Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 25:S0006-3223(25)01352-6.
doi: 10.1016/j.biopsych.2025.07.014. Online ahead of print.

Transposable elements are dynamically regulated in medium spiny neurons and may contribute to the molecular and behavioral adaptations to cocaine

Gabriella M Silva  1 , Amber L Kaplan  1 , Celeste R Park  1 , Joseph A Picone  1 , R Kijoon Kim  1 , Natalie L Truby  1 , Rachel L Neve  2 , Xiaohong Cui  1 , Peter J Hamilton  3
Affiliations

Transposable elements are dynamically regulated in medium spiny neurons and may contribute to the molecular and behavioral adaptations to cocaine

Gabriella M Silva et al. Biol Psychiatry. .

Abstract

Background: Earlier work has established that Zfp189, which encodes a KZFP transcription factor (TF), differentially accumulates in nucleus accumbens (NAc) Drd1+ and Drd2+ medium spiny neurons (MSNs) and drives MSN functional and behavioral adaptations to cocaine. Here, we aimed to illuminate the cell type mechanisms through which this TF contributes to cocaine adaptations, with emphasis on investigating transposable elements (TEs).

Methods: First, we annotated TEs in existing single nuclei RNA-sequencing (snRNAseq) from rodents exposed to either acute or repeated cocaine. To directly test if TE dysregulation participates in cocaine-related brain changes, we virally delivered synthetic ZFP189 TFs, capable of releasing (ZFP189VPR) or repressing (ZFP189WT) brain TEs. Following cocaine exposure, we performed both bulk and snRNAseq of manipulated NAc. Lastly, we conditionally delivered these synthetic TFs to either the Drd1+ or Drd2+ MSNs and performed behavioral and cell morphological experiments.

Results: We discovered that NAc TE transcript expression was dramatically increased by cocaine experience, and the most sensitive NAc cell types were Drd1+, followed by Drd2+ MSNs. Our snRNAseq revealed that ZFP189VPR impeded gene expression across NAc cell types, including both MSN subtypes. Within either MSN subtype, ZFP189WT promoted, and ZFP189VPR restricted, primarily immune-related gene expression. We discovered that behavioral and cell morphological adaptations to cocaine are potentiated by ZFP189VPR function in Drd1+ MSNs or ZFP189WT in Drd2+ MSNs, revealing an MSN opponent process weighted by ZFP189 function.

Conclusions: This research points to TE transcript expression as dynamically regulated within NAc MSNs and may be involved in producing the molecular and behavioral responses to cocaine.

Keywords: Cocaine; addiction; nucleus accumbens; transcription factor; transcriptomics; transposable elements.

PubMed Disclaimer

Conflict of interest statement

Ethics declarations

Declaration of interests

The authors report no biomedical financial interests or potential conflicts of interest.

Similar articles

See all similar articles

References

    1. Abuse NI on D. Drug Overdose Death Rates | National Institute on Drug Abuse (NIDA). May 14, 2024. Accessed July 23, 2024. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
    1. Day JJ, Roitman MF, Wightman RM, Carelli RM. Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens. Nat Neurosci. 2007;10(8):1020–1028. doi: 10.1038/nn1923 - DOI - PubMed
    1. Schultz W, Apicella P, Ljungberg T. Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J Neurosci. 1993;13(3):900–913. doi: 10.1523/JNEUROSCI.13-03-00900.1993 - DOI - PMC - PubMed
    1. Schultz W Dopamine reward prediction error coding. Dialogues in Clinical Neuroscience. 2016;18(1):23–32. doi: 10.31887/DCNS.2016.18.1/wschultz - DOI - PMC - PubMed
    1. Nestler EJ. The Neurobiology of Cocaine Addiction. Sci Pract Perspect. 2005;3(1):4–10. - PMC - PubMed

LinkOut - more resources