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The Relationship Between the Uncinate Fasciculus and Anxious Temperament Is Evolutionarily Conserved and Sexually Dimorphic

  • Do P.M. Tromp
    Affiliations
    Department of Psychiatry, University of Wisconsin, Madison, Wisconsin

    Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin

    HealthEmotion Research Institute, University of Wisconsin, Madison, Wisconsin
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  • Andrew S. Fox
    Affiliations
    Department of Psychology, University of California, Davis, California

    California National Primate Research Center, University of California, Davis, California
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  • Jonathan A. Oler
    Affiliations
    Department of Psychiatry, University of Wisconsin, Madison, Wisconsin

    HealthEmotion Research Institute, University of Wisconsin, Madison, Wisconsin
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  • Andrew L. Alexander
    Affiliations
    Department of Psychiatry, University of Wisconsin, Madison, Wisconsin

    Department of Medical Physics, University of Wisconsin, Madison, Wisconsin
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  • Ned H. Kalin
    Correspondence
    Address correspondence to Ned H. Kalin, M.D., HealthEmotion Research Institute, Department of Psychiatry, 6001 Research Park Boulevard, Madison, WI 53719.
    Affiliations
    Department of Psychiatry, University of Wisconsin, Madison, Wisconsin

    Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin

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

      Abstract

      Background

      Anxious temperament (AT) is an early-life heritable trait that predisposes individuals to develop anxiety and depressive disorders. Our previous work in preadolescent children suggests alterations in the uncinate fasciculus (UF), the white matter tract that connects prefrontal with limbic regions, in boys with anxiety disorders. Here, using a nonhuman primate model of AT, we tested whether this sexually dimorphic finding is evolutionarily conserved and examined the extent to which heritable and environmental influences contribute to UF microstructure.

      Methods

      Diffusion tensor images were collected in 581 young rhesus monkeys (1.89 ± 0.77 years old; 43.9% female). Using tract-based analyses, we assessed the relationship among AT, UF microstructure (as measured with fractional anisotropy), and sex. Heritability of tract microstructure was determined using oligogenic linkage analysis of this large multigenerational pedigree.

      Results

      We predicted and found a negative relation between AT and UF fractional anisotropy in male but not female monkeys (AT × sex; p = .032, 1-tailed). Additionally, heritability analyses revealed that variation in UF fractional anisotropy was largely due to nonheritable factors (h2 = 0.185, p = .077).

      Conclusions

      These results demonstrate a cross-species, male-specific relation between UF microstructure and anxiety and provide a potential substrate for anxiety-related prefrontal-limbic dysregulation. The heritability analyses point to the importance of environmental influences on UF microstructure, which could be important in mediating the nonheritable components of pathological anxiety. These findings have the potential to guide new treatment strategies for childhood anxiety disorders and further support the use of nonhuman primates as a translational model to discover mechanisms underlying the development of anxiety.

      Keywords

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      Linked Article

      • The Uncinate Fasciculus in Anxiety Disorders: A Potential Treatment Target?
        Biological PsychiatryVol. 86Issue 12
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          Anxiety disorders, the most prevalent class of pediatric mental disorders, are viewed as conditions of abnormal threat processing. The circuitry engaged by threats in a range of mammalian species encompasses the amygdala and its connections to the ventral prefrontal cortex, insula, and hippocampus. Thus, this circuitry can be targeted in translational research. Cross-species translational research is crucial for psychiatry given the inaccessibility of the human brain to many research techniques.
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