UC Irvine

Substance use disorders represent a critical public health concern, with nicotine remaining one of the most widely abused substances among adolescents. Adolescence is a sensitive period of brain development characterized by heightened neuroplasticity and synaptic reorganization, leaving the developing reward system uniquely vulnerable to the long-term effects of nicotine exposure. Given these extensive neurobiological consequences, it is essential to uncover the specific genetic and molecular mechanisms that predispose the developing brain to nicotine addiction. Using a humanized rat model, my dissertation evaluates the role of the human CHRNA6 3’ untranslated region single nucleotide polymorphism, rs2304297, in adolescent nicotine vulnerability across broad gene expression networks, post-transcriptional processing, and microRNA interactions within the ventral tegmental area (VTA), a crucial midbrain region mediating drug reward.I demonstrate that this human CHRNA6 3’ UTR SNP acts as a primary genetic driver that establishes distinct basal metabolic and oligodendrocyte-related gene expression in the VTA prior to drug exposure. Following sub-chronic nicotine treatment, I show that the polymorphism induces sex- and genotype-dependent neuroadaptations, driving neuroimmune complement system changes in adolescent males while altering cytoskeletal pathways in females. Furthermore, mapping Chrna6 functional co-expression networks revealed sex- and genotype-dependent circuit remodeling following nicotine exposure, where vulnerable cohorts experience significant network disruption or expansion while resilient animals maintain stable connectivity. To investigate how this variant affects post-transcriptional regulation, I examined the folding and processing of the Chrna6 transcript. While the SNP significantly alters the predicted secondary structure of the 3’ UTR, it does not modify overall mRNA stability or alternative polyadenylation site selection. Finally, I evaluated microRNA-mediated regulation by exploring the relationship between Chrna6 and microRNA-365-5p. I uncovered a positive correlation and subregion-specific spatial association between the microRNA and target mRNA within the anterior VTA, supporting a mechanism of translational control and storage rather than typical transcript degradation. Together, this work provides crucial evidence for how non-coding genetic variations interact with sex to shape reward pathways and adolescent susceptibility to nicotine addiction.