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Sex-Specific Transcriptional Changes in Response to Adolescent Social Stress in the Brain’s Reward Circuitry

  • Author Footnotes
    1 DMW and XZ contributed equally to this work.
    Deena M. Walker
    Correspondence
    Deena M. Walker, Ph.D.
    Footnotes
    1 DMW and XZ contributed equally to this work.
    Affiliations
    Nash Family 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 and XZ contributed equally to this work.
    Xianxiao Zhou
    Footnotes
    1 DMW and XZ contributed equally to this work.
    Affiliations
    Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York

    Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Ashley M. Cunningham
    Affiliations
    Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Andrew P. Lipschultz
    Affiliations
    Nash Family 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
    Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Hannah M. Cates
    Affiliations
    Nash Family 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
    Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Li Shen
    Affiliations
    Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Bin Zhang
    Affiliations
    Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York

    Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Eric J. Nestler
    Correspondence
    Address correspondence to Eric J. Nestler, M.D., Ph.D.
    Affiliations
    Nash Family 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 and XZ contributed equally to this work.
Published:February 24, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.02.964

      Abstract

      Background

      Sex differences in addiction have been described in humans and animal models. A key factor that influences addiction in both males and females is adolescent experience. Adolescence is associated with higher vulnerability to substance use disorders, and male rodents subjected to adolescent social isolation (SI) stress form stronger preferences for drugs of abuse in adulthood. However, little is known about how females respond to SI, and few studies have investigated the transcriptional changes induced by SI in the brain’s reward circuitry.

      Methods

      We tested the hypothesis that SI alters the transcriptome in a persistent and sex-specific manner in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Mice were isolated or group housed from postnatal day P22 to P42, then group housed until ∼P90. Transcriptome-wide changes were investigated by RNA sequencing after acute or chronic cocaine or saline administration.

      Results

      We found that SI disrupts sex-specific transcriptional responses to cocaine and reduces sex differences in gene expression across all three brain regions. Furthermore, SI induces gene expression profiles in males that more closely resemble group-housed females, suggesting that SI “feminizes” the male transcriptome. Coexpression analysis reveals that such disruption of sex differences in gene expression alters sex-specific gene networks and identifies potential sex-specific key drivers of these transcriptional changes.

      Conclusions

      Together, these data show that SI has region-specific effects on sex-specific transcriptional responses to cocaine and provide a better understanding of reward-associated transcription that differs in males and females.

      Keywords

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      Linked Article

      • Multiple Comparisons and Inappropriate Statistical Testing Lead to Spurious Sex Differences in Gene Expression
        Biological PsychiatryVol. 91Issue 1
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          The substantial differences in the incidence and symptoms of stress, depression, and addiction between males and females have motivated studies of sex differences in the brain’s molecular responses to environmental stimuli. In a study of three mouse brain regions from the Nestler laboratory, Walker et al. (1) reported sex-specific transcriptional responses to cocaine and baseline sex differences. They further examined the impact of social isolation on these brain gene expression patterns. However, the transcriptome data (RNA sequencing) and analysis in this study do not support the authors’ conclusions.
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