title: Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department 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.
authors.forename: Ned H
authors.initials: NH
authors.lastname: Kalin
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Fox
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin.
authors.forename: Rothem
authors.initials: R
authors.lastname: Kovner
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin.
authors.forename: Marissa K
authors.initials: MK
authors.lastname: Riedel
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Fekete
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Roseboom
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin.
authors.forename: Do P M
authors.initials: do PM
authors.lastname: Tromp
authors.affiliation: Department of Medical Physics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Grabow
authors.affiliation: Department of Medical Physics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Miles E
authors.initials: ME
authors.lastname: Olsen
authors.affiliation: Department of Medical Physics, University of Wisconsin, Madison, Wisconsin; Department of Radiology (WFB, EKB) University of Wisconsin; Madison, Wisconsin; TherVoyant, Inc., Madison, Wisconsin.
authors.forename: Ethan K
authors.initials: EK
authors.lastname: Brodsky
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McFarlin
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin; Department of Medical Physics, University of Wisconsin, Madison, Wisconsin; TherVoyant, Inc., Madison, Wisconsin.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Alexander
authors.affiliation: Neuroscience 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.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Emborg
authors.affiliation: Department 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.
authors.forename: Walter F
authors.initials: WF
authors.lastname: Block
authors.affiliation: Departments of Neurobiology and Anatomy and Psychiatry (JLF), University of Rochester Medical Center, Rochester, New York.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Fudge
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, Wisconsin. Electronic address: oler@wisc.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Oler
mesh_terms: D000818:Animals; D016880:Anisotropy; D001007:Anxiety / Q000473:pathology*; D001931:Brain Mapping; D066274:Central Amygdaloid Nucleus / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D009434:Neural Pathways / Q000000981:diagnostic imaging*; D010100:Oxygen / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D013694:Temperament; D014161:Transduction, Genetic
chemical_list: D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D003346:Corticotropin-Releasing Hormone; D010100:Oxygen
keywords: AAV2; Central nucleus of the amygdala; DTI; FDG-PET; MRI-guided neurosurgery; fMRI