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Long story short: the serotonin transporter in emotion regulation and social cognition

Abstract

The gene encoding the serotonin transporter (5-HTT) contains a regulatory variation that has been associated with anxiety-related traits and susceptibility for depression. Here we highlight recent discoveries related to allelic variation of 5-HTT function with respect to emotion regulation and social behavior, drawing from an interdisciplinary perspective of behavioral genetics and cognitive neuroscience. Following a reductionistic path that leads from gene-behavior association studies to neuroimaging and epigenetic studies, we compare two models of 5-HTT-dependent modulation of brain activity and discuss the role of life stress experience in modifying 5-HTT function in the brain. Integration of these findings suggests that the impact of the 5-HTT gene on behavior is much broader than is commonly appreciated and may have a role in social cognition.

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Figure 1: Allelic variation of serotonin transporter (5-HTT) function in anxiety-related personality disorders, depression and other disorders of emotion regulation.
Figure 2: The standard 'phasic' versus the 'tonic' model of 5-HTT-dependent modulation of brain activity.
Figure 3
Figure 4: Degree of variation in two genes of the serotonin signaling pathway (serotonin transporter, 5-HTTLPR; monoamine oxidase A, MAOALPR), aggression and social organization in seven macaque species.
Figure 5: Influence of interaction between SLC6A4 and environment on neural networks of social cognition and emotion regulation.

References

  1. Lesch, K.P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996).

    CAS  Article  PubMed  Google Scholar 

  2. Greenberg, B.D. et al. Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am. J. Med. Genet. 96, 202–216 (2000).

    CAS  PubMed  Google Scholar 

  3. Mazzanti, C.M. et al. Role of the serotonin transporter promoter polymorphism in anxiety- related traits. Arch. Gen. Psychiatry 55, 936–940 (1998).

    CAS  PubMed  Google Scholar 

  4. Jorm, A.F. et al. An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Mol. Psychiatry 3, 449–451 (1998).

    CAS  PubMed  Google Scholar 

  5. Willis-Owen, S.A. et al. The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol. Psychiatry 58, 451–456 (2005).

    CAS  PubMed  Google Scholar 

  6. Sirota, L.A., Greenberg, B.D., Murphy, D.L. & Hamer, D.H. Non-linear association between the serotonin transporter promoter polymorphism and neuroticism: a caution against using extreme samples to identify quantitative trait loci. Psychiatr. Genet. 9, 35–38 (1999).

    CAS  PubMed  Google Scholar 

  7. Reif, A. & Lesch, K.P. Toward a molecular architecture of personality. Behav. Brain Res. 139, 1–20 (2003).

    CAS  PubMed  Google Scholar 

  8. Deary, I.J. et al. Neuroticism and polymorphisms in the serotonin transporter gene. Psychol. Med. 29, 735–739 (1999).

    CAS  PubMed  Google Scholar 

  9. Ball, D. et al. The serotonin transporter gene and peer-rated neuroticism. Neuroreport 8, 1301–1304 (1997).

    CAS  PubMed  Google Scholar 

  10. Ioannidis, J.P. Common genetic variants for breast cancer: 32 largely refuted candidates and larger prospects. J. Natl. Cancer Inst. 98, 1350–1353 (2006).

    CAS  PubMed  Google Scholar 

  11. Sen, S., Burmeister, M. & Ghosh, D. Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 127, 85–89 (2004).

    Google Scholar 

  12. Schinka, J.A., Busch, R.M. & Robichaux-Keene, N. A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol. Psychiatry 9, 197–202 (2004).

    CAS  PubMed  Google Scholar 

  13. Munafò, M.R., Clark, T. & Flint, J. Does measurement instrument moderate the association between the serotonin transporter gene and anxiety-related personality traits? A meta-analysis. Mol. Psychiatry 10, 415–419 (2005).

