 受体来实现。虽然该受体在各种生理结果中发挥着重要作用,但关于其 CNS 表达的数据主要限于区域受体结合和单一标记转录表达研究。因此,我们开发了一种细菌人工染色体转基因小鼠,其中红色荧光蛋白 (mApple) 的表达受 GLP-1R 启动子驱动。使用这种报告小鼠,我们通过双标记免疫组织化学和原位杂交,对 CNS 中 GLP-1R 表达细胞的区域和细胞表达模式进行了表征。GLP-1R 表达细胞在几个关键的脑区和回路中丰富,包括外侧隔核、下丘脑、杏仁核、终纹床核、海马体、腹侧中脑、导水管周围灰质和大脑皮层。在大多数区域,GLP-1R 主要与 GABA 能神经元共表达,除了在某些区域如海马体,其中与谷氨酸能神经元共表达。GLP-1R-mApple 细胞在皮层和纹状体中与 5-HT3 受体包含神经元高度共表达,在外侧隔核中与多巴胺受体和钙结合蛋白表达细胞共表达,外侧隔核是 GLP-1R 表达最丰富的脑区。在本手稿中,我们提供了 GLP-1R-mApple 在大脑中的表达和分布的详细图像,并对这些神经元进行了特征描述。

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