Serotonin Transporter Genetic Variation and the Response of the Human Amygdala

American Association for the Advancement of Science (AAAS) - Tập 297 Số 5580 - Trang 400-403 - 2002
Ahmad R. Hariri1, Venkata S. Mattay1, Alessandro Tessitore1, Bhaskar Kolachana1, Francesco Saverio Fera1, David Goldman2, Michael Egan1, Daniel R. Weinberger1
1Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
2Laboratory of Neurogenetics, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.

Tóm tắt

A functional polymorphism in the promoter region of the human serotonin transporter gene ( SLC6A4 ) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.

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Materials and methods are available as supporting material on Science Online.

In both cohorts the two genotype groups were matched for gender (first and second cohort: 5 females and 2 males in each group) age [first cohort: mean ± SEM s group = 27.4 ± 5.6 years and l group = 32.1 ± 3.8 years; F (1 12) = 3.35 P = 0.09; second cohort: s group = 32.7 ± 4.9 years and l group = 32.7 ± 3.8 years; F (1 12) = 0.12 P = 0.73] and mean IQ [first cohort: mean ± SEM s group = 106.9 ± 9.8 and l group = 110.3 ± 6.2; F (1 12) = 0.61 P = 0.45; second cohort: s group = 106.1 ± 4.8 and l group = 96.9 ± 3.9; F (1 12) = 2.25 P = 0.16]. In the first cohort there were 12 Caucasians and 2 African Americans (both female l/l homozygotes) and in the second there were 13 Caucasians and 1 African American (female l/l homozygote).

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All subjects completed a version of the “ n -back” working memory task known to engage the dorsolateral prefrontal cortex and a network of related cortical regions (40). In this task subjects are required to remember the sequence of serially presented numbers in order to identify numbers that appeared “ n -back” (i.e. 1-back 2-back 3-back). There were no significant group differences in performance (accuracy or reaction time) on this task. Analysis of the imaging data (22) revealed no significant differences in any brain regions including the dorsolateral prefrontal cortex between the s and l groups.

Analysis of variance of performance measures on the emotion task revealed no significant group differences in either cohort for mean accuracy [first cohort: % correct ± SEM s group = 93.1 ± 7.0 and l group = 86.1 ± 4.5; F (1 12) = 0.69 P = 0.43; second cohort: s group = 96.4 ± 1.7 and l group = 98.8 ± 1.2; F (1 12) = 1.33 P = 0.27] or mean reaction time [first cohort: ms ± SEM s group = 2274.1 ± 120.8 and l group = 2367.8 ± 108.7; F (1 12) = 0.33 P = 0.58; second cohort: s group = 1761.5 ± 132.6 and l group = 1941.3 ± 159.6; F (1 12) = 0.75 P = 0.40].

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We thank S. Das S. Lee E. O'Hare W. G. Smith and R. Vakkalanka for technical assistance. Supporting Online Material www.sciencemag.org/cgi/content/full/297/5580/400/DC1 Materials and Methods