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The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor

Abstract

A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [18F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.

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Acknowledgements

We thank H Van Valkenberg, T Johnson, E Zao, S Mansavage, A Converse, the staff at the Harlow Center for Biological Psychology and the Wisconsin National Primate Research Center at the University of Wisconsin (RR000167), and R Garcia and W Shelledy of the Southwest Foundation for Biomedical Research for their technical support. This work was supported by grants MH046729, MH052354, MH069315, The HealthEmotions Research Institute and Meriter Hospital.

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Correspondence to N H Kalin.

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Author contributions: NK designed the research, analyzed data and wrote the paper. SS designed and performed the research and wrote the paper. JR performed the genotype analyses and wrote the paper. AF, TO and RD analyzed the data and wrote the paper.

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Kalin, N., Shelton, S., Fox, A. et al. The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol Psychiatry 13, 1021–1027 (2008). https://doi.org/10.1038/mp.2008.37

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