Each year, approximately 10 million senior Americans suffer from postoperative delirium, a sudden brain failure that manifests after anesthesia and surgery and is characterized by memory loss, inattention, disorganized thinking, and altered consciousness. The risk of developing delirium can be as high as 80% among patients aged 65 and older who require sedation and breathing support in the Intensive Care Unit (ICU) after major surgery. Postoperative delirium is strongly associated with many adverse outcomes, including prolonged hospital stays, greater morbidity and mortality rates, and an increased risk of long-term cognitive decline and dementia. Unfortunately, there is currently no FDA-approved medication for treating delirium. Previous studies have focused on neuroinflammation, microglia activation, and a compromised blood-brain barrier as potential cause of delirium. However, interventions targeting these factors have failed to translate into successful clinical treatments. Perineuronal nets (PNN) are a promising area of investigation for developing new approaches against postoperative delirium. These extracellular matrix structures form a protective shield around specialized neurons known as parvalbumin- positive interneurons. These neurons play a crucial role in supporting cognitive functions that are impaired during delirium, including memory, attention, decision-making, and thought organization. This proposal aims to test the central hypothesis that the development of delirium-like cognitive impairment is linked to PNN remodeling in aged mice exposed to anesthesia, surgery and ICU- like conditions. In Aim #1, we will investigate whether a decrease in the number of parvalbumin- positive neurons enmeshed with PNN and increased levels of chondroitin sulfate isomers C and E within hippocampal PNN coincide with delirium-like cognitive impairment in aged mice subjected to anesthesia, surgery and ICU-like conditions. In Aim #2, we will test the idea that young mice exposed to anesthesia, surgery, and a simulated ICU environment do not experience changes in the quantity and composition of their PNN, and consequently, do not develop delirium- like behaviors. Impact: If our hypothesis proves true and the development of delirium-like cognitive impairment is indeed linked to PNN remodeling following anesthesia, surgery, and ICU conditions, this discovery would revolutionize our current understanding of the neurobiology of delirium. It could also open unprecedented opportunities to target PNN as a novel therapeutic approach against this condition that currently lacks effective pharmacological treatment options.