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Amygdalar and hippocampal substrates of anxious temperament differ in their heritability

Abstract

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli1,2,3,4. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse5. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution 18F-labelled deoxyglucose positron-emission tomography (FDG–PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.

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Figure 1: Glucose metabolism in the anterior temporal lobes is predictive of AT.
Figure 2: Peak correlations between AT and glucose metabolism in the anterior temporal lobe.
Figure 3: Overlap between regional metabolic activity predictive of AT and regions that are significantly heritable.

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Acknowledgements

This work has been supported by National Institutes of Health grants MH046729 (to N.H.K.), MH081884 (to N.H.K. and J.R.), MH084051 (to R.J.D. and N.H.K.), MH018931 (to J.A.O., A.S.F. and R.J.D.) and the HealthEmotions Research Institute. The SOLAR statistical genetics computer package is supported by National Institutes of Health grant MH059490 (to J.B.). The supercomputing facilities used for this work were supported in part by a gift from the AT&T Foundation. We thank the staff at the Wisconsin National Primate Center, the Harlow Center for Biological Psychology, the HealthEmotions Research Institute, the Waisman Laboratory for Brain Imaging and Behavior, B. Christian, P. Roseboom, H. Van Valkenberg, K. Myer, E. Larson, I. Monosov, F. Spector and R. Stone. We also thank R. Garcia for assistance in genotyping the 5HTTLPR polymorphism.

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Authors

Contributions

N.H.K., S.E.S., J.R. and A.S.F. designed the study. S.E.S. oversaw data collection. J.A.O., A.S.F. and N.H.K. analysed the imaging data. T.R.O., A.S.F. and J.B. developed analytical tools. R.J.D. provided theoretical assistance. J.R. and W.S. performed the genotyping and maintained the pedigree record. J.R., W.S., T.D.D. and J.B. performed the genetic analyses. J.A.O., N.H.K., A.S.F., J.R. J.B. and R.J.D. wrote the paper.

Corresponding author

Correspondence to Ned H. Kalin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Materials, Methods and Data, Supplementary Figures 1-2, Supplementary Tables 1-2 and References. (PDF 814 kb)

Supplementary Movie 1- Dorsal Amygdala AT Peak 95cr

This movie shows a single slice (y = -0.625mm relative to the anterior commissure) from each monkey's MRI in standard space. The 95% confidence interval representing the location of the peak correlation with AT in the dorsal amygdala is overlaid on each image. (AVI 7369 kb)

Supplementary Movie 2 Anterior Hippocampal AT Peak 95cr

This movie shows a single slice (y = -3.75mm relative to the anterior commissure) from each monkey's MRI in standard space. The 95% confidence interval representing the location of the peak correlation with AT in the anterior hippocampus is overlaid on each image. (AVI 7400 kb)

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Oler, J., Fox, A., Shelton, S. et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature 466, 864–868 (2010). https://doi.org/10.1038/nature09282

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