Date of Award

2025

Document Type

Honors Thesis (Open Access)

Department

Colby College. Biology Dept.

Advisor(s)

Tariq Ahmad

Second Advisor

Suegene Noh

Third Advisor

Elissa Chesler

Abstract

Cocaine use disorder (CUD) remains a significant public health concern, yet the molecular mechanisms underlying individual susceptibility are poorly understood. This study investigates early transcriptional responses to acute cocaine exposure in two key brain regions implicated in addiction, the prefrontal cortex (PFC) and striatum, using genetically diverse Diversity Outbred (DO) mice. Paired tissue samples were collected following a standardized sensitization protocol and analyzed via bulk RNA sequencing. Differential expression analysis revealed 37 significantly differentially expressed genes in the striatum. These genes overlapped with gene sets associated with substance use, neurodevelopmental disorders, and immune signaling, implicating shared pathways in central nervous system homeostasis. Notably, Lbp, a regulator of TLR4/NF-κB–mediated neuroinflammation, was uniquely identified in a cocaine-specific context, suggesting a compensatory mechanism against cocaine-induced inflammatory signaling. Additionally, downregulation of Otx2, Msx1, and Cdkn1c in the dopaminergic neurogenesis pathway highlights a potential mechanism by which cocaine disrupts the development and maintenance of dopamine-producing neurons, thereby increasing addiction vulnerability. Together, these findings provide insight into early molecular adaptations to cocaine and identify neuroimmune and neurodevelopmental pathways as key contributors to individual differences in susceptibility to CUD.

Keywords

Cocaine Use Disorder, Bioinformatics, Differential Expression

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