1. Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates
- Author
-
Fox, Andrew S, Souaiaia, Tade, Oler, Jonathan A, Kovner, Rothem, Kim, Jae Mun Hugo, Nguyen, Joseph, French, Delores A, Riedel, Marissa K, Fekete, Eva M, Rabska, Matthew R, Olsen, Miles E, Brodsky, Ethan K, Alexander, Andrew L, Block, Walter F, Roseboom, Patrick H, Knowles, James A, and Kalin, Ned H
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Neurosciences ,Basic Behavioral and Social Science ,Behavioral and Social Science ,Mental Illness ,Prevention ,Biomedical Imaging ,Brain Disorders ,Mental Health ,Genetics ,Anxiety Disorders ,Good Health and Well Being ,Amygdala ,Animals ,Anxiety ,Disease Models ,Animal ,Gene Expression ,Macaca mulatta ,Male ,Neurotrophin 3 ,Receptor ,trkC ,AAV ,Anxious temperament ,Behavioral inhibition ,Central nucleus of the amygdala ,Extended amygdala ,FDG-PET ,Neurotrophic ,NTF3 ,NTRK3 ,Primate ,RNA-seq ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological sciences ,Biomedical and clinical sciences - Abstract
BackgroundAn early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates.MethodsIn response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group).ResultsThis discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit.ConclusionsTogether, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.
- Published
- 2019