Picturing Fear

Image: Courtesy of Ahmad Hariri, NIMH FEAR AS SEEN BY fMRI: The blue crosshairs in each fMRI image highlight the increased activity in the amygdala of patients with one or two short alleles in response to fearful stimuli. The alleles are in the promoter region of the serotonin transporter, which is associated with higher concentrations of synaptic serotonin and increased rates of anxiety and neuroticism. A team of scientists at the National Institute of Mental Health has found that a variant of the gene responsible for transporting the neurotransmitter serotonin is linked to greater activity of the amygdala within the brain.1 The researchers, led by Daniel Weinberger, chief of NIMH's Clinical Brain Disorders Branch, used functional magnetic resonance imaging in patients with one or two copies of the short allele of the serotonin transporter promoter. The fMRI demonstrated in-creased neuronal activity while these patients viewed faces showing emotional expressions. The findings show that the gene SLC6A4 affects cognition and emotionality and can be studied directly at the level of brain, says Weinberger. "This will ultimately inform us about why certain genes contribute to emotionality." The research involved 28 subjects: 14 had two copies of the long allele; the remainder had at least one copy of the short allele. MELDING TECHNOLOGIES "What's really interesting about this research is that it's the first time a certain gene [SLC6A4] has been tied to a clear-cut brain response that we can measure," says psychiatry professor Ned Kalin, University of Wisconsin-Madison. "It really melds two exciting technologies--fMRI and genomics--and puts them together in a creative way." Klaus-Peter Lesch, vice chair and professor in the Department of Psychiatry and Psychotherapy, University of Würzburg, commented in an E-mail, "The paper is an outstanding piece of work into the influence of gene variation on emotion processing and behavior." In individuals with one or two copies of the short allele, serotonin remains at the synapse for a slightly longer time than in individuals with two copies of the long allele, explains Weinberger. In other words, reuptake of serotonin is quicker in individuals who are homozygous for the long allele. Serotonin is crucially important in the amygdala's function. "Serotonin excites certain critical neurons in the transfer of information in the amygdala," Weinberger says. "The sensory information comes in depending on the genetically determined amount of serotonin signaling." The results, Weinberger emphasizes, show that small biases exist in the amygdala's activity in people with the short allele. "The way we think about genes for temperament is [that] they modestly bias the system to respond with a slightly greater excitation." THE ENVIRONMENTAL IMPACT? About 70% of Europeans and North Americans have at least one copy of the short allele. While they might show more anxiety or fear on personality tests than those with the long allele,2,3 Weinberger notes that a personality questionnaire showed no behavioral difference between the two groups. Kalin muses that the short allele has varying effects. "If 70% of the population has this mutation, does that mean these people are going to be less likely to get themselves into threatening and dangerous situations or to be more wary when they are in those situations?" Weinberger says that this gene is not responsible for anxiety expression per se, only that it affects how the amygdala responds. Kalin suggests that the development of anxiety could be traced to how environmental influences, especially in one's early years, influenced gene expression. "That's where the environmental impact will be, somewhere between the hard-wired, blue-print copy of the gene and the endpoint response. Somehow, environment is modulating how that gene expresses itself, how much serotonin reuptake there is." Weinberger notes in the paper: "The differential response of the amygdala may be rooted in early postnatal developmental processes that are critical for establishing emotional behavior." John Aggleton, professor of cognitive neuroscience at Cardiff University, Wales, said in an E-mail that trying to tie genes to brain activity is "a first step down a very complex path. It's really promising. But, there's a long way to go." Harvey Black (hblack@chorus.net) is a freelance writer in Madison, Wisc. References 1. A.R. Hariri et al., "Serotonin transporter genetic variation and the response of the human amygdala," Science, 297:400-3, July 19, 2002. 2. K.P. Lesch et al., "Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region," Science, 274:1527-31, 1996. 3. K.P. Lesch, R. Mossner, "Genetically driven variation in serotonin uptake: is there a link to the affective spectrum, neurodevelopmental, and neurodegenerative disorders?" Biological Psychiatry, 44:179-92,1988.

Picturing Fear

Interested in reading more?

Become a Member of

Image: Courtesy of Ahmad Hariri, NIMH

		FEAR AS SEEN BY fMRI: The blue crosshairs in each fMRI image highlight the increased activity in the amygdala of patients with one or two short alleles in response to fearful stimuli. The alleles are in the promoter region of the serotonin transporter, which is associated with higher concentrations of synaptic serotonin and increased rates of anxiety and neuroticism.