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

Emerging evidence increasingly indicates that astrocytes are involved in neuropsychiatric disorders, including addiction, but the cocaine-induced astrocyte transcriptome has yet to be investigated. We performed RNA sequencing on whole-cell sorted astrocytes from the nucleus accumbens and bioinformatically characterized the astrocyte transcriptome following cocaine self-administration in male mice. We found that astrocytes exhibit robust and contextually specific transcriptional signatures that implicate adenosine 3',5'-monophosphate response element-binding protein (CREB) as a cocaine-induced transcriptional regulator in astrocytes. Cleavage under targets and release using nuclease sequencing (CUT&RUN) revealed increased astrocytic CREB DNA binding in response to cocaine. Viral-mediated manipulation of nucleus accumbens astrocytic CREB activity in combination with addiction-related behaviors revealed that astrocytic CREB increases the rewarding and reinforcing properties of cocaine. Furthermore, we identified potential molecular mechanisms of astrocytic CREB's influence through modulating astrocytic calcium dynamics and selectively increasing D1-type medium spiny neuronal activity.