Subclinical Infection Combined with Surgery-Induced Cogni-tive Dysfunction: A Novel Adult Mouse Model for Periopera-tive Neurocognitive Disorder

Yizhe Zhang^1,2Xiao Zhang^1,2Wanbing Dai^1,2Ye Liu³Xiangyang Cheng⁴Yeke Zhu⁴Lili Huang^1,2Minghao Tang⁵Yongxing Yao⁴Xuwu Xiang⁴Weifeng Yu^1,2*Diansan Su^4*

• ¹Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China, Shanghai, China
• ²Key Laboratory of Anesthesiology (Shanghai Jiaotong University), Ministry of Education, Shanghai, China, Shanghai, China
• ³Second School of Clinical Medicine, Binzhou Medical University, Yantai, Shandong Province, China, Yantai, China
• ⁴Department of Anesthesiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
• ⁵The First People’s Hospital of Jiashan, Jiashan Hospital Affiliated with Jiaxing University, Jiaxing, Zhejiang, China, Jiaxing, China

Perioperative neurocognitive disorder (PND) is a spectrum of cognitive impairments associated with surgery and anesthesia, in which neuroinflammation plays a central role. Although aging is a recognized risk factor, PND also occurs in younger individuals, yet validated adult animal models remain lacking. Here, we established a novel adult mouse model in which preoperative subclinical infection, induced by low-dose lipopolysaccha-ride (0.75 mg/kg, intraperitoneal), was followed 2 hours later by tibial fracture fixation or appendectomy under anesthesia. This combined insult triggered robust neuroinflam-mation, microglial activation, and marked reductions in synaptic proteins, including PSD-95, GAP-43, SYN, and mature BDNF, accompanied by impairments in learning and memory. Behavioral outcomes were assessed by the open field test, novel object recognition test, and Morris water maze. Hippocampal inflammatory and synaptic markers were quantified, and label-free quantitative proteomics was performed to explore mo-lecular changes. Proteomic analysis revealed alterations in pathways related to immune responses, synaptic organization, and energy metabolism, providing mechanistic in-sights into the observed cognitive deficits. This reproducible and clinically relevant model captures a common yet underrecognized perioperative risk scenario—preoperative low-grade inflammation—and offers a valuable platform for mechanistic studies and the development of targeted preventive strategies.