A Cocaine-Activated Ensemble Exerts Increased Control Over Behavior While Decreasing in Size.

Background: Substance use disorder is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens. Previous work has shown that cocaine exposure induces plasticity in broad, genetically defined cell types in the nucleus accumbens; however, in response to a stimulus, only a small percentage of neurons are transcriptionally active-termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure.

The transcriptional response to acute cocaine is inverted in male mice with a history of cocaine self-administration and withdrawal throughout the mesocorticolimbic system.

A large body of work has demonstrated that cocaine-induced changes in transcriptional regulation play a central role in the onset and maintenance of cocaine use disorder. An underappreciated aspect of this area of research, however, is that the pharmacodynamic properties of cocaine can change depending on an organism's previous drug-exposure history. In this study, we utilized RNA sequencing to characterize how the transcriptome-wide effects of acute cocaine exposure were altered by a history of cocaine self-administration and long-term withdrawal (30 days) in the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC) in male mice.