Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI:10.1016/j.metabol.2024.156099

Kristine M. Conde , HueyZhong Wong , Shuzheng Fang , Yongxiang Li , Meng Yu , Yue Deng , Qingzhuo Liu , Xing Fang , Mengjie Wang , Yuhan Shi , Olivia Z. Ginnard , Yuxue Yang , Longlong Tu , Hesong Liu , Hailan Liu , Na Yin , Jonathan C. Bean , Junying Han , Megan E. Burt , Sanika V. Jossy , Yong Xu

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Abstract

Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HT^DRN➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HT^DRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABA_A receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HT^DRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.

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5 -羟色胺神经元整合GABA和多巴胺输入来调节进餐起始。

肥胖是一种日益严重的全球健康流行病，口服治疗方法有限。5-羟色胺（5-HT）是一种神经递质，仍然是新的减肥疗法的一个很好的靶点，但在了解中隔背核（DRN）产生的5-羟色胺及其参与进餐的机制方面仍然存在空白。使用光遗传喂养模式，我们发现5-HTDRN《弓形核》（ARH）回路在起始进食中起作用。结合电生理学和channel rhodopins -2- assisted Circuit Mapping，我们证明了5-HTDRN神经元接受部分来自DRN中gaba能神经元的抑制性输入，并且饥饿可以增强5-HT反应。此外，5-HT神经元中GABAA受体亚基的缺失会抑制进食开始，但对饱足过程没有影响。最后，我们确定了多巴胺能输入通过多巴胺受体D2在增强对gaba诱导的摄食反应中的作用。因此，我们的研究结果表明，5-HTDRN神经元受到GABA和多巴胺的协同抑制作用的抑制，开始进食。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism