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Author ORCID Identifier

https://orcid.org/0009-0008-5659-9493

Date Available

4-30-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Faculty

Jill Turner

Faculty

David Feola

Abstract

Despite the availability of several approved medications for opioid use disorder (OUD), it remains a significant public health concern characterized by persistent neurobiological adaptations that drive relapse and impede successful recovery. The medial prefrontal cortex (mPFC), a region critical for executive control and decision-making, undergoes pronounced functional changes during chronic opioid exposure and withdrawal, yet the cellular mechanisms underlying these adaptations remain poorly understood. This dissertation aims to investigate longitudinal alterations in mPFC neural activity across opioid exposure and withdrawal using in vivo single-photon calcium imaging and newly developed computational frameworks.

Following standard preprocessing to extract and normalize calcium traces, custom computational pipelines were developed to analyze longitudinal patterns of neuronal activity across recording sessions. These frameworks incorporated dimensionality reduction and clustering approaches to identify neuronal ensemble activity patterns that evolved across time and treatment conditions. The developed tools were applied to calcium imaging datasets from two complementary experiments: (1) chronic oxycodone administration via osmotic minipump followed by a short withdrawal period and (2) twice-daily injections of oxycodone or atoxifent, a novel μ-opioid receptor agonist, followed by extended withdrawal.

Across both models, longitudinal analysis revealed distinct neuronal populations that either maintained stable activity profiles or exhibited dynamic, treatment-dependent changes during exposure and withdrawal. These findings suggest that chronic opioid administration induces circuit-level remodeling within the mPFC, characterized by shifting ensemble activity states that likely contribute to impaired behavioral regulation observed in OUD. Significant baseline sex differences in neural activity were also detected, whereas limited sample sizes in post-treatment recordings precluded robust evaluation of sex-dependent effects following drug exposure.

Collectively, this work advances analytical approaches for longitudinal calcium imaging and demonstrates their value in revealing temporal and treatment-dependent neurophysiological changes during opioid exposure and withdrawal. By enabling quantitative assessment of circuit-level adaptations over time, these frameworks provide a foundation for evaluating how candidate compounds influence neuronal ensemble activity within addiction-relevant networks. This approach supports preclinical drug screening and the identification of novel therapeutic targets aimed at restoring prefrontal function disrupted by chronic opioid use. More broadly, the analytical strategies developed here expand the utility of in vivo calcium imaging and strengthen the link between mechanistic neurobiology and translational pharmacotherapy development.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.235

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