INTEGRATED STRESS RESPONSE GOVERNED EARLY ENDOPLASMIC RETICULUM STRESS TRIGGER WINDOW PRECEDES PERSISTENT NEUROINFLAMMATION AND MITOCHONDRIA DYSFUNCTION AFTER PERIPHERAL SURGERY

Peripheral surgery elicits systemic inflammation that can propagate to the brain and drive postoperative central nervous system (CNS) neuroinflammatory injury, yet the upstream stress-integration mechanism that converts a transient peripheral insult into sustained CNS pathology remains unclear. Here, we propose that integrated stress response–governed organelle stress dynamics in microglia define an early endoplasmic reticulum (ER) stress “trigger window” that precedes persistent mitochondrial dysfunction after peripheral surgery. Using a sterile peripheral surgical trauma model, we will map the temporal and regional evolution of ER stress, mitochondrial stress adaptation, mitochondrial quality control, and neuroinflammation across acute and delayed postoperative phases in hippocampus and prefrontal cortex. We combine immunofluorescence and confocal imaging in microglia reporter mice, ultrastructural assessment by transmission electron microscopy, and molecular profiling by qPCR and western blot on tissue and flow-sorted microglia to quantify ER stress markers, mitochondrial stress responses, mitochondrial dynamics/biogenesis programs, inflammatory cytokines, and mtDNA damage readouts. Our preliminary observations support a temporal decoupling: ER stress responses peak early and progressively normalize by three days after surgery, whereas mitochondrial dysfunction persists beyond this recovery phase and is accompanied by signatures consistent with mtDNA damage. To test causality, we will perturb the early ER stress window using targeted pharmacologic and/or viral strategies and determine whether this reprograms downstream mitochondrial recovery trajectories and attenuates CNS neuroinflammatory injury. Defining this trigger window provides a mechanistic framework for how systemic inflammation is translated into sustained CNS damage and highlights an actionable early intervention period after surgery.