Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Amygdalar and hippocampal substrates of anxious temperament differ in their heritability


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Schwartz, C. E. et al. Inhibited and uninhibited infants “grown up”: adult amygdalar response to novelty. Science 300, 1952–1953 (2003)

    ADS  CAS  Article  Google Scholar 

  2. Fox, A. S. et al. Trait-like brain activity during adolescence predicts anxious temperament in primates. PLoS ONE 3, e2570 (2008)

    ADS  Article  Google Scholar 

  3. Kagan, J., Reznick, J. S. & Snidman, N. Biological bases of childhood shyness. Science 240, 167–171 (1988)

    ADS  CAS  Article  Google Scholar 

  4. Fox, N. A. et al. Behavioral inhibition: linking biology and behavior within a developmental framework. Annu. Rev. Psychol. 56, 235–262 (2005)

    Article  Google Scholar 

  5. Biederman, J. et al. Further evidence of association between behavioral inhibition and social anxiety in children. Am. J. Psychiatry 158, 1673–1679 (2001)

    CAS  Article  Google Scholar 

  6. Kessler, R. C. et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005)

    Article  Google Scholar 

  7. Kalin, N. H. & Shelton, S. E. Nonhuman primate models to study anxiety, emotion regulation, and psychopathology. Ann. NY Acad. Sci. 1008, 189–200 (2003)

    ADS  Article  Google Scholar 

  8. Kalin, N. H. & Shelton, S. E. Defensive behaviors in infant rhesus monkeys: environmental cues and neurochemical regulation. Science 243, 1718–1721 (1989)

    ADS  CAS  Article  Google Scholar 

  9. Kalin, N. H., Shelton, S. E. & Davidson, R. J. The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate. J. Neurosci. 24, 5506–5515 (2004)

    CAS  Article  Google Scholar 

  10. Gray, J. A. & McNaughton, N. The Neuropsychology of Anxiety 2nd edn (Oxford Univ. Press, New York, 2000)

    Google Scholar 

  11. LeDoux. J. E Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000)

    Article  Google Scholar 

  12. Davis, M. & Whalen, P. J. The amygdala: vigilance and emotion. Mol. Psychiatry 6, 13–34 (2001)

    CAS  Article  Google Scholar 

  13. Fudge, J. L., Breitbart, M. A. & McClain, C. Amygdaloid inputs define a caudal component of the ventral striatum in primates. J. Comp. Neurol. 476, 330–347 (2004)

    Article  Google Scholar 

  14. Price, J. L. & Drevets, W. C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010)

    Article  Google Scholar 

  15. Phelps, E. A. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr. Opin. Neurobiol. 14, 198–202 (2004)

    CAS  Article  Google Scholar 

  16. McHugh, S. B., Deacon, R. M., Rawlins, J. N. & Bannerman, D. M. Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behav. Neurosci. 118, 63–78 (2004)

    CAS  Article  Google Scholar 

  17. Chudasama, Y., Izquierdo, A. & Murray, E. A. Distinct contributions of the amygdala and hippocampus to fear expression. Eur. J. Neurosci. 30, 2327–2337 (2009)

    Article  Google Scholar 

  18. Machado, C. J. & Bachevalier, J. Behavioral and hormonal reactivity to threat: effects of selective amygdala, hippocampal or orbital frontal lesions in monkeys. Psychoneuroendocrinology 33, 926–941 (2008)

    CAS  Article  Google Scholar 

  19. O’Rourke, H. & Fudge, J. L. Distribution of serotonin transporter labeled fibers in amygdaloid subregions: implications for mood disorders. Biol. Psychiatry 60, 479–490 (2006)

    Article  Google Scholar 

  20. Rogers, J. et al. Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. Genes Brain Behav. 7, 463–469 (2008)

    ADS  CAS  Article  Google Scholar 

  21. Hettema, J. M., Neale, M. C. & Kendler, K. S. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am. J. Psychiatry 158, 1568–1578 (2001)

    CAS  Article  Google Scholar 

  22. Lyons, D. M. et al. Early life stress and inherited variation in monkey hippocampal volumes. Arch. Gen. Psychiatry 58, 1145–1151 (2001)

    CAS  Article  Google Scholar 

  23. Davis, O. S., Haworth, C. M. & Plomin, R. Dramatic increase in heritability of cognitive development from early to middle childhood: an 8-year longitudinal study of 8,700 pairs of twins. Psychol. Sci. 20, 1301–1308 (2009)

    Article  Google Scholar 

  24. Visscher, P. M., Hill, W. G. & Wray, N. R. Heritability in the genomics era–concepts and misconceptions. Nature Rev. Genet. 9, 255–266 (2008)

    CAS  Article  Google Scholar 

  25. Hariri, A. R. et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400–403 (2002)

    ADS  CAS  Article  Google Scholar 

  26. Zubieta, J. K. et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299, 1240–1243 (2003)

    ADS  CAS  Article  Google Scholar 

  27. Zhou, Z. et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 452, 997–1001 (2008)

    ADS  CAS  Article  Google Scholar 

  28. Meyer-Lindenberg, A. et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc. Natl Acad. Sci. USA 103, 6269–6274 (2006)

    ADS  CAS  Article  Google Scholar 

  29. Kalin, N. H. et al. The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol. Psychiatry 13, 1021–1027 (2008)

    CAS  Article  Google Scholar 

  30. Viviani, R. et al. Baseline brain perfusion and the serotonin transporter promoter polymorphism. Biol. Psychiatry 67, 317–322 (2010)

    CAS  Article  Google Scholar 

  31. Paxinos, G., Huang, X., Petrides, M. & Toga, A. The Rhesus Monkey Brain in Stereotaxic Coordinates 2nd edn (Academic Press, 2009)

    Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

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)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing