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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Further evidence of association between behavioral inhibition and social anxiety in children.Am J Psychiatry. 2001; 158: 1673-1679
- Behavioral inhibition and risk for developing social anxiety disorder: a meta-analytic study.J Am Acad Child Adolesc Psychiatry. 2012; 51: 1066-1075.e1
- Early risk factors and developmental pathways to chronic high inhibition and social anxiety disorder in adolescence.Am J Psychiatry. 2010; 167: 40-46
- A translational neuroscience approach to understanding the development of social anxiety disorder and its pathophysiology.Am J Psychiatry. 2014; 171: 1162-1173
- Fear of the unknown: uncertain anticipation reveals amygdala alterations in childhood anxiety disorders.Neuropsychopharmacology. 2015; 40: 1428-1435
- Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.Am J Psychiatry. 2007; 164: 1476-1488
- Intergenerational neural mediators of early-life anxious temperament.Proc Natl Acad Sci U S A. 2015; 112: 9118-9122
- Trait-like brain activity during adolescence predicts anxious temperament in primates.PLoS ONE. 2008; 3: e2570
- Dispositional negativity: an integrative psychological and neurobiological perspective.Psychol Bull. 2016; 142: 1275-1314
- The concepts of the ventral striatopallidal system and extended amygdala.in: McGinty J.F. Advancing from the ventral striatum to the extended amygdala: Implications for neuropsychiatry and drug abuse. The New York Academy of Sciences, New York1999: 1-32
- Connectivity between the central nucleus of the amygdala and the bed nucleus of the stria terminalis in the non-human primate: neuronal tract tracing and developmental neuroimaging studies.Brain Struct Funct. 2017; 222: 21-39
- Evidence for coordinated functional activity within the extended amygdala of non-human and human primates.Neuroimage. 2012; 61: 1059-1066
- Intrinsic functional connectivity of the central extended amygdala.Hum Brain Mapp. 2018; 39: 1291-1312
- New perspectives on central amygdala function.Curr Opin Neurobiol. 2018; 49: 141-147
- Extending the amygdala in theories of threat processing.Trends Neurosci. 2015; 38: 319-329
- The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate.J Neurosci. 2004; 24: 5506-5515
- The central nucleus of the amygdala is a critical substrate for individual differences in anxiety.in: Amaral D.G. Adolphs R. Living Without an Amygdala. Guilford Press, New York2016: 218-251
- Amygdalar and hippocampal substrates of anxious temperament differ in their heritability.Nature. 2010; 466: 864-868
- Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates.Proc Natl Acad Sci U S A. 2012; 109: 18108-18113
- RseqFlow: workflows for RNA-Seq data analysis.Bioinformatics. 2011; 27: 2598-2600
- A new rhesus macaque assembly and annotation for next-generation sequencing analyses.Biol Direct. 2014; 9: 20
- trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3.Cell. 1991; 66: 967-979
- New insights into BDNF function in depression and anxiety.Nat Neurosci. 2007; 10: 1089-1093
- A new role for FGF2 as an endogenous inhibitor of anxiety.J Neurosci. 2009; 29: 6379-6387
- BDNF at the synapse: why location matters.Mol Psychiatry. 2017; 22: 1370-1375
- Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals.Proc Natl Acad Sci U S A. 2011; 108: 8021-8025
- A competitive inhibitory circuit for selection of active and passive fear responses.Nature. 2017; 542: 96-100
- Amygdala circuitry mediating reversible and bidirectional control of anxiety.Nature. 2011; 471: 358-362
- The central extended amygdala in fear and anxiety: closing the gap between mechanistic and neuroimaging research.Neurosci Lett. 2019; 693: 58-67
- Overexpressing corticotropin-releasing hormone in the primate amygdala increases anxious temperament and alters its neural circuit.Biol Psychiatry. 2016; 80: 345-355
- A central amygdala CRF circuit facilitates learning about weak threats.Neuron. 2017; 93: 164-178
- Intraoperative intracerebral MRI-guided navigation for accurate targeting in nonhuman primates.Cell Transplant. 2010; 19: 1587-1597
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.
