Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates. Biol Psychiatry 2019 Dec 15;86(12):881-889
Date
08/20/2019Pubmed ID
31422797Pubmed Central ID
PMC6999854DOI
10.1016/j.biopsych.2019.06.022Scopus ID
2-s2.0-85070560196 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
BACKGROUND: An 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.
METHODS: In 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).
RESULTS: This 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.
CONCLUSIONS: Together, 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.
Author List
Fox AS, Souaiaia T, Oler JA, Kovner R, Kim JMH, Nguyen J, French DA, Riedel MK, Fekete EM, Rabska MR, Olsen ME, Brodsky EK, Alexander AL, Block WF, Roseboom PH, Knowles JA, Kalin NHAuthor
Eva M. Fekete PhD Research Scientist I in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmygdalaAnimals
Anxiety
Disease Models, Animal
Gene Expression
Macaca mulatta
Male
Neurotrophin 3
Receptor, trkC
