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Cocaine and sucrose rewards recruit different seeking ensembles in the nucleus accumbens core

Molecular Psychiatry volume 25, pages 3150–3163 (2020)Cite this article

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Abstract

Poorly regulated reward seeking is a central feature of substance use disorder. Recent research shows that rewarding drug-related experiences induce synchronous activation of a discrete number of neurons in the nucleus accumbens that are causally linked to reward-related contexts. Here we comprehensively characterize the specific ensemble of neurons built through experience that are linked to seeking behavior. We additionally address the question of whether or not addictive drugs usurp the neuronal networks recruited by natural rewards by evaluating cocaine- and sucrose-associated ensembles within the same mouse. We used FosCreERT2/+/Ai14 transgenic mice to tag cells activated by and potentially encoding cocaine and sucrose seeking. We tagged ~1% of neurons in the core subregion of the accumbens (NAcore) activated during cue-induced seeking for cocaine or sucrose. The majority of tagged cells in the seeking ensembles were D1-MSNs, and specifically activated during seeking, not during extinction or when mice remained in the home cage. To compare different reward-specific ensembles within the same mouse, we used a dual cocaine and sucrose self-administration protocol allowing reward-specific seeking. Using this model, we found ~70% distinction between the cells constituting the cocaine- compared to the sucrose-seeking ensemble. Establishing that cocaine recruits an ensemble of NAcore neurons largely distinct from neurons recruited into an ensemble coding for sucrose seeking suggest a finely tuned specificity of ensembles. The findings allow further exploration of the mechanisms that transform reward-based positive reinforcement into maladaptive drug seeking.

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Fig. 1: Cocaine seeking ensembles in the NAcore.
Fig. 2: Sucrose seeking ensembles in the NAcore.
Fig. 3: Dual cocaine and sucrose self-administration and cue-induced reward-specific seeking.
Fig. 4: Within subject reward-specific ensembles in the NAcore.

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Acknowledgements

The authors thank Drs. Chris Cowan and Makoto Taniguchi for kindly providing the initial cFos-TRAP mice, Jordan Hopkins and Dr. Ahlem Assali for their help optimizing the RNAscope protocol, and the members of the Kalivas lab for helpful comments on the manuscript. This work was supported by NIH DA046522 (A-CB), DA040004 (MDS), DA003906 (PWK), DA12513 (PWK).

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Authors and Affiliations

  1. Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA

    Ana-Clara Bobadilla, Eric Dereschewitz, Lucio Vaccaro, Michael D. Scofield & Peter W. Kalivas

  2. School of Pharmacy, University of Wyoming, Laramie, WY, USA

    Ana-Clara Bobadilla

  3. Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    Jasper A. Heinsbroek

  4. Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, SC, USA

    Michael D. Scofield

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Bobadilla, AC., Dereschewitz, E., Vaccaro, L. et al. Cocaine and sucrose rewards recruit different seeking ensembles in the nucleus accumbens core. Mol Psychiatry 25, 3150–3163 (2020). https://doi.org/10.1038/s41380-020-00888-z

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