# Perineuronal nets: a new player in postoperative delirium?

> **NIH NIH R03** · UNIVERSITY OF VIRGINIA · 2024 · $161,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10869690
- **Project number:** 1R03AG086840-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Nadia Lunardi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,500
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869690

## Citation

> US National Institutes of Health, RePORTER application 10869690, Perineuronal nets: a new player in postoperative delirium? (1R03AG086840-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10869690. Licensed CC0.

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