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Developmental Biology - Brain
Molecule Identified As Key to Anxiety
Anxiety study of nonhuman primates opens new strategies for treating anxiety disorders...
Boosting a single molecule in the brain can change "dispositional anxiety," the tendency to perceive many situations as threatening, in nonhuman primates, researchers from the University of California, Davis, and the University of Wisconsin-Madison have found. The molecule, neurotrophin-3, stimulates neurons to grow and make new connections.
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. Current treatments work for only a subset of people and often only partially relieve symptoms.
"There are millions of people worldwide who suffer from debilitating anxiety and depressive disorders. These disorders are also some of the leading causes of disability and days lost to disability."
Andrew Fox, Assistant Professor, University of California Davis, Department of Psychology, and researcher at the California National Primate Research Center.
Fox co-led the study with Tade Souaiaia of the State University of New York Downstate Medical Center. Ned Kalin, chair of psychiatry at the University of Wisconsin-Madison School of Medicine and Public Health, is also a corresponding author on the study published August 15 in the journal Biological Psychiatry.
Anxiety 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.
Amygdala Changes
The roots of the study come from research done by the group about eight years ago in preadolescent rhesus macaques, when researchers got their first glimpse of molecular alterations in the dorsal amygdala, a brain region important in emotional responses.
The authors speculated that altered processes in this region might underlie early-life anxiety. Since then, the research team sequenced RNA from the dorsal amygdala to identify molecules related to dispositional anxiety and dorsal amygdala function.
They eventually narrowed the potential molecules and selected neurotrophin-3, a growth factor, for further study.
They then used an altered virus to boost levels of neurotrophin-3 in the dorsal amygdala of juvenile rhesus macaques, finding the increase of neurotrophin-3 in the dorsal amygdala lead to a decrease in anxiety-related behaviors, particularly behaviors associated with inhibition, a core feature of the early-life risk for developing anxiety disorders in humans.
Subsequent brain imaging studies of these animals found that neurotrophin-3 changed activity throughout the distributed brain regions that contribute to anxiety.
Fox hopes other scientists can build on their research as an example of the kind of "deep science" that can transform how we understand psychopathology. The team has included a list of additional promising molecules that may warrant future investigation.
"We're only just beginning. Neurotrophin-3 is the first molecule that we've been able to show in a non-human primate to be causally related to anxiety. It's one of potentially many molecules that could have this affect. There could be hundreds or even thousands more."
Andrew S. Fox PhD, University of California, Davis, Department of Psychology and the California National Primate Research Center, Davis, California, USA.
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 (NHP) 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 forty-six young rhesus monkeys. We identified AT-related transcripts using RNA-seq 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 MRI guided surgery (n=5/group).
Results
This discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between neurotrophin receptor kinase 3 (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.
Discussion
Together, these data implicate NT-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step towards 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.
Authors
Andrew S. Fox, Tade Souaiaia, Jonathan A. Oler, Rothem Kovner, Jae Mun Kim, Joseph Nguyen, Delores A. French, Marissa Riedel, Eva Fekete, Matthew R. Rabska, Miles E. Olsen, Ethan K. Brodsky, Andrew L. Alexander, Walter F. Block, Patrick H. Roseboom, James A. Knowles, Ned H. Kalin.
Funding
At the time of writing, Dr. Kalin had received honoraria from CME Outfitters, Elsevier, and the Pritzker Consortium; served on scientific advisory boards for Actify Neurotherapies, Neuronetics, and currently serves as an advisor to the Pritzker Neuroscience Consortium and consults to Corcept Therapeutics; served as co-editor of Psychoneuroendocrinology, and currently serves as Editor-in-Chief of The American Journal of Psychiatry; and has patents on promoter sequences for corticotropin-releasing factor CRF2alpha and a method of identifying agents that alter the activity of the promoter sequences (7,071,323; 7,531,356), promoter sequences for urocortin II and the use thereof (7,087,385), and promoter sequences for corticotropin-releasing factor binding protein and the use thereof (7,122,650). All other authors report no biomedical financial interests or potential conflicts of interest.
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Aug 21 2019 Fetal Timeline Maternal Timeline News
_in_Kinnarsani_WS,_AP_W_IMG_5792.jpg) Rhesus macaque in Kinnerasani Wildlife Sanctuary, Andhra Pradesh, India. Brain imaging studies of these animals found that neurotrophin-3 changed activity throughout their brain regions that contribute to anxiety. CREDIT Wikimedia.
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