In contrast to CREB—a prominently studied member of CRE-binding transcription factors32—few neurobiological investigations have focused on CREM. This paucity may be partly due to the relatively lower and more restricted abundance of CREM in the brain and the complexity of CREM isoforms for which activator or repressor activities are not fully understood33, 34. Despite the strong sequence homology, Creb1 was not significantly altered in the AcbC of SHRs (Supplementary Table 1). Our findings demonstrate a reproducible genetic association between CREM genotype and hyperactivity in humans, in line with some locomotor patterns observed in knock-out mice35. While our animal studies demonstrated that Crem in the AcbC—the motor component of the ventral striatum—specifically mediates impulsive action, not general activity or impulsive choice, it is possible that CREM expression in other striatal subregions contributes to different features of impulsivity. Moreover, it will be important to assess the impact of long-term perturbation of Crem on behavior using viral vectors with persistent expression.
