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Biol Psychiatry. 2016 Sep 1;80(5):345-55. doi: 10.1016/j.biopsych.2016.01.010. Epub 2016 Jan 30.

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

Author information

  • 1Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin; Wisconsin National Primate Research Center (NHK, MEE); Madison, Wisconsin.
  • 2Department of Psychiatry, University of Wisconsin, Madison, Wisconsin.
  • 3Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin.
  • 4Department of Medical Physics, University of Wisconsin, Madison, Wisconsin.
  • 5Department of Medical Physics, University of Wisconsin, Madison, Wisconsin; Department of Radiology (WFB, EKB) University of Wisconsin; Madison, Wisconsin; TherVoyant, Inc., Madison, Wisconsin.
  • 6Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Department of Medical Physics, University of Wisconsin, Madison, Wisconsin; TherVoyant, Inc., Madison, Wisconsin.
  • 7Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin; Department of Medical Physics, University of Wisconsin, Madison, Wisconsin; Wisconsin National Primate Research Center (NHK, MEE); Madison, Wisconsin.
  • 8Department of Medical Physics, University of Wisconsin, Madison, Wisconsin; Department of Biomedical Engineering (WFB); Department of Radiology (WFB, EKB) University of Wisconsin; Madison, Wisconsin; TherVoyant, Inc., Madison, Wisconsin.
  • 9Departments of Neurobiology and Anatomy and Psychiatry (JLF), University of Rochester Medical Center, Rochester, New York.
  • 10Department of Psychiatry, University of Wisconsin, Madison, Wisconsin. Electronic address: oler@wisc.edu.

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:

AAV2; Central nucleus of the amygdala; DTI; FDG-PET; MRI-guided neurosurgery; fMRI

PMID:
27016385
PMCID:
PMC4967405
[Available on 2017-09-01]
DOI:
10.1016/j.biopsych.2016.01.010
[PubMed - in process]
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