Graduation Date

Fall 12-15-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Integrative Physiology & Molecular Medicine

First Advisor

Sowmya Yelamanchili

Abstract

There has been a long history of research investigating the role of the gestational environment on later life health and disease. The progressive widespread illicit and prescribed use of opioids in the 21st century has seen opioids become one of the most significant gestational insults in the last century. The ability of opioids to pass both the placental barrier and blood-brain barrier makes them a particularly dangerous teratogen capable of altering the peripheral physiology, neurobiology, and behavior of affected children. The works herein investigate the impact of a widely prescribed opioid, oxycodone, on developmental neurobiology in the context of response to a later traumatic brain injury using a rat model of in utero opioid exposure.

Maternal opioid use poses a significant health concern not just to the expectant mother but also to the fetus. While epidemiological research has shown the heightened risk factors associated with in utero opioid exposure, little research has investigated what molecular mechanisms underly the vulnerabilities these children carry throughout development and into later life. To understand the implications of in utero opioid exposure on the developing brain, we sought to assess the response to one of the most common pediatric injuries: minor traumatic brain injury (mTBI). Using a rat model of in utero oxycodone (IUO) exposure and a low force weight drop model of mTBI, we show not only that neonatal opioid exposure significantly affects neuroinflammation, brain metabolites, synaptic proteome, mitochondrial function, and altered behavior in juvenile rats, but also, in conjunction with mTBI these aberrations are further exacerbated. Specifically, we observed long term metabolic dysregulation, neuroinflammation, alterations in synaptic mitochondria, and impaired behavior were impacted severely by mTBI. Our research highlights the specific vulnerability caused by IUO exposure to a secondary stressor such as later life brain injury. In summary, we present a broad study to highlight the damaging effects of in utero opioid exposure in conjunction with mild brain injury on the developing brain.

Comments

2023 Copyright, the authors

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