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Prenatal Δ9-Tetrahydrocannabinol Exposure in Males Leads to Motivational Disturbances Related to Striatal Epigenetic Dysregulation

  • Author Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
    Randall J. Ellis
    Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Addiction Institute of Mount Sinai, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
    Anissa Bara
    Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
    Affiliations
    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Addiction Institute of Mount Sinai, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
    Claudia A. Vargas
    Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Amy L. Frick
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Eddie Loh
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Joseph Landry
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Teddy O. Uzamere
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • James E. Callens
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Qammarah Martin
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Prashanth Rajarajan
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Kristen Brennand
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Aarthi Ramakrishnan
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Li Shen
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Henrietta Szutorisz
    Correspondence
    Henrietta Szutorisz, Ph.D.
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Yasmin L. Hurd
    Correspondence
    Address correspondence to Yasmin L. Hurd, Ph.D.
    Affiliations
    Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Addiction Institute of Mount Sinai, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 RJE, AB, and CAV contributed equally to this work as joint first co-authors.
Published:September 27, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.09.017

      Abstract

      Background

      Cannabis remains one of the most widely abused drugs during pregnancy. In utero exposure to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), can result in long-term neuropsychiatric risk for the progeny. This study investigated epigenetic signatures underlying these enduring consequences.

      Methods

      Rat dams were exposed daily to THC (0.15 mg/kg) during pregnancy, and adult male offspring were examined for reward and depressive-like behavioral endophenotypes. Using unbiased sequencing approaches, we explored transcriptional and epigenetic profiles in the nucleus accumbens (NAc), a brain area central to reward and emotional processing. An in vitro CRISPR (clustered regularly interspaced short palindromic repeats) activation model coupled with RNA sequencing was also applied to study specific consequences of epigenetic dysregulation, and altered molecular signatures were compared with human major depressive disorder transcriptome datasets.

      Results

      Prenatal THC exposure induced increased motivation for food, heightened learned helplessness and anhedonia, and altered stress sensitivity. We identified a robust increase specific to males in the expression of Kmt2a (histone-lysine N-methyltransferase 2A) that targets H3K4 (lysine 4 on histone H3) in cellular chromatin. Normalizing Kmt2a in the NAc rescued the motivational phenotype of prenatally THC-exposed animals. Comparison of RNA- and H3K4me3-sequencing datasets from the NAc of rat offspring with the in vitro model of Kmt2a upregulation revealed overlapping, significant disturbances in pathways that mediate synaptic plasticity. Similar transcriptional alterations were detected in human major depressive disorder.

      Conclusions

      These studies provide direct evidence for the persistent effects of prenatal cannabis exposure on transcriptional and epigenetic deviations in the NAc via Kmt2a dysregulation and associated psychiatric vulnerability.

      Keywords

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