Chronic alcohol exposure contributes to postoperative cognitive dysfunction via NR2B upregulation in the hippocampus of adult mice

  • Transl Psychiatry. 2026 May 14;16(1):341. doi: 10.1038/s41398-026-04087-2.
Linhui Ma  #  1 ,  Shuai Li  #  1 ,  Wei Dong  #  2 ,  Jie Wan  2 ,  Zhichao Li  1 ,  Chudi Zhang  2 ,  Xinjie Zhou  2 ,  Zhifan Wang  2 ,  Chenghua Zhou  3 ,  Yuqing Wu  4 ,  Hui Zheng  5
Affiliations
  • 1. Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 2. Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
  • 3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. [email protected].
  • 4. Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China. [email protected].
  • 5. Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. [email protected].
  • # Contributed equally.
PMID: 42129152 DOI: 10.1038/s41398-026-04087-2
Abstract

Postoperative cognitive dysfunction (POCD) is a common perioperative complication of the central nervous system, and patients with chronic alcohol exposure frequently require surgery under anesthesia. However, the contribution of chronic alcohol exposure to POCD and its underlying mechanisms remains unclear. In this study, eight-week-old female and male mice were subjected to chronic alcohol exposure using the intermittent access two-bottle choice (IA2BC) paradigm. Compared with controls, mice with chronic alcohol exposure exhibited greater susceptibility to POCD. Specifically, chronic alcohol exposure increased NR2B expression in hippocampal CA1 glutamatergic neurons, enhancing A/S-induced hyperexcitability, which led to neuronal Apoptosis and cognitive impairment. Notably, knockdown of NR2B or chemogenetic inhibition of CA1 glutamatergic neurons in IA2BC mice could reduce neuronal Apoptosis and rescue A/S-induced cognitive dysfunction. These findings demonstrate that chronic alcohol exposure heightens susceptibility to POCD in young adult mice through NR2B-mediated excitotoxicity, revealing a mechanistic link between chronic alcohol exposure and POCD that warrants further investigation.

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