Document Type



Doctor of Philosophy



Date of Defense


Graduate Advisor

George T. Taylor, PhD


David F. Wozniak

Michael G. Griffin

Catherine E. Creeley


Clinical studies have reported multiple exposures to anesthesia are associated with an increased risk of later learning disabilities. The general anesthetic Isoflurane (ISO) is commonly used in pediatric anesthesia and decreases the activity of the central nervous system through activation of the GABAA receptor. Other drug classes, such as anxiolytics, anticonvulsants, and alcohol, that share this mechanism increase neuroapoptosis during the developmental brain growth spurt period. Exposure to these agents during this time also can have detrimental consequences on behavior. Two experiments were conducted to examine the acute neuroapoptotic response and long-term behavioral impact of postnatal ISO exposure using an in vivo mouse model of brain development. In Experiment 1, mouse pups were treated on a single day or across multiple days to 1.5% ISO for 3 hr on postnatal days (PND) 3, 5, or 7. Densities of neurons positively stained for activated caspase-3, an immunohistochemical stain for neuroapoptotic degeneration, were quantified. The greatest neuroapoptotic response was observed in the cortex on PND 5, the caudate on PND 5, the thalamus on PND 3, and the hippocampus on PND 3 and 5. A greater density of cells undergoing apoptosis was observed on PND 5 following a single exposure and on PND 7 following a double exposure. To examine long-term influence, Experiment 2 followed mice into adulthood after neonatal exposure to isoflurane on PND 3+5+7. Male ISO mice demonstrated increased activity levels as juveniles and slightly heightened anxiety-like behaviors in the EPM as adolescents. During adulthood, female ISO mice failed to exhibit a preference for social novelty by spending comparable time investigating a novel versus a familiar conspecific during the social approach test. Contextual-cued fear conditioning was also disrupted in female ISO mice as demonstrated by a decrease in freezing behavior. In conclusion, isoflurane heightened levels of neuroapoptosis, suggesting possible alteration of neural circuitry, and influenced behavior long-term. These findings bring attention to exaggerated cell death during development and modifications in later functioning following developmental exposure to an anesthetic agent. This study provides grounds for developing into adjunctive therapies for the prevention of these disruptions in a clinical setting.

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