Transposable Elements Are Dynamically Regulated in Medium Spiny Neurons and May Contribute to the Molecular and Behavioral Adaptations to Cocaine.

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-nucleus RNA sequencing (snRNAseq) from rodents exposed to either acute or repeated cocaine. To directly test whether TE dysregulation participates in cocaine-related brain changes, we virally delivered synthetic ZFP189 TFs, capable of releasing (ZFP189^VPR) or repressing (ZFP189^WT) 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 ZFP189^VPR impeded gene expression across NAc cell types, including both MSN subtypes. Within either MSN subtype, ZFP189^WT promoted, and ZFP189^VPR restricted, primarily immune-related gene expression. We discovered that behavioral and cell morphological adaptations to cocaine are potentiated by ZFP189^VPR function in Drd1+ MSNs or ZFP189^WT 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 possibly involved in producing the molecular and behavioral responses to cocaine.