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 stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. 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 (18)F-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.

Figure 1. Glucose metabolism in the anterior temporal lobes is predictive of AT

a, amygdala and e, hippocampus (significance of correlations - yellow: p < 0.05, light orange: p < 0.01, dark orange: p < 0.001, corrected). Pink areas represent 95% spatial confidence intervals of the peak correlations. b and f, corresponding slices adapted from The Rhesus Monkey Brain in Stereotaxic Coordinates (2009). c, g, 5-HTT binding differentiates the CeA region from the anterior hippocampus. d, The CeA, defined by the 5-HTT map, encompasses the amygdala peak. h, The hippocampal peak is distinct and does not overlap with the 5-HTT map.

Figure 2. Peak correlations between AT and anterior temporal lobe glucose metabolism

a, Voxel within the amygdala (see Fig 1a) reflecting the peak correlation between metabolism and AT (r=0.44, p=2.38e-13) and b, voxel within the hippocampus (see Fig 1e) reflecting the peak correlation between metabolism and AT (r=0.45, p=8.3e-13). ¹⁸F-deoxyglucose values were extracted from each animal, residualized for the effects of age, sex and gray matter probability, and plotted against individual differences in AT.

Figure 3. Overlap between regional metabolic activity predictive of AT with regions that are significantly heritable

a and b, No significantly heritable voxels were observed in the dorsal amygdala region, although within the same slice significant heritability was detected in the superior temporal sulcus. c, Glucose metabolism was significantly heritable in both the right hippocampus and left hippocampus, d, where it overlaps with the left anterior hippocampal region that correlated with AT. (yellow = regions predictive of AT from Fig 1; dark green to light green: FDR: q < 0.05, q < 0.01, q < 0.001).