A neural substrate of comorbid depressive symptoms in alcohol use

Zhenlei Chen; Shangchen Yang; Lige Leng; Jinjun Ding; Ziqi Yuan; Kai Zhuang; Dan Can; Tingting Zou; Ya Wang; Huifang Li; Ti-Fei Yuan; Jie Zhang

doi:10.1038/s41380-025-03061-6

A neural substrate of comorbid depressive symptoms in alcohol use

Mol Psychiatry. 2025 May 27. doi: 10.1038/s41380-025-03061-6. Online ahead of print.

Authors

Zhenlei Chen^#¹, Shangchen Yang^#¹, Lige Leng^#^{2

3

4}, Jinjun Ding⁵, Ziqi Yuan¹, Kai Zhuang¹, Dan Can¹, Tingting Zou¹, Ya Wang¹, Huifang Li¹, Ti-Fei Yuan^{6

7}, Jie Zhang^{8

9

10

11}

Affiliations

¹ Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
² Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China. lenglige@xmu.edu.cn.
³ Department of Pediatrics, Xiamen Maternity and Child Health Hospital affiliated to Xiamen University, Xiamen, Fujian, China. lenglige@xmu.edu.cn.
⁴ The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China. lenglige@xmu.edu.cn.
⁵ Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine and School of Psychology, Shanghai, China.
⁶ Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine and School of Psychology, Shanghai, China. ytf0707@126.com.
⁷ Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. ytf0707@126.com.
⁸ Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China. jiezhang@xmu.edu.cn.
⁹ The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China. jiezhang@xmu.edu.cn.
¹⁰ Department of Anesthesiology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. jiezhang@xmu.edu.cn.
¹¹ Institute of Neuroscience, Fujian Medical University, Fuzhou, Fujian, China. jiezhang@xmu.edu.cn.

^# Contributed equally.

PMID: 40425852
DOI: 10.1038/s41380-025-03061-6

Abstract

Alcohol use disorder (AUD) is commonly associated with depression, which may exacerbate the clinical outcome and increase treatment difficulty. The neural substrates underlying such comorbid symptoms are unclear. Here, we identify the regulatory role of amygdala Menin (multiple endocrine neoplasia type 1) signaling in orchestrating local GABAergic inhibition, which modulates the emotional state following alcohol use. Alcohol intake reduces Menin expression in the amygdala, decreasing GAT1 transcription. Restoring Menin signaling or overexpressing GAT1 in the amygdala could suppress alcohol preference and prevent depressive-like behaviors in these animals. Notably, knocking-in mice expressing a human MEN1 variant (Menin-G503D) that associates with MDD exhibit strong alcohol preference. These findings uncover a previously unknown mechanism for a common clinical element of alcohol addiction and point to a novel candidate therapeutic target against depression.

Abstract

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