Lunardi Lab members
New study identifies reversible molecular changes linking surgical stress, circadian disruption, and cognitive vulnerability.
Researchers at the University of Virginia School of Medicine have uncovered evidence that postoperative delirium, a sudden loss of cognition that develops after surgery, may leave a molecular imprint on the aging brain, helping explain why the condition is associated with poorer long-term cognitive outcomes in older adults.
Hari Prasad Osuru, PhD, and Navya Atluri, PhD
In a study published in Alzheimer’s & Dementia, investigators found that anesthesia, surgery and Intensive Care Unit-related stress triggered epigenetic changes in the brains of aged mice. These changes disrupted pathways involved in memory formation and regulation of the body’s biological clock, leading to delirium-like cognitive impairments.
The research identified coordinated disruptions in two systems critical for brain health: the BDNF-ARC signaling pathway, which supports learning and memory, and the circadian clock, which regulates daily sleep-wake cycles. The investigators found that perioperative stress altered gene activity through reduced histone acetylation and changes in DNA methylation, two epigenetic mechanisms that control how genes are turned on and off.
Nadia Lunardi, MD
“Postoperative delirium affects millions of older adults worldwide and is associated with longer hospital stays, increased complications and a greater risk of subsequent cognitive decline. Despite this, the biological mechanisms driving this condition and linking an acute episode of delirium to long-term cognitive decline remain poorly understood,” said Nadia Lunardi, MD, associate professor in the UVA Department of Anesthesiology at the University of Virginia School of Medicine, senior author and principal investigator of the study.
Importantly, the researchers found that treatment with the histone deacetylase inhibitor vorinostat, a drug already FDA-approved for clinical use, reversed many of these effects. The treatment restored expression of memory- and circadian-related genes, improved neuronal structure, and enhanced cognitive performance in the animals.
“These findings provide an important biological substrate for how the cognitive vulnerability associated with delirium develops and identify epigenetic pathways as promising preventative and therapeutic targets,” said Hari Prasad Osuru, research scientist in the UVA Department of Anesthesiology and corresponding author in the study.
The researchers are now using advanced single-cell technologies and Spatial transcriptomics to determine how specific brain cell populations respond to perioperative stress.
The findings were published in Alzheimer’s & Dementia in the article, “Epigenetically Driven Impairment of BDNF-ARC Signaling Contributes to Circadian and Cognitive Disarray in a Mouse Model of Postoperative Delirium.”
Osuru HP, Atluri N, Le T, Park J, Jedrusiak M, Dulko E, Illendula M, Lunardi N. Alzheimer’s & Dementia. 2026;22. https://doi.org/10.1002/alz.71556
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