23 August 2010. Brain activity that correlates with anxious temperament may arise through different paths, according to a study published August 12 in Nature. In the largest imaging study of non-human primates, Ned Kalin of the University of Wisconsin in Madison, Wisconsin, and colleagues found that activity in the amygdala and in the hippocampus, regions involved in emotional memory formation, predicted anxious behavior in monkeys. However, genes influenced the activity in the hippocampus more so than that in the amygdala.
This surprising difference not only validates the idea that anxious temperament stems from both genetic and environmental factors, but it suggests that these factors differentially regulate different brain regions—even highly related and interconnected ones like the amygdala and hippocampus. This is important to bear in mind when considering the neural underpinnings of psychiatric disorders like schizophrenia, which is also thought to arise from a combination of genetic and environmental influences, and for which anxious temperament is a risk factor.
"Oler and coworkers' paper could, therefore, not only change thinking about how genes act in the brain to affect our habitual reactions to stress and adversity, but also benefit patients with mental conditions such as depression, anxiety disorders, and psychosis," writes Andreas Meyer-Lindenberg in an accompanying article about the study (Meyer-Lindenberg, 2010).
First authors Jonathan Oler and Andrew Fox and colleagues studied 238 rhesus monkeys from a multigenerational single-family pedigree, comprising a mix of closely related, distantly related, and unrelated monkeys. To get a read on how anxious the monkeys were, each was exposed to a human intruder. This stimulus elicited anxious behaviors such as “freezing” and raised levels of the stress hormone cortisol, but to a different degree in different monkeys, with some more anxious than others.
Next, the researchers searched for brain regions with activity that correlated with the anxious behavior, using 18F-labeled deoxyglucose positron-emission tomography (FDG-PET). Because metabolically active neurons take up and trap FDG, this technique provides a snapshot of brain glucose use—an indicator of neural activity. Unlike fMRI, it doesn't measure brain activity in relation to a baseline. The authors used FDG-PET because they wanted to get a sense of personality-related brain activity—something that would stay more or less the same in different contexts, but that would vary according to temperament.
The technique revealed striking correlations between anxious behavior and FDG uptake in the amygdala and in the anterior hippocampus: the more anxious monkeys had higher FDG uptake in these regions, and the less anxious ones had less. The correlations were strong enough that this measure of brain activity was predictive of an animal's anxious behavior. The most predictive regions included the central nucleus of the amygdala (r = 0.44, p = 2.38 x 10-13) and the left hippocampus (r = 0.45, p = 8.3 x 10-13).
Then the researchers asked what amount of the anxiety-related activity in these areas was genetic. To do this, they made use of their vast pedigree to calculate the heritability of brain activity—that is, the amount of variance in brain activity across monkeys that could be explained by genetic variation. This analysis found that the anterior hippocampus and the amygdala differed in heritability values: in the anterior hippocampus, up to 76 percent of the variation in activity there was attributable to genes—meaning related monkeys had more similar brain activity values than unrelated ones—whereas for amygdala, no significantly heritable regions were detected.
A web of possibilities—traits and states
That genetic influences hold more sway over the anterior hippocampus than over the amygdala is a surprise, because activity in both regions were similarly predictive of anxious temperament, and because anxious temperament itself is significantly heritable. This suggests that the amygdala is more prone to environmental influences than to genetic ones, and it may be the substrate upon which life experiences contribute to the development of an anxious temperament.
But the findings do not rule out a role for genes in tilting the amygdala toward maladaptive anxiety. In fact, previous studies have found single gene effects on amygdala responses to fearful stimuli (e.g., Hariri et al., 2002). Looking at other aspects of amygdala function—its shape, size, or functional connectivity with other regions—may well reveal other heritable components. This illustrates how test- and technique-dependent measures of brain activity are, which may well lead to a range of heritability values. It will be important to distinguish between studies designed to measure chronic, personality-related brain activity like this one, and others that aim to measure the brain's acute reaction to certain stimuli.
Another possibility is that abnormalities in the amygdala reflect consequences (“state”) of anxious temperament, rather than something that lies on the causal pathway to this personality feature (“trait”). As the amygdala and other limbic structures have traditionally been of interest to schizophrenia researchers, it is interesting to note that a recent fMRI study of amygdala dysfunction in schizophrenia found just this: amygdala activity measured on fMRI reflected the dosage of drugs taken by schizophrenic individuals, rather than their genetic risk for the disorder (Rasetti et al., 2009). Figuring out whether a certain brain variation or abnormality is a trait or state requires inclusion of family members in imaging studies, and careful consideration of clinical records.
In this regard, the study's hippocampal findings may warrant an examination from schizophrenia researchers. Hippocampal volume is reduced in schizophrenia (see SRF Live Discussion), and given the region's sensitivity to stress hormones, this abnormality is often thought of as a consequence of living with the disease. The new study suggests that the anterior hippocampus is on the causal pathway—one most heavily influenced by genes—toward an anxious temperament, which may then predispose someone to schizophrenia.
With a clear genetic influence on the hippocampus, the researchers will next chase down the genes in question using genomewide association studies of hippocampal brain activity itself. Though this activity is far removed from genes, it is a good deal closer than behavior or diagnosis in emphasizing the value of finding useful intermediate phenotypes. As more researchers try to relate genetic variants to signals obtained from brain imaging, this study will provide a telling test case for research into psychiatric disorders.—Michele Solis.
Oler JA, Fox AS, Shelton SE, Rogers J, Dyer TD, Davidson RJ, Shelledy W, Oakes
TR, Blangero J, Kalin NH. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature. 2010 Aug 12; 466: 864-868. Abstract
Meyer-Lindenberg A. Behavioural neuroscience: Genes and the anxious brain. Nature. 2010 Aug 12;466(7308):827-8. Abstract