ORCID ID
Graduation Date
Summer 8-9-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Interdisciplinary Graduate Program in Biomedical Sciences
First Advisor
Gurudutt Pendyala
Abstract
In recent decades, the rising number of neonates born in the Neonatal Intensive Care Unit (NICU) due to prematurity has raised concerns about their overall well-being and development. Premature neonates are at higher risk of health complications and often require invasive procedures. These invasive procedures often induce stress and agitation, prompting physicians and healthcare providers to provide sedation or general anesthesia to manage discomfort. Epidemiological studies of human patients have revealed a correlation between childhood exposure to general anesthetic and sedative agents and subsequent cognitive deficits. This association is also supported in animal models, which shows that exposure to anesthetics and sedatives causes lasting impairments in learning along with heightened neuroapoptosis. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative agent on neonates in the NICU. We hypothesize that chronic midazolam use during the early stages of life negatively impacts the developmental trajectory, and such changes could extend into adulthood. Using a preclinical rodent model, we performed a dose-escalation regime to comprehensively characterize how chronic MDZ exposure during early age influences the neurodevelopment outcomes at different tiers ─ phenotypic, molecular, behavioral, and high throughput- “omics” levels.
We specifically investigated how repetitive doses of MDZ during early neonatal life influence physical attributes (e.g., body weight, body length, and head size circumference), molecular aspects (blood-brain barrier components, key signaling molecules expression, brain metabolites), synaptic proteome, and complex behaviors (social-interaction and obsessive-compulsive and anxiety-like behavior), at key developmental timepoints such as childhood, adolescent, and adulthood. Our data demonstrated that repetitive exposure to MDZ during the neonatal period negatively affects the overall physique attributes in early childhood. In addition, we observed various alterations in neurochemistry in both childhood and adulthood. Remarkably, we observed increases in inflammatory cytokines expressions in adulthood, while there was no significant difference in these inflammatory signals in early childhood. For behavior, we observed trends of increasing anxiety-like behavior and reducing social interaction effort, especially during adolescence. The results from the study can advance further insights into mechanisms that could contribute to overcoming neurodevelopmental complications associated with long-term MDZ use in neonates.
Recommended Citation
Nguyen, Nghi M., "Long-Term Neurodevelopmental Outcomes Post-Chronic Midazolam Exposure during Early Life" (2024). Theses & Dissertations. 859.
https://digitalcommons.unmc.edu/etd/859