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Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain’s Reward Circuitry

  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Deena M. Walker
    Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Hannah M. Cates
    Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Yong-Hwee E. Loh
    Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Immanuel Purushothaman
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Aarthi Ramakrishnan
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Kelly M. Cahill
    Affiliations
    Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Casey K. Lardner
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Arthur Godino
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Hope G. Kronman
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Jacqui Rabkin
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Zachary S. Lorsch
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Philipp Mews
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Marie A. Doyle
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Jian Feng
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Benoit Labonté
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Ja Wook Koo
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Rosemary C. Bagot
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Ryan W. Logan
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine
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  • Marianne L. Seney
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Erin S. Calipari
    Correspondence
    Erin S. Calipari, Ph.D., Department of Pharmacology, Vanderbilt Center for Addiction Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, 865F Light Hall, 2215 Garland Ave, Nashville, TN 37232.
    Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Affiliations
    Department of Pharmacology, Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, Tennessee
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  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Li Shen
    Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Eric J. Nestler
    Correspondence
    Address correspondence to Eric J. Nestler, M.D., Ph.D., Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, Box 1065, New York, New York10029.
    Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 DMW, HMC, and Y-HEL contributed equally to this work as joint first authors. ESC, LS, and EJN contributed equally to this work as joint senior authors.

      Abstract

      Background

      Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain’s reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD).

      Methods

      We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes.

      Results

      We focused on three patterns of gene expression that reflect responses to 1) acute cocaine, 2) context re-exposure, and 3) drug + context re-exposure. These patterns revealed region-specific regulation of gene expression. Further analysis revealed that each of these gene expression patterns correlated with an addiction index—a composite score of several addiction-like behaviors during cocaine SA—in a region-specific manner. Cyclic adenosine monophosphate response element binding protein and nuclear receptor families were identified as key upstream regulators of genes associated with such behaviors.

      Conclusions

      This comprehensive picture of transcriptome-wide regulation in the brain’s reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.

      Keywords

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