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Advisory Committee Chair

Jeremy J Day

Advisory Committee Members

Erik D Roberson

Robinna G Lorenz

Rita M Cowell

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Exposure to drugs of abuse alters transcriptional programs and neuronal activity, leading to long-lasting cellular and behavioral adaptations that may contribute to addiction. The nucleus accumbens (NAc), part of the mesocorticolimbic dopamine pathway, plays a central role in motivation, reward, and reward-related learning, and this brain region is highly implicated in the development and maintenance of addiction. However, the specific contributions of defined cell populations in the NAc to drug reward processes is still poorly understood. Here, we used electrophysiological, optogenetic, and single-nucleus RNA-sequencing (snRNA-seq) approaches in a rodent model system to define the acute physiological and transcriptional responses of NAc medium spiny neurons (MSNs) following acute cocaine experience. Acute cocaine exposure produced rapid but prolonged increases in neuronal activity of a subpopulation of neurons in the NAc. Using a real-time place conditioning behavioral assay in combination with viral vectors expressing channelrhodopsin, we demonstrate that photoactivation of MSNs in the NAc core is sufficient for reward-seeking behavior, independent of cocaine. In order to better characterize the cell populations driving these physiological and behavioral adaptations to cocaine, we employed snRNA-seq to generate a comprehensive transcriptional map of NAc cell subtypes following cocaine experience. Furthermore, RNA-seq revealed that cocaine experience in vivo and dopamine treatment in vitro robustly upregulated Gadd45b, a gene that has been implicated in activity-dependent DNA demethylation. However, the role of Gadd45b in cocaine reward has not been examined. Using unbiased genome-wide transcriptional profiling, pharmacological manipulations, electrophysiological recordings, and transgenic animal lines, and CRISPR tools both in vitro and in vivo, we showed that striatal Gadd45b expression is induced upregulated by dopamine and affects striatal physiology. Additionally, we demonstrate that Gadd45b is necessary for dopamine-dependent DNA methylation dynamics and cocaine reward memory. Overall, these data suggest that cocaine triggers a rapid transcriptional response in specific neuronal populations in the NAc, and these activity-induced changes are likely important for guiding physiological and behavioral adaptations to drugs of abuse.

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