Surgical Stress and Non‐Surgery Related Stress Synergistically Trigger Meningeal <scp>CD8</scp> ⁺ T Cells Accumulation and Subsequent Brain Dysfunction in Mice

Patients are usually highly stressed during the immediate perioperative period. It remains unclear whether increased stress contributes to postoperative brain dysfunction. Here, the clinical perioperative setting was mimicked via exploratory laparotomy and perioperative restraint stress. The stress response was assessed by measuring the levels of stress hormones and IL-6 in peripheral blood. Behaviors were evaluated with the open field, novel object recognition, and Barnes maze tests. We found that surgical stress and non-surgery-related stress synergistically trigger meningeal CD8⁺T cell accumulation, brain dysfunction, and increased stress hormone and IL-6 levels in the peripheral blood of adult mice, but simple surgical stress or non-surgery-related stress had no significant effect on these parameters. Limiting meningeal CD8⁺ T cell accumulation with an anti-CD8 antibody alleviated the impact of surgery plus perioperative stress on brain function, neuroinflammation, and neurogenesis. The partial elimination of microglia before surgery alleviated postoperative meningeal CD8⁺ T cell accumulation, cognitive dysfunction, and decreased hippocampal chemotactic factor levels. Our findings indicate that the synergistic effect of surgical stress and non-surgery-related stress contributes to postoperative brain dysfunction by triggering meningeal CD8⁺ T cell accumulation, suggesting the potential of limiting non-surgery-related stress as a preventive method for postoperative brain dysfunction.