Eric Nestler, Dept of Neuroscience, Mount Sinai School of Medicine
Drug addiction is associated with long-lasting changes in gene expression, yet the molecular basis of this persistence has remained unknown. Our laboratory has provided evidence that one unique mechanism underlying the lasting effects of drugs of abuse on changes in gene expression in the brain’s reward circuitry involves the Fos family transcription factor, ∆FosB. We have shown that ∆FosB is induced in the nucleus accumbens and other key brain reward regions in response to chronic administration of all classes of drugs of abuse, but not in response to other, non-abused psychotropic drugs. Unlike all other Fos family proteins, variants of ∆FosB are highly stable proteins. This stability underlies the unique accumulation of ∆FosB after chronic drug administration. Moreover, this stability also means that ∆FosB persists in brain reward regions for a relatively prolonged period (weeks-months) after cessation of drug exposure. In this way, regulation of ∆FosB provides a unique mechanism by which drugs of abuse induce some of their lasting effects on gene expression. Indeed, transcriptomic and ChIP analyses have established that ∆FosB is an important mediator of many of the effects of drugs of abuse on gene expression. Importantly, ∆FosB regulates a partially distinct set of target genes in brain reward regions compared to other Fos family proteins.
The goal of the proposed studies is to characterize the molecular basis of ∆FosB action to better understand the biochemical mechanisms underlying its unique stability and its unique transcriptional effects on target genes. With respect to the former, we have demonstrated that phosphorylation of ∆FosB on Ser27 by CaM-kinase 2 or by casein kinase 2 increases the protein’s stability in vitro and in vivo. We have also demonstrated phosphorylation of ∆FosB at Thr149 by CaM-kinase 2 and established that this modification dramatically enhances ∆FosB’s transcriptional activity without affecting the protein’s stability. We now want to extend proteomic studies of ∆FosB by characterizing its several binding partners which help sculpt the chromatin architecture around ∆FosB target genes in concert with their induction or repression. Since ∆FosB’s target genes predominate at the synapse, we also want to use proteomic methods to interrogate the changes that ∆FosB orchestrates at glutamatergic synapses in brain reward regions through the regulation of its target genes.
Together, these studies promise important advances in our understanding of the molecular basis of addiction.
Drug addiction is a serious public health concern and is associated with considerable loss of life, loss of productivity, and suffering to affecting patients and their families. Addiction is a life-long condition, and is thought to involve changes in the way that the genome functions. We propose to better understand these mechanisms of gene regulation via advanced studies of the drug-regulated transcription factor, ∆FosB.