NPAS4 supports cocaine-conditioned cues in rodents by controlling the cell type-specific activation balance in the nucleus accumbens

Brandon W. Hughes, Jessica L. Huebschman, Evgeny Tsvetkov, Benjamin M. Siemsen, Kirsten K. Snyder, Rose Marie Akiki, Daniel J. Wood, Rachel D. Penrod, Michael D. Scofield, Stefano Berto, Makoto Taniguchi () and Christopher W. Cowan ()
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Brandon W. Hughes: Medical University of South Carolina
Jessica L. Huebschman: Medical University of South Carolina
Evgeny Tsvetkov: Medical University of South Carolina
Benjamin M. Siemsen: Medical University of South Carolina
Kirsten K. Snyder: Medical University of South Carolina
Rose Marie Akiki: Medical University of South Carolina
Daniel J. Wood: Medical University of South Carolina
Rachel D. Penrod: Medical University of South Carolina
Michael D. Scofield: Medical University of South Carolina
Stefano Berto: Medical University of South Carolina
Makoto Taniguchi: Medical University of South Carolina
Christopher W. Cowan: Medical University of South Carolina

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Powerful associations that link drugs of abuse with cues in the drug-paired environment often serve as prepotent relapse triggers. Drug-associated contexts and cues activate ensembles of nucleus accumbens (NAc) neurons, including D1-class medium spiny neurons (MSNs) that typically promote, and D2-class MSNs that typically oppose, drug seeking. We found that in mice, cocaine conditioning upregulated transiently the activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), in a small subset of NAc neurons. The NPAS4+ NAc ensemble was required for cocaine conditioned place preference. We also observed that NPAS4 functions within NAc D2-, but not D1-, MSNs to support cocaine-context associations and cue-induced cocaine, but not sucrose, seeking. Together, our data show that the NPAS4+ ensemble of NAc neurons is essential for cocaine-context associations in mice, and that NPAS4 itself functions in NAc D2-MSNs to support cocaine-context associations by suppressing drug-induced counteradaptations that oppose relapse-related behaviour.

Date: 2024
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DOI: 10.1038/s41467-024-50099-1

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