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Edited by Huda Akil, University of Michigan, Ann Arbor, MI, and approved June 9, 2015 (received for review May 4, 2015)
Significance
According to the World Health Organization, anxiety and depressive disorders are a leading source of disability, affecting hundreds of millions of people. Children can inherit an extremely anxious temperament, which is a prominent risk factor for the later development of anxiety, depression, and comorbid substance abuse. This study uses high-resolution functional and structural imaging in our well-established developmental nonhuman primate model to identify the heritable neural substrate that underlies extreme childhood anxious temperament. Using a large multigenerational family pedigree, genetic correlation analyses revealed a tripartite neural circuit where metabolism likely shares a genetic substrate with early-life dispositional anxiety. Interestingly, we found that brain function—not structure—is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.
Abstract
Understanding the heritability of neural systems linked to psychopathology is not sufficient to implicate them as intergenerational neural mediators. By closely examining how individual differences in neural phenotypes and psychopathology cosegregate as they fall through the family tree, we can identify the brain systems that underlie the parent-to-child transmission of psychopathology. Although research has identified genes and neural circuits that contribute to the risk of developing anxiety and depression, the specific neural systems that mediate the inborn risk for these debilitating disorders remain unknown. In a sample of 592 young rhesus monkeys that are part of an extended multigenerational pedigree, we demonstrate that metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression. Importantly, although brain volume is highly heritable early in life, it is brain metabolism—not brain structure—that is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.
Footnotes
- ↵1To whom correspondence may be addressed. Email: asfox{at}wisc.edu or nkalin{at}wisc.edu.
Author contributions: A.S.F., S.E.S., R.J.D., J.R., and N.H.K. designed research; A.S.F., J.A.O., S.E.S., M.R., J.R., and N.H.K. performed research; A.S.F., D.R.M., A.K.C., A.A., and J.B. contributed new reagents/analytic tools; A.S.F., J.A.O., and A.J.S. analyzed data; and A.S.F., J.A.O., A.J.S., and N.H.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The full voxelwise maps are available in Dataset S1.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1508593112/-/DCSupplemental.
Intergenerational mediators of anxious temperament
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