© 2002, AAAS

Using BOLD fMRI, researchers demonstrate that carriers of the serotonin transporter gene s (short) allele, which presumably have higher synaptic serotonin levels, exhibit greater neuronal activity in the amygdala than individuals homozygous for the l (long) allele when confronted with threatening stimuli. The difference may account for increased fear and anxiety associated with the s allele. (Reprinted from A.R. Hariri et al., Science, 297:400–3, 2002.)

Deciphering genetic relationships in cognitive function takes serious effort. Michael Posner at the University of Oregon in Eugene and colleagues found that a diminished ability to focus could be linked to two specific mutations.1 The study involved a battery of genetic and cognitive tests given to more than 200 people. A year later, in 2003, Posner added clarity to the finding using functional magnetic resonance imaging (fMRI). The researchers linked the mutations to differing activity in the...


The studies published so far using neuroimaging to study genes – Egan counts about a dozen – hint at this complexity with some puzzling results. Posner and colleagues studied two other genes with mood-disorder associated variants: DRD4 encoding the dopamine receptor D4, and MAOA encoding the monoamine oxidase A.4 They linked variants with slower reaction times for a task that involves viewing a row of arrows, and judging whether the central arrow is pointing right or left. The study found that faster reactions are associated with greater brain activation. But, previous research has found that improving performance on mental tasks is associated with less, not more, brain activation as the brain learns to work more efficiently.

Other contradictions arise. Weinberger and colleagues study the human serotonin transporter, which clears serotonin from nerve junctions. Inhibiting this clearance, as selective serotonin reuptake inhibitors such as Prozac do, tends to reduce anxiety. Yet fMRI studies show that mutations reducing serotonin reuptake are associated with increased anxiety and activity in the amygdala, a brain region linked with fear.5 Weinberger says this may be because early in development, high serotonin levels eventually desensitize people to serotonin.

Some researchers have approachedthe complexities of gene-brain interactions using positron emission tomography. PET lets researchers track the activities of specific brain chemicals rather than assessing regional brain activation more generally. Using PET, Jon-Kar Zubieta, an assistant professor of psychiatry and radiology at the University of Michigan, Ann Arbor, and colleagues found that mutations in COMT increase pain sensitivity by reducing the enzyme's ability to activate the μ-opioid system.6

More work is needed to resolve such philosophically loaded questions as: What changes are due to nature, and what is due to nurture? Zubieta says the imaging studies may already suggest a partial answer: that genes account for a greater fraction of behavioral variation than many think. "There are clearly models that can be built about how genes interact in certain critical pathways related to behavior," he explains. These models "can be really validated using imaging strategies."

Jack Lucentini (jlucentini@the-scientist.com)

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