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Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit

      ABSTRACT

      Background

      Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT’s neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region.

      Methods

      Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions.

      Results

      Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity.

      Conclusions

      This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT’s neural circuitry.

      Keywords

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      Linked Article

      • Corticotropin-Releasing Factor From Rodents to Primates: Translational Hope Expresses Itself, Pun Intended
        Biological PsychiatryVol. 80Issue 5
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          Corticotropin-releasing factor (CRF) is a neuropeptide in the brain and body that coordinates hormonal, sympathetic, and behavioral responses to stressors. Since its discovery in 1981 (1), literally thousands of articles have been published that support its role in these three functional domains. CRF controls corticotropin secretion and in turn glucocorticoid activation in the face of acute stressor exposure via its actions as a releasing factor in the paraventricular nucleus of the hypothalamus.
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