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How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5-HTTLPR

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Abstract

Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected “safety” of the environment; this response is obtained in part through serotonergic modulation of the hypothalamic–pituitary–adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles.

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Acknowledgments

This study was supported in part by DFG FOR 1617. JK is deeply thankful to CL Licht for the inspiring discussions and to F Bermpohl for the scientific and financial (through BMBF-01GWSO61) support. UK is supported by the Leibniz Graduate School “Foundations of Primate Behaviour”.

Conflict of interest

Jan Kalbitzer, Urs Kalbitzer, Gitte Moos Knudsen, Paul Cumming, and Andreas Heinz reported no biomedical financial interests or potential conflicts of interest.

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  1. Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin (Campus Mitte), Berlin, Germany

    Jan Kalbitzer & Andreas Heinz

  2. Psychiatrische Universitätsklinik der Charité, Im St. Hedwig Krankenhaus, Große Hamburger Str. 5-11, 10115, Berlin, Germany

    Jan Kalbitzer

  3. Cognitive Ethology Laboratory, German Primate Center, University of Göttingen, Göttingen, Germany

    Urs Kalbitzer

  4. Neurobiology Research Unit and Cimbi, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Gitte Moos Knudsen

  5. Department of Nuclear Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Paul Cumming

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Kalbitzer, J., Kalbitzer, U., Knudsen, G.M. et al. How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5-HTTLPR. Psychopharmacology 230, 333–343 (2013). https://doi.org/10.1007/s00213-013-3308-1

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  • DOI: https://doi.org/10.1007/s00213-013-3308-1

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