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Updated: Jun 24, 2026
Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
Effect of hypercarbia and isoflurane on brain cell death and neurocognitive dysfunction in 7-day-old rats
Greg Stratmann1, Laura D V May, Jeffrey W Sall
1Department of Anesthesia and Perioperative Car, University of California, San Francisco, California 94143, USA. stratman@anesthesia.ucsf.edu
Insights
Anesthesia can cause brain cell death and neurocognitive dysfunction in young rats. However, cell death alone doesn't fully explain long-term cognitive deficits, suggesting other mechanisms are involved.
Area of Science:
- Neuroscience
- Anesthesiology
- Developmental Biology
Background:
- Millions of neonates receive anesthesia annually.
- Anesthetic agents may cause brain cell death and neurocognitive dysfunction in developing brains.
- A direct causal link between anesthesia-induced cell death and long-term cognitive deficits remains unestablished.
Purpose of the Study:
- To investigate if anesthesia duration correlates with neurocognitive dysfunction.
- To determine if anesthesia-induced brain cell death is linked to long-term cognitive deficits.
Main Methods:
- Neonatal rats (postnatal day 7) were exposed to isoflurane (1 minimum alveolar concentration) for 0, 1, 2, or 4 hours.
- Carbon dioxide exposure served as a control for respiratory depressant effects.
- Brain cell death was assessed using FluoroJade staining, and neurocognitive function was evaluated 8 weeks later via fear conditioning and memory tasks.
Main Results:
- Isoflurane for 2 and 4 hours, and carbon dioxide for 4 hours, induced widespread brain cell death.
- Thalamic cell death was comparable between 4-hour isoflurane and 4-hour carbon dioxide groups.
- Only 4-hour isoflurane exposure resulted in long-term deficits in spatial reference and working memory, which were not observed in carbon dioxide-treated rats.
Conclusions:
- Hypercarbia may contribute to isoflurane-induced brain cell death.
- The dissociation between cell death and cognitive outcomes suggests alternative mechanisms for anesthesia-induced neurocognitive dysfunction.
Background:
Millions of neonates undergo anesthesia each year. Certain anesthetic agents cause brain cell death and long-term neurocognitive dysfunction in postnatal day (P)7 rats. Despite its intuitive appeal, a causal link between cell death and neurocognitive decline after anesthesia has not been established. If one existed, the degree of cell death would be expected to correlate with the degree of neurocognitive dysfunction caused by anesthesia. The authors therefore tested if cell death caused by various durations of isoflurane at 1 minimum alveolar concentration causes duration-dependent long-term neurocognitive dysfunction.
Methods:
Isoflurane was administered to P7 rats at 1 minimum alveolar concentration for 0, 1, 2, or 4 h. To control for the respiratory depressant effects of anesthesia, a group of rats was treated with 4 h of carbon dioxide. Cell death was assessed by FluoroJade staining 12 h after the end of each intervention, and neurocognitive outcome was assessed 8 weeks later by using fear conditioning, spatial reference memory, and spatial working memory tasks.
Results:
Widespread brain cell death was caused by 2 h and 4 h of isoflurane and by 4 h of carbon dioxide. The degree and distribution of thalamic cell death was similar in 4 h isoflurane-treated and 4-h carbon dioxide-treated rats. Only 4 h of isoflurane caused a long-term neurocognitive deficit affecting both spatial reference memory and spatial working memory. Working memory was improved in carbon dioxide-treated rats.
Conclusion:
Isoflurane-induced brain cell death may be partly caused by hypercarbia. The inconsistencies between cell death and neurocognitive outcome suggest that additional or alternative mechanisms may mediate anesthesia-induced long-term neurocognitive dysfunction.
