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.
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