??FosB: a Molecular Switch for Reward
Author(s): Eric J. Nestler
ΔFosB is a member of the Fos family of transcription factors. While all other family members are induced rapidly but transiently in response to a host of acute stimuli, ΔFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such a prolonged induction of ΔFosB, within the brain’s reward regions, has been implicated in animal models of drug addiction, with a wealth of evidence indicating that ΔFosB promotes reward and motivation and serves as a key mechanism of drug sensitization and increased drug self-administration. This has been validated in humans postmortem, with elevated ΔFosB levels seen in reward regions of the addicted brain. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes. We are identifying such transcriptional targets of ΔFosB by use of a candidate gene approach as well as by use of genome-wide methods. Recent work has analyzed chromatin remodeling—changes in the posttranslational modifications of histones and other nuclear proteins at drug-regulated genes— to delineate the detailed molecular mechanisms by which ΔFosB regulates target gene expression in vivo to mediate drug-induced synaptic, neural, and behavioral plasticity. These studies of ΔFosB are providing new insight into the molecular basis of drug addiction, which is defining a host of new targets for possible therapeutic development.