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Nai-Li Wei,1,2,* Zi-Fang Quan,3,4,* Tong Zhao,1,* Xu-Dong Yu,4 Qiang Xie,1 Jun Zeng,1 Fu-Kai Ma,1 Fan Wang,1 Qi-Sheng Tang,1 Heng Wu,3 Jian-Hong Zhu11Fudan University Huashan Hospital, Department of Neurosurgery, State Key Laboratory for Medical neurobiology, Institutes of Brain Science, Shanghai Medical College-Fudan University, Shanghai, 20040, People’s Republic of China; 2Department of Neurosurgery, The Second Hospital of Lanzhou University, Lanzhou Gansu China, 730030, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 4Institute of Neuroscience, Medical College, University of South China, Hengyang, Hunan, 421001, People’s Republic of China *These authors contributed equally to this workBackground: Stress-related obesity might be related to the suppression of the hypothalamic-pituitary- adrenocortical axis and dysregulation of the metabolic system. Chronic stress also induces the dysregulation of the reward system and increases the risk of food addiction, according to recent clinical findings. However, few studies have tested the effect of chronic stress on food addiction in animal models.Purpose: The objective of this study was to identify whether chronic stress promotes food addiction or not and explore the possible mechanisms.Method: We applied adaily 2 hrsflashing LED irradiation stress to mice fed chow or palatable food to mimic the effect of chronic stress on feeding. After 1 month of chronic stress exposure, we tested their binge eating behaviors, cravings for palatable food, responses for palatable food, and compulsive eating behaviors to evaluate the effect of chronic stress on food addiction-like behaviors. We detected changes in the levels of various genes and proteins in the nucleus accumbens (NAc), ventral tegmental area (VTA) and lateral hypothalamus using qPCR and immunofluorescence staining, respectively.Results: Behaviors results indicated chronic stress obviously increased food addiction score (FAS) in the palatable food feeding mice. Moreover, the FAS had astrong relationship with the extent of the increase in body weight. Chronic stress increased the expression of corticotropin-releasing factor receptor 1(CRFR1) was increased in the NAc shell and core but decreased in the VTA of the mice fed with palatable food. Chronic stress also increased expression of both dopamine receptor 2 (DR2) and mu-opioid receptor (MOR) in the NAc.Conclusion: Chronic stress aggravates the FAS and contributed to the development of stress-related obesity. Chronic stress drives the dysregulation of the CRF signaling pathway in the reward system and increases the expression of DR2 and MOR in the nucleus accumbens.Keywords: chronic stress, obesity, food addiction, dopamine receptor 2, mu-opioid receptor, nucleus accumbens