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

• Published in: Biological psychiatry (1969) 2016-09, Vol.80 (5), p.345-355
• Main Authors: Kalin, Ned H, Fox, Andrew S, Kovner, Rothem, Riedel, Marissa K, Fekete, Eva M, Roseboom, Patrick H, Tromp, Do P.M, Grabow, Benjamin P, Olsen, Miles E, Brodsky, Ethan K, McFarlin, Daniel R, Alexander, Andrew L, Emborg, Marina E, Block, Walter F, Fudge, Julie L, Oler, Jonathan A
• Format: Article
• Language: English
• Subjects: AAV2; Animals; Anisotropy; Anxiety - pathology; Brain Mapping; Central Amygdaloid Nucleus - diagnostic imaging; Central Amygdaloid Nucleus - metabolism; Central nucleus of the amygdala; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Dependovirus - genetics; Diffusion Tensor Imaging; Disease Models, Animal; DTI; FDG-PET; Female; fMRI; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Image Processing, Computer-Assisted; Macaca fascicularis; Macaca mulatta; Male; MRI-guided neurosurgery; Neural Pathways - diagnostic imaging; Oxygen - blood; Psychiatry; RNA, Messenger - metabolism; Temperament; Transduction, Genetic
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2016.01.010

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.