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

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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Fig. 1: Theoretical mechanisms of gene activation or suppression by transcription factors.
Fig. 2: Priming and desensitization of gene expression in NAc after prolonged withdrawal from cocaine self-administration.
Fig. 3: Intracellular signaling pathways in D1 MSNs after chronic cocaine administration.
Fig. 4: Postulated mechanisms regulating FosB gene expression after cocaine administration.

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Teague, C.D., Nestler, E.J. Key transcription factors mediating cocaine-induced plasticity in the nucleus accumbens. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01163-5

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