Abstract
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.
Keywords
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Article info
Publication history
Published online: July 02, 2019
Accepted:
June 25,
2019
Received in revised form:
June 18,
2019
Received:
May 13,
2019
Identification
Copyright
© 2019 Society of Biological Psychiatry.
