Scientific Understanding of Consciousness
Amygdalar and Hippocampal substrates of Anxious Temperament
Nature Volume: 466, 864–868 (12 August 2010)
Amygdalar and hippocampal substrates of anxious temperament differ in their heritability
Jonathan A. Oler, Andrew S. Fox, Steven E. Shelton, Jeffrey Rogers, Thomas D. Dyer, Richard J. Davidson, Wendy Shelledy, Terrence R. Oakes, John Blangero & Ned H. Kalin
Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin 53719, USA
Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
HealthEmotions Research Institute, University of Wisconsin-Madison, Madison, Wisconsin 53719, USA
Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA
Baylor College of Medicine, Houston, Texas 77030, USA
Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, USA
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 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.
Anxiety disorders are among the most common forms of psychopathology, and frequently begin during childhood and adolescence. Although all children experience acute anxiety, children with AT display extreme behavioural and physiological reactivity to novel stimuli, and in the presence of strangers inhibit their locomotor activity and vocalizations. Furthermore, children with AT are maladaptively shy and chronically suffer from worry and apprehension. Some children with AT also exhibit increased pituitary–adrenal and autonomic activity. Identifying neural intermediate phenotypes of AT is a critical step in elaborating how environmental and genetic factors influence the development of anxiety and emotion related psychopathology. Although AT is assumed to be partly heritable, the extent to which genetic variation influences metabolic activity in the neural circuit that underlies AT remains to be determined. We previously validated a non-human primate model of AT and demonstrated that brain activity assessed across stressful and non-stressful contexts predicted AT, revealing the stable trait-like characteristics of brain metabolic activity associated with this disposition.
To characterize the extent to which individual differences in AT-related brain activity are heritable, we concomitantly assessed AT and regional brain metabolism in 238 young rhesus monkeys (116 males, 122 females, mean age 2.4 years, range 0.74–4.2 years) belonging to a multigenerational single-family pedigree of more than 1,500 individuals. The statistical power of an extended pedigree approach to quantitative genetic analysis is derived from the presence of substantial numbers of closely related, more distantly related and unrelated pairs that all contribute information about the effects of kinship (shared genes) on phenotypic similarity.
Similar to AT in children, AT in monkeys was assessed by using measures of threat-induced freezing behaviour and inhibited vocalizations, as well as plasma cortisol concentrations. AT and brain metabolism were assessed when monkeys freely behaved in a test cage by themselves for 30 min in a potentially threatening situation in which a human ‘intruder’ entered the room and stood 2.5 m from the cage. During this time the intruder presented his profile to the monkey ensuring that he avoided eye contact with the animal (no eye contact; NEC). Animals with the greatest AT froze longer, vocalized less and had elevated plasma cortisol levels. The rationale underlying the use of the NEC challenge is (1) it optimally elicits the behaviours associated with the AT phenotype, (2) increased amygdala metabolism occurs during NEC and (3) selective dorsal amygdala lesions attenuate NEC-induced behavioural and physiological responses
Results confirmed that the heritability of metabolic activity in the anterior hippocampal voxel was significantly greater than that in the dorsal amygdala voxel (χ2 = 6.08, d.f. = 1, P < 0.0137). A similar difference in heritability was found for the amygdala and hippocampal regions defined by the 95% spatial confidence intervals of the most AT-predictive peaks (χ2 = 6.24, d.f. = 1, P < 0.0125). For these regions the observed difference in heritability was 0.508 (95% CI 0.218–0.798). These results suggest that the heritable risk of developing AT is more likely to be related to hippocampal, and not amygdala, metabolic activity when assessed during the NEC condition. Given that the amygdala and anterior hippocampus are anatomically linked, and are both highly predictive of AT, we did not expect the heritability of these regions to be dissociable. Demonstrating differential heritability between these two closely related structures is highly valuable as it provides new insight into the neural circuits underlying AT. Additionally, it establishes a model system that can be used to investigate further the genetic and environmental mechanisms that may differentially affect amygdala and hippocampal function relevant to the development of anxiety-related psychopathology.
Although the amygdala and hippocampus have been recognized as important in emotion and psychopathology, few data exist regarding the role of these regions in the development of temperamental dispositions such as AT. Recent theories have implicated the amygdala in mediating acute fear and vigilance, whereas the hippocampus has primarily been linked to mechanisms underlying declarative memory. Of interest, earlier theorists emphasized the septo-hippocampal system as being central to anxiety and specifically involved in threat-related behavioural inhibition. The current findings provide support for an important role of the anterior hippocampus in the development of anxious dispositions, and suggest that the highly interconnected regions of the hippocampus and amygdala are differentially influenced by genetic and environmental factors. These data support a new model combining measures of metabolic brain activity with ethologically relevant behavioural challenges to discover genes that mediate the endophenotype underlying the risk of developing anxiety and depression.
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