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