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Astrocyte Molecular Clock Function in the Nucleus Accumbens Is Important for Reward-Related Behavior

  • Darius D. Becker-Krail
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Kyle D. Ketchesin
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Jennifer N. Burns
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Wei Zong
    Affiliations
    Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Mariah A. Hildebrand
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Lauren M. DePoy
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Chelsea A. Vadnie
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • George C. Tseng
    Affiliations
    Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Ryan W. Logan
    Affiliations
    Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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  • Yanhua H. Huang
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Colleen A. McClung
    Correspondence
    Address correspondence to Colleen A. McClung, Ph.D.
    Affiliations
    Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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Published:February 18, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.02.007

      Abstract

      Background

      Substance use disorders are associated with disruptions in circadian rhythms. Both human and animal work have shown the integral role for circadian clocks in the modulation of reward behaviors. Astrocytes have emerged as key regulators of circadian rhythmicity. However, no studies to date have identified the role of circadian astrocyte function in the nucleus accumbens (NAc), a hub for reward regulation, or determined the importance of these rhythms for reward-related behavior.

      Methods

      Using astrocyte-specific RNA sequencing across time of day, we first characterized diurnal variation of the NAc astrocyte transcriptome. We then investigated the functional significance of this circadian regulation through viral-mediated disruption of molecular clock function in NAc astrocytes, followed by assessment of reward-related behaviors, metabolic-related molecular assays, and whole-cell electrophysiology in the NAc.

      Results

      Strikingly, approximately 43% of the astrocyte transcriptome has a diurnal rhythm, and key metabolic pathways were enriched among the top rhythmic genes. Moreover, mice with a viral-mediated loss of molecular clock function in NAc astrocytes show a significant increase in locomotor response to novelty, exploratory drive, operant food self-administration, and motivation. At the molecular level, these animals also show disrupted metabolic gene expression, along with significant downregulation of both lactate and glutathione levels in the NAc. Loss of NAc astrocyte clock function also significantly altered glutamatergic signaling onto neighboring medium spiny neurons, alongside upregulated glutamate-related gene expression.

      Conclusions

      Taken together, these findings demonstrate a novel role for astrocyte circadian molecular clock function in the regulation of the NAc and reward-related behaviors.

      Keywords

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