104-OR：后脑胰高血糖素样肽 1（Glucagon-Like Peptide 1）产生神经元的状态依赖性活动通过功能上相互关联的下丘脑和边缘环路调控消费行为和价值行为

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-104-or

MIGUEL DURAN, SONJA VIRKUS, KYLIE A. MCMICHEN, YASLLE ANDRADE CAVALCANTE MORAES, ESHITA YADAV, JAGJOT K. SINGH, ZOE FOKAKIS, SAMANTHA Q. STOCKING, SAMUEL O. POOLE, CHAD S. HUNTER, KIRK M. HABEGGER, JAMES A. HARDAWAY

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引用次数: 0

摘要

简介：胰高血糖素样肽1（GLP-1）治疗药物的应用如雨后春笋般涌现，但我们对产生GLP-1的内源性系统及其如何调节行为的了解仍不全面。孤束核中的前胰高血糖素神经元（GcgNTS 神经元）是大脑中 GLP-1 的主要来源。在这项研究中，我们考察了 GcgNTS 神经元对消耗行为和情绪行为的神经生理学和因果贡献。方法：电生理学、体内光遗传学、纤维光度计。结果通过电生理学研究，我们观察到 GcgNTS 神经元的神经发射和兴奋性在 24 小时食物剥夺后会降低，且因性别而异。相反，GcgNTS神经元在被剥夺食物后短暂进食1小时后，其发射率会显著增加。与此相一致的是，GcgNTS神经元在暴饮暴食般摄入适口的高脂肪饮食后显示出升高的Fos水平。我们使用体内光遗传学方法观察到，光遗传学激活 GcgNTS 神经元会产生焦虑和负性情绪，并因性别而异。高频激活 GcgNTS 神经元也会减少进食和食欲行为。有趣的是，高频激活 GcgNTS 神经元产生的持久效应在停止激光照射后仍然存在。利用一种新型转基因小鼠 Gcg-IRES-FlpO 与 Glp1r-Cre 小鼠杂交，并结合病毒和转基因报告，我们发现 GcgNTS 神经元与下丘脑和杏仁核中的 Glp1r 神经元之间存在相互联系。目前，我们正在测量 GcgNTS 神经元与下丘脑室旁核和杏仁核中 Glp1r 神经元之间的功能连接。结论GcgNTS神经元与下丘脑和杏仁核中相互关联的GLP-1R表达网络相互作用，控制着情绪和消耗。披露 M. Duran：无。S. Virkus: 无。K.A. McMichen：无。Y. Andrade Cavalcante Moraes: None.E. Yadav：无。J.K. Singh：无。Z. Fokakis：Z. Fokakis: None.S.Q. Stocking：无。S.O. Poole：无。C.S. Hunter：无。K.M. Habegger：研究支持；礼来公司。顾问；Glyscend Inc.股票/股东；Glyscend Inc.顾问；Merck & Co.研究支持；诺和诺德顾问团; Abvance Therapeutics.J.A. Hardaway：无。Funding K01DK115902R03DK129561P30DK079626P30DK056336

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104-OR: State-Dependent Activity in Hindbrain Glucagon-Like Peptide 1—Producing Neurons Regulates Consummatory and Valence Behavior through Functionally Interconnected Hypothalamic and Limbic Circuits

Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (GcgNTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of GcgNTS neurons to consummatory and valence behavior. Methods: electrophysiology, in vivo optogenetics, fiber photometry. Results: Using electrophysiology, we observed that GcgNTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, GcgNTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, GcgNTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of GcgNTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of GcgNTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of GcgNTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that GcgNTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between GcgNTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala. Conclusions: GcgNTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala. Disclosure M. Duran: None. S. Virkus: None. K.A. McMichen: None. Y. Andrade Cavalcante Moraes: None. E. Yadav: None. J.K. Singh: None. Z. Fokakis: None. S.Q. Stocking: None. S.O. Poole: None. C.S. Hunter: None. K.M. Habegger: Research Support; Eli Lilly and Company. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Consultant; Merck & Co., Inc. Research Support; Novo Nordisk. Advisory Panel; Abvance Therapeutics. J.A. Hardaway: None. Funding K01DK115902R03DK129561P30DK079626P30DK056336

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.

104-OR： 后脑胰高血糖素样肽 1（Glucagon-Like Peptide 1）产生神经元的状态依赖性活动通过功能上相互关联的下丘脑和边缘环路调控消费行为和价值行为

摘要

104-OR：后脑胰高血糖素样肽 1（Glucagon-Like Peptide 1）产生神经元的状态依赖性活动通过功能上相互关联的下丘脑和边缘环路调控消费行为和价值行为