Hippocampal Endoplasmic Reticulum Stress Drives a Pro-inflammatory Microglial Bias and Neuroinflammation in Aged Mice with Perioperative Neurocognitive Disorder

Background Perioperative neurocognitive disorder (PND) is a frequent postoperative complication in older individuals and is commonly linked to microglial activation. Endoplasmic reticulum (ER) stress has been implicated in neuroinflammation and postoperative cognitive decline; however, whether hippocampal ER stress acts upstream to bias microglia toward a pro-inflammatory M1 phenotype, rather than serving only as a trigger of cytokine cascades, remains insufficiently defined in PND. Objective To determine whether hippocampal ER stress promotes an M1-like microglial shift and amplifies neuroinflammation after anesthesia and surgery. Methods Eighteen-month-old male C57BL/6 mice underwent aseptic tibial fracture surgery under isoflurane anesthesia. TUDCA, a pharmacological ER stress suppressor, was delivered bilaterally into dorsal hippocampal CA1 as a perioperative mechanistic probe. ER ultrastructure in hippocampal cells was examined using transmission electron microscopy (TEM). ER stress related proteins (GRP78, p-PERK, p-eIF2ɑ, p-IRE1ɑ, ATF4, and ATF6) in hippocampus were quantified by Western blotting. Microglial phenotypic signatures were assessed by Western blotting (CD86, iNOS, CD206, ARG-1) and double immunofluorescence (CD86/Iba-1 and CD206/Iba-1). Open-field testing was performed to control for locomotion/anxiety, followed by memory assessments using novel object recognition and Morris water maze starting on postoperative day 3. Results Anesthesia and surgery induced postoperative cognitive deficits, accompanied by heightened hippocampal inflammatory signaling and a shift toward a pro-inflammatory microglial signature characterized by increased CD86 and iNOS with concomitant reductions in CD206 and ARG-1. In parallel, hippocampal ER stress activation was evident, including ER ultrastructural disruption and increased GRP78 with engagement of PERK/eIF2ɑ/ATF4-, IRE1ɑ-, and ATF6-related pathways. hippocampus-targeted delivery of TUDCA attenuated ER stress activation, mitigated the pro-inflammatory microglial shift (decreasing CD86/iNOS and restoring CD206/ARG-1), reduced inflammatory readouts, and improved postoperative memory performance. Conclusions These findings support a mechanistic link between hippocampal ER stress and the pro-inflammatory microglia bias linked to postoperative neuroinflammation and cognitive impairment in aged mice.