Functional connectivity within the primate extended amygdala is heritable and associated with early-life anxious temperament

Bibliographic Collection: 
Publication Type: Journal Article
Authors: Fox, Andrew S.; Oler, Jonathan A.; Birn, Rasmus M.; Shackman, Alexander J.; Alexander, Andrew L.; Kalin, Ned H.
Year of Publication: 2018
Journal: The Journal of Neuroscience
Date Published: 07/2018
Publication Language: eng

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc)—including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)—is associated with trait-like variation in AT. Here, we use fMRI to examine relations between Ce-BST functional connectivity and AT in a large multi-generational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce-BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT and is co-heritable with AT. Interestingly, Ce-BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce-BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components.SIGNIFICANCE STATEMENTAnxiety disorders directly impact the lives of nearly 1 in 5 people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and co-inherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing life-long disability in at-risk children.

Short Title: J. Neurosci.