Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates

Autor: Delores A. French, Jonathan A. Oler, Andrew S. Fox, Matthew R Rabska, Jae Mun ‘Hugo’ Kim, Andrew L. Alexander, Ned H. Kalin, Miles Olsen, Joseph D. Nguyen, Patrick H. Roseboom, Rothem Kovner, Eva M. Fekete, Marissa K. Riedel, Walter F. Block, Tade Souaiaia, James A. Knowles, Ethan K. Brodsky
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Gene Expression
Anxiety
NTRK3
Medical and Health Sciences
0302 clinical medicine
Neurotrophin 3
Neurotrophic factors
FDG-PET
Psychiatry
biology
Central nucleus of the amygdala
AAV
Biological Sciences
Amygdala
Mental Health
medicine.anatomical_structure
trkC
Neurotrophic
Biomedical Imaging
medicine.symptom
Receptor
Neurotrophin
1.1 Normal biological development and functioning
NTF3
Neurotrophin-3
Basic Behavioral and Social Science
Article
03 medical and health sciences
Extended amygdala
Underpinning research
Behavioral and Social Science
Neuroplasticity
Genetics
medicine
Animals
Receptor
trkC
Biological Psychiatry
Animal
Anxious temperament
Primate
Psychology and Cognitive Sciences
Neurosciences
Macaca mulatta
Brain Disorders
Disease Models
Animal
Behavioral inhibition
Good Health and Well Being
030104 developmental biology
Disease Models
biology.protein
RNA-seq
Neuroscience
030217 neurology & neurosurgery
Zdroj: Biological psychiatry, vol 86, iss 12
Biol Psychiatry
ISSN: 0006-3223
Popis: 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.
Databáze: OpenAIRE
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