Astrocytic CREB regulates transcriptional, neuronal, and behavioral responses to cocaine

While neuronal adaptations in the nucleus accumbens (NAc) are well-documented in addiction, the role of astrocytes—the brain's most abundant glial cells—remains less understood. This study investigates the astrocyte-specific transcriptional response to cocaine self-administration and identifies the molecular mechanisms by which these cells influence addiction-related behaviors.

The researchers performed RNA-sequencing on NAc astrocytes from male mice across various stages of cocaine self-administration, including abstinence and relapse. Using bioinformatic analysis, they identified the transcription factor CREB as a primary upstream regulator. They then used CUT&RUN-sequencing to map CREB binding sites, followed by viral-mediated gene manipulation (overexpression and knockout) to assess the behavioral consequences of altering astrocytic CREB activity. Finally, they employed fiber photometry to monitor calcium dynamics and electrophysiology to examine the impact of astrocytic CREB on neuronal circuit activity.

The study reveals that the NAc astrocyte transcriptome responds robustly and context-specifically to cocaine, showing significant convergence with human cocaine use disorder signatures. CREB was identified as a central regulator activated by cocaine, with increased binding to genes involved in calcium signaling, such as Atp2b1. Manipulating CREB levels in NAc astrocytes bidirectionally altered cocaine reward: CREB overexpression increased the rewarding and reinforcing properties of the drug, while CREB knockout decreased them. Mechanistically, astrocytic CREB modulates calcium transients and selectively enhances excitatory synaptic transmission onto D1-type medium spiny neurons (D1-MSNs). Inhibiting these D1-MSNs abolished the behavioral effects of astrocytic CREB, establishing a direct link between astrocytic gene regulation and neuronal circuit output.