A new study shows, for the first time in primates, that altering one particular molecule in a specific brain region can change “dispositional anxiety,” the tendency to perceive many situations as threatening. The finding provides hope for new strategies focused on intervening early in life to treat people at risk for anxiety disorders, depression, and related substance abuse.

Ned Kalin, MD, chair of psychiatry at UW School of Medicine and Public Health, is corresponding author on the study, published today in the journal Biological Psychiatry.

Ned Kalin
Ned Kalin

Anxiety and depressive disorders affect millions of people worldwide and are some of the greatest contributors to daily suffering. Current treatments work for only a subset of people and often only partially relieve symptoms.

These disorders often emerge around adolescence and can continue to affect people for most of their lives. Currently, researchers can identify children who display an extreme anxious or inhibited temperament; these young people are at risk to develop stress-related psychopathologies as they transition to adulthood. The study, led by Andrew Fox, PhD, a former Kalin lab member now a faculty member at the University of California-Davis, used cutting-edge neuroscientific tools in a nonhuman primate model of early-life anxious temperament to investigate this problem.

The roots of the current work come from research done by this group around eight years ago in preadolescent nonhuman primates, when researchers got their first glimpse of molecular alterations in the dorsal amygdala, a subsection of the amygdala, a brain region important in emotional responses. At that time, the authors speculated that altered “neuroplasticity-related processes” might underlie early-life anxiety. In addition, they hypothesized that this was not just true for hippocampal regions, as others had speculated, but extended to the dorsal amygdala— a region recognized for its role in responding to unconditioned and inborn threats.

Now, using an approach to understand gene function, a transcriptome-wide search, this study confirmed earlier findings and implicated the NT-3/NTRK3 pathway in the genesis of early-life dispositional anxiety. The authors then used gene manipulation to increase levels of the NT-3 molecule in the relevant region of the dorsal amygdala. This study demonstrated that this molecular pathway is causally related to anxious temperament, and strongly implicates the neurotrophin-3 (NT-3)/neurotrophic tyrosine kinase receptor type 3 (NTRK3, also known as TrkC) pathway in the dorsal amygdala as anxiety-reducing.
Additionally, by combining behavioral, neuroimaging, and molecular studies in the same animals, the research team was able to show that NT-3 was sufficient to increase activation in the dorsal amygdala, which has been implicated in early-life anxious temperament.

Rather than focusing on a single technique or tool, the authors propose that their work is an example of the kind of “deep science” that can transform how we understand psychopathology. The authors maintain that the study is highly relevant to humans because it uses molecular techniques in a well-validated primate model in conjunction with some of the same behavioral and neuroimaging measures commonly used in humans.

The ability to alter dispositional anxiety by changing a single molecule in a specific brain region shows that it is possible to develop early-life interventions that target the brain’s plasticity – its ability to change – when neural circuits are still developing. The end result could be that those with an early-life, at-risk brain disposition could avoid their biologically determined tendency to develop pathological anxiety.