Dynamic Expression of Transposable Elements Contributes to Molecular and Behavioral Adaptations to Cocaine

Author

Gabriella M. Silva, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/BGA7-1R84

Author ORCID Identifier

0000-0001-6293-1052

Defense Date

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Dr. Peter Hamilton

Abstract

The comorbidity of substance use disorder (SUDs) — specifically cocaine use disorder (CUD)— with anxiety and social deficit disorders complicates effective long-term treatment. More research is needed to understand the brain-region and cell type-specific mechanisms underlying these disorders to better address treatment gaps. This dissertation investigates the role of the transcription factor of interest ZFP189, a Krüppel-associated box (KRAB) zinc finger protein (ZFP), in governing pro-social behavior and the development of CUD across interconnected brain regions. We show that ZFP189 directly regulates transposable elements (TEs), repetitive DNA sequences capable of mobilizing and reinserting into the genome, which leads to subsequent molecular and behavioral responses. Using synthetic biology, we show that ZFP189 maintains pro-social behavior in the prefrontal cortex (PFC) by regulating TEs. Reversing ZFP189 function with ZFP189^VPR down-regulated immune responses and impaired pro-social behavior. Utilizing the same synthetic biological approaches, the same opposing synthetic ZFP189 transcription factor variants were shown to function similarly in the opposing medium spiny neurons (MSNs) of the nucleus accumbens (NAc) to facilitate (ZFP189^WT) or blunt (ZFP189^VPR) cocaine responses again by differentially modulating immune responses. Collectively, this work points to a previously understudied area of research linking KZFPs, TEs, and immune responses to the maintenance of pro-social behaviors and the development of CUD within intertwined brain regions. Future research should investigate the link between social behavior and CUD progression through ZFP189-TE interactions in the diverse cell types of the brain to develop targeted intervention strategies without altering parallel but similarly involved pathways.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

6-16-2025