Epigenetic remodelling

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. Grueter et al investigated the mechanism linking chrimatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. They found that histone  methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior. 

In another study, Heller E.A. et al  showed that synaptic modifications in nucleus accumbens medium spiny neurons  (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modifications of NAc MSN synapses  may occur in part via changes in the trancscriptional potential of certain genes in a cell type-specific manner. The transcription factor ΔFosB is of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. The same study demonstrated that overexpression of ΔFosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor-expressing direct pathway MSNs in both the NAc shell and core. In contrast, ΔFosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor-expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that ΔFosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. Also, direct but indirect pathway MSN expression enhances behavioral responses to cocaine. These results reveal that ΔFosB in NAc differentially modulated synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.

References 

Grueter BA, Robison AJ, Neve RL, et al. (2012) ΔFosB differentially modulates nucleus accumbens direct and indirect pathway function. PNAS, 2012, 110(5):1923-1928

Heller EA, Cates HM, Peña CJ, et al. (2014) Locus-specific epigenetic remodeling controls addiction and depression-relared behaviors. Nature Neuroscience, 2014. doi:10.1038/nn.3871.