Alzheimer's & Dementia · Jun 2026

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

By Osuru HP, Atluri N, Le T et al.

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.

doi.org/10.1002/alz.71556 Open access PubMed 42298296 Mechanisms