Epigenetically driven impairment of BDNF–ARC signaling contributes to circadian and cognitive disarray in a mouse model of postoperative delirium

INTRODUCTION Postoperative delirium (POD) is common in older surgical patients and is clinically associated with an increased risk of long‐term cognitive decline and dementia; disrupted BDNF signaling and circadian dysregulation are implicated, but their coordinated mechanisms remain unclear. METHODS Aged male C57BL/6J mice were exposed to anesthesia, surgery, and intensive care unit‐like stress (ASI). Hippocampal neuroplasticity, dendritic morphology, epigenetic regulation, and circadian signaling were assessed using molecular assays, imaging, and protein–protein interaction (PPI) network analysis. RESULTS ASI reduced brain‐derived neurotrophic factor (BDNF)–activity‐regulated cytoskeleton‐associated protein signaling, dendritic structural complexity, and attention, with accompanying histone hypoacetylation, an increased 5‐methylcytosine/5‐hydroxymethylcytosine ratio, and disruption of network hubs centered on BDNF and circadian regulators. Suberoylanilide hydroxamic acid mitigated these effects and improved short‐term cognitive performance. DISCUSSION Perioperative stress is associated with an epigenetically repressed, synaptically impaired hippocampal state linked to delirium‐like behavior and cognitive vulnerability. Targeting chromatin accessibility and BDNF–circadian coupling with histone deacetylase inhibition may mitigate acute cognitive consequences following surgery.