Advisor(s)
Jeremy Day
Committee Member(s)
Aurelio Galli
J Hardaway
Sofia Beas
Stefanie Krick
Document Type
Dissertation
Date of Award
6-1-2026
Degree Name
Doctor of Philosophy (PhD)
School
Joint Health Sciences (Interdisciplinary)
Department
Neurobiology
Abstract
Substance use disorder is a complex neurobiological disease characterized by impaired control over drug taking and drug seeking. Drugs of abuse exert their reinforcing effects largely through dopaminergic (DAergic) projections from the ventral tegmental area (VTA) to the nucleus accumbens, where all drugs of abuse increase DA transmission. Beyond reward processing and reward learning, the VTA contributes to a range of psychiatric conditions, including schizophrenia and attention-related disorders. Although DA signaling has long been a major focus of addiction research, recent transcriptomic studies have revealed substantial heterogeneity of cell types within the VTA. Previous work from our lab identified two transcriptionally distinct Th+ subpopulations utilizing single nucleus RNA sequencing: a “DA-only” neuron marked by Gch1 and a DA/glutamate/GABA “Combinatorial” neuron marked by Slc26a7. Despite their molecular distinction, the functional properties of these neurons remain unknown. In this dissertation, I present novel adeno-associated viral tools to selectively target each subpopulation. Using these tools, I characterized differences in electrophysiological properties, projection patterns, and responsiveness to acute cocaine. Combinatorial neurons exhibited a tradeoff between sustained firing during periods of high energetic demand and delayed recruitment near the action potential threshold compared to DA-only neurons. These neurons also showed projection bias to CA1 of the hippocampus and the olfactory tubercle and were selectively recruited by acute cocaine exposure. Although Slc26a7 has been identified as a selective marker of Combinatorial neurons in the VTA, the role of this anion transporter in reward behavior remains unknown. To address this question, I generated a CRISPR-Cas9-mediated knockout of Slc26a7 in the adult rat VTA. Behavioral analyses revealed a selective role for Slc26a7 in modulating early cue-reward responding, while associative memory, appetitive operant motivation, and cocaine-paired contextual learning remained intact. Together, the findings presented in this dissertation further distinguishes two previously identified VTA DA subpopulations, identifies a selective behavioral role for Slc26a7 in the mesolimbic pathway, and introduces viral tools that establish a foundation for future causal interrogation of these neurons in reward-related behavior.
Keywords
addiction;combinatorial;dopamine;Slc26a7;VTA
Recommended Citation
Fitzgerald, Natalie Dalton, "From Transcriptome To Function: Multimodal Characterization Of Transcriptionally Defined Ventral Tegmental Area Dopamine Neurons" (2026). ETDs from 2020-2029. 196.
https://digitalcommons.library.uab.edu/etd-2020s/196
