Emmitt, Nicole2023-02-162023-02-162022-12https://hdl.handle.net/11299/252550University of Minnesota Ph.D. dissertation. December 2022. Major: Comparative and Molecular Biosciences. Advisors: Maxim Cheeran, Walter Low. 1 computer file (PDF); x, 191 pages.Traumatic brain injury (TBI) affects 64-74 million people every year worldwide. A history of mild brain injury increases the risk of substance use disorder (SUD) by 2-6 times that of the general population. With the rise of the opiate epidemic, it is imperative to understand the link between TBI and opiate use disorder. Therefore, a model of mild TBI was developed in mice. Mice that received mild TBI had a transient motor deficit at the acute stage of injury and a long-term spatial learning deficit at the chronic stage of injury. The innate immune response in the brain was active at the acute and chronic stage, with macrophage and neutrophil infiltrate peaking at 3 days post injury (DPI), and an increase in the activated macrophage phenotype at both 15 and 30-DPI. Next, to understand how drug seeking behavior is modified, mice with mild TBI or sham injury were subjected to intravenous (IV) self-administration and conditioned place preference (CPP) behavioral assays to evaluate drug seeking behavior. Injured mice had increased consumption of and preference to morphine. The innate immune response was also altered after IV self-administration, with increased macrophage and neutrophil infiltrate on the side ipsilateral to injury. Furthermore, both IV self-administration and CPP with morphine resulted in increased lymphocyte infiltrate on the side ipsilateral to injury. Considering the increased inflammation observed due to morphine, the neuroinflammatory response to a consistent clinical dose morphine was examined, since the majority of people are first exposed to opiates through prescription for pain relief. After TBI or sham injury, mice received morphine twice daily (5mg/kg) for up to 15 days. A biphasic immune response was observed to this dose of morphine with increased macrophage infiltrate and a lymphocyte infiltrate at 15-DPI. This was accompanied by a dynamic, temporally distinct cytokine response, a decrease in the phagocytic activity of macrophages and microglia at 15-DPI and increased leakage of the blood brain barrier in the mid brain. Results from these studies demonstrate a novel increase in the proinflammatory response at the chronic stage of traumatic brain injury when exposed to morphine. The models developed here will provide new insights to help identify new targets to reduce the risk of SUD following TBI.enImmunologyNeuroscienceSubstance Use DisoderTraumatic Brain InjuryThesis or Dissertation