Summary: Increasing levels of neurotrophin-3 in the dorsal amygdala alters dispositional anxiety in nonhuman primates, suggesting a potential pathway for early interventions to reduce anxiety risk in humans.
Source: UC Davis
Overview: Researchers at the University of California, Davis, and the University of Wisconsin–Madison report that boosting a single brain molecule, neurotrophin-3 (NT-3), reduces anxious temperament in juvenile nonhuman primates. Neurotrophin-3 supports neuronal growth and synaptic connectivity, and manipulating its levels in a key emotion-processing region of the brain produced measurable reductions in anxiety-related behavior and altered activity across the broader anxiety network.
Anxious temperament that appears early in life is a known risk factor for later anxiety disorders, depression, and substance misuse. Existing treatments provide relief for many people but often leave symptoms only partly controlled and do not reach everyone in need. This study identifies a molecular target that could inform new preventive strategies, especially interventions applied during development to lower long-term risk.
“Millions of people worldwide live with disabling anxiety and depression,” said Andrew Fox, assistant professor in the UC Davis Department of Psychology and a researcher at the California National Primate Research Center. “These disorders are leading causes of disability and lost productivity. Understanding the biological mechanisms that drive early-life anxiety is essential for developing more effective, targeted treatments.”
The study was co-led by Andrew Fox and Tade Souaiaia of SUNY Downstate Medical Center, with Ned Kalin of the University of Wisconsin–Madison as a corresponding author. The results were published in the journal Biological Psychiatry on August 15.
Origins and Rationale
Previous work by this research group identified molecular differences in the dorsal amygdala of preadolescent rhesus macaques. The dorsal amygdala is centrally involved in emotional processing and fear responses. That earlier work suggested that altered molecular signaling in this region could underlie a persistent, dispositional tendency to react to many situations as threatening.
To build on those findings, the team performed RNA sequencing of dorsal amygdala tissue to find transcripts associated with anxious temperament. From this discovery-based approach they prioritized several candidate genes and selected neurotrophin-3 for targeted manipulation because of its known role in promoting neuronal growth and plasticity.
Methods and Key Findings
The researchers used a viral-vector technique to increase expression of the neurotrophin-3 gene (NTF3) specifically in the dorsal amygdala of juvenile rhesus macaques. They guided injections with intraoperative MRI to ensure accurate targeting. Behavioral measures of anxious temperament and functional brain imaging were collected before and after the intervention.
Animals with elevated neurotrophin-3 in the dorsal amygdala displayed reduced anxiety-related behaviors, particularly a decline in behavioral inhibition—a core feature linked to early-life risk for anxiety disorders in humans. Functional imaging revealed that changing NT-3 levels in this localized region influenced activity across a distributed network of brain structures implicated in anxiety, indicating downstream circuit-level effects.
These results demonstrate a causal relationship between dorsal amygdala NT-3 signaling and dispositional anxiety in a primate model. The findings establish proof of principle that molecular manipulation within a specific node of the anxiety circuit can alter temperament and brain function.
Implications and Future Directions
The study highlights NT-3/NTRK3 signaling as an important biological pathway for anxious temperament. NTRK3, a receptor for NT-3, showed an inverse relationship with anxious temperament in the discovery data, pointing to neurotrophic signaling and intracellular plasticity pathways as promising targets for future work.
Andrew Fox emphasized that NT-3 is likely one among many molecules that influence anxiety. The team provided a list of additional candidate transcripts that merit further investigation. Continued research may reveal other molecular targets and inform development of interventions that prevent the progression from early-life anxious temperament to full-blown anxiety disorders.
“This study represents the first demonstration in a nonhuman primate that a single molecule in the dorsal amygdala can causally influence anxiety-related temperament,” Fox said. “Our approach—combining molecular discovery with targeted gene manipulation and imaging—offers a roadmap for identifying and testing other molecular contributors to anxiety.”
The paper lists additional contributors from SUNY Downstate Medical Center and the University of Wisconsin–Madison who participated in sequencing, behavioral testing, imaging, and analysis.
Funding: This work was supported by grants from the National Institutes of Health.
Source:
UC Davis
Media Contacts:
Andy Fell – UC Davis
Image Source:
California National Primate Research Center
Original Research: “Dorsal amygdala neurotrophin-3 decreases anxious temperament in primates.” Andrew Fox et al., Biological Psychiatry. DOI: 10.1016/j.biopsych.2019.06.022
Abstract (summary): Early-life anxious temperament increases risk for anxiety, depression, and comorbid substance abuse. Using a validated nonhuman primate model, the dorsal amygdala was identified as key to anxious temperament. RNA sequencing revealed AT-related transcripts and an inverse association between NTRK3 expression and anxious temperament. Overexpressing NTF3 in the dorsal amygdala decreased anxious temperament and altered function in the associated neural circuit, implicating NT-3/NTRK3 signaling in primate anxiety and guiding future therapeutic development.