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Review
. 2022 Jan;27(1):687-709.
doi: 10.1038/s41380-021-01163-5. Epub 2021 Jun 2.

Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens

Collin D Teague  1 , Eric J Nestler  2
Affiliations
Review

Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens

Collin D Teague et al. Mol Psychiatry. 2022 Jan.

Abstract

Repeated cocaine use induces coordinated changes in gene expression that drive plasticity in the nucleus accumbens (NAc), an important component of the brain's reward circuitry, and promote the development of maladaptive, addiction-like behaviors. Studies on the molecular basis of cocaine action identify transcription factors, a class of proteins that bind to specific DNA sequences and regulate transcription, as critical mediators of this cocaine-induced plasticity. Early methods to identify and study transcription factors involved in addiction pathophysiology primarily relied on quantifying the expression of candidate genes in bulk brain tissue after chronic cocaine treatment, as well as conventional overexpression and knockdown techniques. More recently, advances in next generation sequencing, bioinformatics, cell-type-specific targeting, and locus-specific neuroepigenomic editing offer a more powerful, unbiased toolbox to identify the most important transcription factors that drive drug-induced plasticity and to causally define their downstream molecular mechanisms. Here, we synthesize the literature on transcription factors mediating cocaine action in the NAc, discuss the advancements and remaining limitations of current experimental approaches, and emphasize recent work leveraging bioinformatic tools and neuroepigenomic editing to study transcription factors involved in cocaine addiction.

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Conflict of interest statement

Conflicts of interest:

None.

Figures

Figure 1:
Figure 1:. Theoretical mechanisms of gene activation or suppression by transcription factors.
Transcription factors bind to specific DNA sequences, termed response elements, at their target genes and recruit secondary epigenetic enzymes and transcriptional machinery to regulate gene transcription. While many transcription factors either activate or suppress gene transcription at their target genes, some transcription factors may have opposite effects on transcription at different target genes via distinct mechanisms downstream of transcription factor binding. In this scheme, a transcription factor binds to its response element at a given target gene and recruits various chromatin-modifying enzymes (A). These enzymes remove repressive DNA methylation (Me) and deposit permissive modifications (e.g., acetylation [Ac]) on local histones (B), which are subsequently recognized by chromatin remodeling proteins that increase nucleosome spacing and enable recruitment of the transcriptional machinery (C). Conversely, a transcription factor bound to its response element (D) may recruit chromatin-modifying enzymes that deposit repressive modifications on local histones and DNA (E). These repressive modifications are then recognized by chromatin remodeling proteins that reduce nucleosome spacing and prevent the binding of transcriptional machinery (F). It is important to note that many additional proteins, chromatin modifications, and non-coding RNAs also regulate gene transcription, but these mechanisms remain poorly characterized in the context of drug-induced adaptations in NAc MSNs. TATA box denotes promoter region of the gene just 5’ of the transcription start site (TSS). The purple and light blue shapes in (C) show subunits of the basal transcription machinery and RNA polymerase II (Pol II).
Figure 2:
Figure 2:. Priming and desensitization of gene expression in NAc after prolonged withdrawal from cocaine self-administration.
Mice self-administered saline (Sal) or cocaine (Coc) for 10 d. One cohort was analyzed 24 h after the last self-administration session (24 h - Coc). The other cohorts remained in their home cages for 30 d and then returned to the self-administration chambers and given an intraperitoneal injection of saline or cocaine yielding three groups: Sal-Coc (acute cocaine); Coc-Sal (30 d withdrawal, saline challenge: “Incubated genes”); Coc-Coc (30 d withdrawal, cocaine challenge: primed/desensitized genes). Heatmaps show RNAs whose expression levels exhibit statistically significant differential expression (yellow: upregulated; blue, downregulated) from all other conditions at both Coc-Sal and Coc-Coc conditions (left) or after the Coc-Coc condition (right). From Walker et al., 2018.
Figure 3:
Figure 3:. Intracellular signaling pathways in D1 MSNs after chronic cocaine administration.
Chronic cocaine potentiates dopaminergic, glutamatergic, and BDNF-TRKB signaling in D1 MSNs in the NAc. Here, we represent several known intracellular signaling pathways that contribute to cocaine-induced regulation of transcription factor activity, but many additional pathways are involved in regulating these and other transcription factors, mechanisms which remain less well understood. Post-translational modifications of transcription factors are important regulators of their activity, and may have an inhibitory or activating effect depending on the type of modification (phosphorylation, acetylation, etc.) and site of modification. Each regulated transcription factor then controls the expression levels of a unique set of target genes. This is illustrated for ΔFOSB, the accumulation of which after chronic cocaine exposure activates or represses the expression of many intracellular signaling molecules, including CDK5, CaMKIIα, and SIRT1, among many others. Each of these targets in turn influences the activity of many additional transcription factors. Delineating the complex web of interactions among intracellular messengers and transcription factors remains an important frontier in understanding the molecular basis of cocaine addiction. The box around CREB regulation denotes the fact that these phosphorylation events occur in the cell nucleus, whereas it remains uncertain whether post-translational modification of the other transcription factors shown occurs in the nucleus or cytoplasm. Note that Ca2+ entry is shown for both AMPARs and NMDARs, although only AMPARs of particular subunit compositions flux Ca2+. Ca2+ can also enter cells through voltage-gated Ca2+ channels (not shown).
Figure 4:
Figure 4:. Postulated mechanisms regulating FosB gene expression after cocaine administration.
Chronic cocaine exposure promotes the recruitment of four known transcription factors, permissive epigenetic modifications, and RNA Pol II to the FosB locus, in concert with the removal of repressive histone dimethylation (Me2) and repressive DNA methylation and MeCP2 binding. After prolonged withdrawal, the FosB locus remains in a “primed” state, as indicated by persisting, long-lived removal of repressive histone methylation marks and stalling of RNA Pol II near the gene’s transcription start site (TSS). Cocaine re-exposure after prolonged withdrawal is thought to revert the FosB locus to the activated state, contributing further to the accumulation of ΔFOSB protein in NAc D1 MSNs.
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