2. Academic Validation
  3. Sleep Deprivation Induces Anxiety-like Behaviors in Mice by Impairing ApoE/AMPK/mTOR-Mediated Autophagy

Sleep Deprivation Induces Anxiety-like Behaviors in Mice by Impairing ApoE/AMPK/mTOR-Mediated Autophagy

  • Mol Neurobiol. 2025 Dec 13;63(1):293. doi: 10.1007/s12035-025-05610-0.
Xianbing Bai # 1 2,  Hongmei Du # 2,  Xiangxuan Liu 2,  Wanyu Yi 2,  Yunlu Hu 1,  Jinru Wang 2,  Fanzhi Yan 2,  Zimeng Cheng 2,  Genying Zhu 1,  Zhiping Cao 3,  Ming Chen 4 5,  Binliang Tang 6
Affiliations

Affiliations

  • 1 Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
  • 2 Department of Pharmacology, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China.
  • 3 Department of Clinical Psychology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518031, China. [email protected].
  • 4 Department of Pharmacology, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China. [email protected].
  • 5 Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China. [email protected].
  • 6 Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41390598 DOI: 10.1007/s12035-025-05610-0
Abstract

Sleep Deprivation (SD) severely disrupts emotional regulation, predisposing individuals to mood disturbances and anxiety. However, the precise mechanisms underlying anxiety triggered by sleep loss remain elusive. In this study, a mouse model of chronic SD was established using a continuously running treadmill paradigm for 28 days. SD induced anxiety-like behaviors and hippocampal apoE downregulation. Furthermore, SD downregulated the expression of the autophagy-related protein ATG5 and upregulated p62. In addition, SD inhibited AMPK phosphorylation and induced mTOR phosphorylation. Levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-18, were markedly increased. Immunofluorescence staining revealed a notable increase in the activation of microglia and astrocytes in the hippocampi of SD mice. Either hippocampal overexpression of apoE via bilateral AAV injection or rapamycin treatment significantly alleviated anxiety-like behaviors, enhanced Autophagy, and reduced neuroinflammation in SD mice. Thus, SD induces anxiety by suppressing Autophagy level. This effect is mediated through the inhibition of ApoE-dependent AMPK phosphorylation and the concomitant promotion of mTOR phosphorylation, revealing a potential therapeutic target.

Keywords

AMPK/mTOR; Anxiety; Apolipoprotein E; Autophagy; Sleep deprivation.

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