Author ORCID Identifier

https://orcid.org/0000-0002-9927-8939

Semester

Summer

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Courtney DeVries-Nelson

Committee Co-Chair

Zachary M. Weil

Committee Member

Zachary M. Weil

Committee Member

Kathleen Morrison

Committee Member

Candice Brown

Committee Member

Erin Winstanley

Abstract

Traumatic brain injury (TBI) and alcohol use disorder (AUD) exhibit a bidirectional relationship: AUD increases the risk of incurring a TBI and, inversely, a history of TBI increases the risk of future AUD. The second portion of this relationship has not been as thoroughly investigated. Our lab previously demonstrated that a juvenile TBI significantly increases alcohol self-administration in females compared to uninjured females and the injured females developed a conditioned place preference (CPP) for ethanol. Given this stark sex difference, this dissertation will examine the mechanism through which this occurred by investigating how manipulations of sex steroids might affect this result. We found that injured ovariectomized females and females that were exposed to testosterone perinatally did not develop a CPP for ethanol. Meanwhile, male mice that were gonadectomized at postnatal day (PND) 4 and male mice that were gonadectomized in adulthood did not display any difference in their alcohol-related behaviors. Additionally, we analyzed axonal degeneration to investigate whether there was an effect of hormone manipulation on injury severity, and we found an impact of injury wherein axonal degeneration was significantly increased. Still, there was no effect of sex steroid manipulation. We also saw that hormone manipulation did not have any impact on microglia number, indicating that the difference we see in alcohol-related behaviors is not due to changes in injury severity. However, we did find that TBI increased microglia in males while there was no injury effect in females. These results indicate that sex hormones are involved in the mechanism by which alcohol-related behaviors are altered in females following a TBI early in life. Previous work in this lab also demonstrated that the increase in alcohol self-administration in females following a juvenile TBI was attenuated after they were placed in an enriched environment (EE) immediately after injury and kept there until adulthood. Given that environmental enrichment is traditionally shown to increase neurogenesis and brain-derived neurotrophic factor (BDNF) levels and that BDNF dysregulation is associated with both TBI pathology and AUD, we investigated how different durations of EE would alter the expression of BDNF and genes related to neuroplasticity in the context of TBI. We found that one week of EE following injury significantly decreased the expression of these genes. However, five weeks of EE significantly increased the expression of neuroplasticity-related genes. We then asked whether 7,8-dihydroxyflavone, an agonist for tropomyosin receptor kinase (TrkB), which is activated by BDNF, would mimic the effects of EE on alcohol self-administration. Interestingly, 7,8-DHF did not alter alcohol consumption in the context of TBI but did significantly increase drinking in the uninjured animals. Additionally, given the compelling overlap of TBI, AUD, and posttraumatic stress disorder (PTSD), we employed an elevated plus maze to assess anxiety-related behaviors after 7,8-DHF treatment, but we did not see an effect of injury or 7,8-DHF treatment. We then examined how EE and 7,8-DHF might differentially impact TBI recovery through axonal degeneration and found that although EE significantly reduced axonal degeneration, there was no effect of 7,8-DHF. Lastly, we investigated the effects of short-term EE and 7,8-DHF treatment on hippocampal neurogenesis. 7,8-DHF treatment did not alter hippocampal neurogenesis. Importantly, EE decreased the amount of newly formed cells in the hippocampus, suggesting that short-term EE could negatively impact neuroplasticity in females when employed at this time point.

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