A septal inhibitory circuit constrains alcohol reward and mediates liraglutide's suppressive effects on alcohol intake in mice

  • Neuron. 2026 Mar 27:S0896-6273(26)00125-X. doi: 10.1016/j.neuron.2026.02.019.
Yu Tian  1 ,  Yutong Liu  2 ,  Haiyang Jing  2 ,  Cuijie Shi  3 ,  Yao Li  4 ,  Shiyu Dong  5 ,  Long Li  5 ,  Bingchen Chen  6 ,  Yanming Chen  7 ,  Jufang He  8 ,  Yixiao Luo  9 ,  Zijun Chen  10 ,  Yingjie Zhu  11
Affiliations
  • 1. Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
  • 2. Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Neher Neural Plasticity Laboratory, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3. Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China.
  • 4. Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Neher Neural Plasticity Laboratory, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shandong Normal University, Jinan 250014, China.
  • 5. Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 6. Department of Endocrinology and Metabolic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China.
  • 7. Department of Endocrinology and Metabolic Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 8. Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
  • 9. Hunan Province People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410081, China. Electronic address: [email protected].
  • 10. Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Neher Neural Plasticity Laboratory, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China; University of Chinese Academy of Sciences, Beijing 100049, China; Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen 518055, China. Electronic address: [email protected].
  • 11. Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Neher Neural Plasticity Laboratory, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China; University of Chinese Academy of Sciences, Beijing 100049, China; Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen 518055, China; CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: [email protected].
PMID: 41903537 DOI: 10.1016/j.neuron.2026.02.019
Abstract

Alcohol use disorder (AUD) lacks effective brain-targeted treatments. Here, using mouse models, we show that glucagon-like peptide-1 receptor (GLP-1R) signaling in the dorsal lateral septum (dLS) regulates alcohol consumption and reward. Systemic administration of the GLP-1R agonist liraglutide decreased alcohol intake and ethanol-evoked dopamine release in the nucleus accumbens, requiring GLP-1R expression in the dLS. Alcohol consumption suppressed dLSGLP-1R neuronal activity, whereas liraglutide prevented alcohol-induced suppression of transient calcium dynamics. Inactivation of these neurons increased alcohol consumption and abolished the behavioral effects of liraglutide, whereas chemogenetic activation suppressed alcohol-directed behavior. Circuit-level analysis identified a local inhibitory projection from dLSGLP-1R neurons to Estrogen receptor 1-expressing neurons in the ventral lateral septum (vLSEsr1 neurons), and targeted manipulation of this circuit confirmed its role in regulating alcohol intake. Together, these findings delineate a septal inhibitory circuit through which GLP-1R signaling modulates alcohol-related behaviors and highlight the dLS as a therapeutic target for AUD.

Keywords
GLP-1R; LS; alcohol; dopamine release; glucagon-like peptide-1 receptor; inhibitory local circuit; lateral septum; liraglutide.
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