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Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early-Life Anxious Temperament

  • Rothem Kovner
    Correspondence
    Address correspondence to Rothem Kovner, Ph.D.
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    Neuroscience Training Program, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
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  • Tade Souaiaia
    Affiliations
    Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York
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  • Andrew S. Fox
    Affiliations
    Department of Psychology, University of California, Davis, Davis, California

    California National Primate Research Center, University of California, Davis, Davis, California
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  • Delores A. French
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
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  • Cooper E. Goss
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin
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  • Patrick H. Roseboom
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    Neuroscience Training Program, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
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  • Jonathan A. Oler
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
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  • Marissa K. Riedel
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
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  • Eva M. Fekete
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
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  • Julie L. Fudge
    Affiliations
    Department of Psychiatry, University of Rochester Medical Center, Rochester, New York

    Department of Neuroscience/Del Monte Institute for Brain Research, University of Rochester Medical Center, Rochester, New York
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  • James A. Knowles
    Affiliations
    Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York
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  • Ned H. Kalin
    Correspondence
    Ned H. Kalin, M.D.
    Affiliations
    Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin

    Neuroscience Training Program, University of Wisconsin–Madison, Madison, Wisconsin

    HealthEmotions Research Institute, University of Wisconsin–Madison, Madison, Wisconsin
    Search for articles by this author

      Abstract

      Background

      Children exhibiting extreme anxious temperament (AT) are at an increased risk for developing anxiety and depression. Our previous mechanistic and neuroimaging work in young rhesus monkeys linked the central nucleus of the amygdala to AT and its underlying neural circuit.

      Methods

      Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT’s molecular underpinnings by focusing on neurons from the lateral division of the central nucleus of the amygdala (CeL). RNA sequencing identified numerous AT-related CeL transcripts, and we used immunofluorescence (n = 3) and tract-tracing (n = 2) methods in a different sample of monkeys to examine the expression, distribution, and projection pattern of neurons expressing one of these transcripts.

      Results

      We found 555 AT-related transcripts, 14 of which were confirmed with high statistical confidence (false discovery rate < .10), including protein kinase C delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared its distribution with that of the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis.

      Conclusions

      These findings demonstrate that CeL PKCδ is associated with primate anxiety, provides evidence of a CeL to laterodorsal bed nucleus of the stria terminalis circuit that may be relevant to understanding human anxiety, and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.

      Keywords

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      • Central Amygdala Discovery Efforts in Primates Reveals New Clues on Anxious Temperament
        Biological PsychiatryVol. 88Issue 8
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          Our brains are built to consider and reflect on the unknown. These adaptive features protect us from potential threats in dynamic and complex environments, but they can also lead us to perseverate on perceived threats and fear an unknown future. Ranging across a spectrum from adaptive to maladaptive, anxious and fearful behavior exists in many animal species. In an effort to develop new therapeutics and understand the etiology of anxiety-related conditions, such as anxiety disorders, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder, research using laboratory animal models has focused on the genetic, molecular, cellular, and brain systems contribution to anxiety and fear.
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