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.