The Administration of Circulating Extracellular Vesicles Modified by Anesthesia and Surgery Induces Delirium-Like Behaviors in Aged Mice

Background: The mechanisms by which peripheral surgery remotely affects brain function remain unclear. Circulating extracellular vesicles (EVs) are a complex membrane vesicle system composed of peripheral immune cells and other tissue sources. They can carry proteins and nucleic acids without being restricted by the blood-brain barrier. They transfer peripheral pro-inflammatory factors and damage proteins to the brain, regulate intracellular signaling by acting on specific cells, and therefore play a role in cell-to-cell communication. It remains uncertain whether postoperative delirium occurs after anesthesia and surgery because peripheral blood EVs transfer peripheral pathogenic factors into the brain, inducing pathological changes in neuronal cells and cognitive and behavioral abnormalities. This study aimed to investigate the effects of circulating EVs from mice under anesthesia and surgery on the cognitive behavior and neuronal cells of recipient mice through animal experiments. Moreover, the expression profiles of differential proteins and microRNAs were analyzed in circulating EVs from mice undergoing anesthesia and surgery. Methods: We used aged mice and performed laparotomy under sevoflurane anesthesia to simulate the clinical environment. Twenty-four hours after anesthesia and surgery, circulating EVs were extracted and injected into the control mice via the tail vein to observe cognitive behaviors and neuronal pathological changes in the recipient mice. To further identify the key pathogenic factors in circulating EVs, we used high-throughput technology to detect the differential proteins and miRNAs in the circulating EVs of mice undergoing anesthesia and surgery compared to control mice. Candidate differential proteins and miRNAs were then screened and verified. Results: The administration of anesthesia and surgery-derived EVs to control mice led to the manifestation of delirium-like behavioral changes and pathological changes in nerve cells in recipient mice. SAA1, miR-103-3p, and miR-31-5p are potential target molecules implicated in POD. Conclusions: Circulating EVs are novel potential mediators involved in POD.