    PubMed  Google Scholar 

  14. Munafò, M.R., Clark, T.G. & Flint, J. Promise and pitfalls in the meta-analysis of genetic association studies: a response to Sen and Shinka. Mol. Psychiatry 10, 895–897 (2005).

    Google Scholar 

  15. Plomin, R., Owen, M.J. & McGuffin, P. The genetic basis of complex human behaviors. Science 264, 1733–1739 (1994).

    CAS  PubMed  Google Scholar 

  16. Gottesman, I.I. & Shields, J. Genetic theorizing and schizophrenia. Br. J. Psychiatry 122, 15–30 (1973).

    CAS  PubMed  Google Scholar 

  17. Hariri, A.R., Drabant, E.M. & Weinberger, D.R. Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing. Biol. Psychiatry 59, 888–897 (2006).

    CAS  PubMed  Google Scholar 

  18. Meyer-Lindenberg, A. & Weinberger, D.R. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat. Rev. Neurosci. 7, 818–827 (2006).

    CAS  PubMed  Google Scholar 

  19. Hamer, D. Genetics. Rethinking behavior genetics. Science 298, 71–72 (2002).

    CAS  PubMed  Google Scholar 

  20. de Geus, E.J., Wright, M.J., Martin, N.G. & Boomsma, D.I. Genetics of brain function and cognition. Behav. Genet. 31, 489–495 (2001).

    CAS  PubMed  Google Scholar 

  21. Gottesman, I.I. & Gould, T.D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636–645 (2003).

    PubMed  Google Scholar 

  22. Flint, J. & Munafò, M.R. The endophenotype concept in psychiatric genetics. Psychol. Med. 37, 163–180 (2007).

    PubMed  Google Scholar 

  23. Heinz, A. et al. A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol. Psychiatry 47, 643–649 (2000).

    CAS  PubMed  Google Scholar 

  24. Reimold, M. et al. Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. J. Neural Transm. 114, 635–639 (2007).

    CAS  PubMed  Google Scholar 

  25. Praschak-Rieder, N. et al. Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [11C] DASB positron emission tomography study. Biol. Psychiatry, published online 8 January 2007 (doi:10.1016/j.biopsych.2006.09.022).

    CAS  PubMed  Google Scholar 

  26. Shioe, K. et al. No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 48, 184–188 (2003).

    CAS  PubMed  Google Scholar 

  27. Parsey, R.V. et al. Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am. J. Psychiatry 163, 48–51 (2006).

    PubMed  Google Scholar 

  28. Fallgatter, A., Jatzke, S., Bartsch, A., Hamelbeck, B. & Lesch, K. Serotonin transporter promoter polymorphism influences topography of inhibitory motor control. Int. J. Neuropsychopharmacol. 2, 115–120 (1999).

    CAS  PubMed  Google Scholar 

  29. Fallgatter, A.J., Bartsch, A.J. & Herrmann, M.J. Electrophysiological measurements of anterior cingulate function. J. Neural Transm. 109, 977–988 (2002).

    CAS  PubMed  Google Scholar 

  30. Hariri, A.R. et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400–403 (2002).

    CAS  PubMed  Google Scholar 

  31. Hariri, A.R. et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry 62, 146–152 (2005).

    CAS  PubMed  Google Scholar 

  32. Heinz, A. et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat. Neurosci. 8, 20–21 (2005).

    CAS  PubMed  Google Scholar 

  33. Canli, T. et al. Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. Proc. Natl. Acad. Sci. USA 102, 12224–12229 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pezawas, L. et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat. Neurosci. 8, 828–834 (2005).

    CAS  PubMed  Google Scholar 

  35. Bertolino, A. et al. Variation of human amygdala response during threatening stimuli as a function of 5′HTTLPR genotype and personality style. Biol. Psychiatry 57, 1517–1525 (2005).

    CAS  PubMed  Google Scholar 

  36. Furmark, T. et al. Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neurosci. Lett. 362, 189–192 (2004).

    CAS  PubMed  Google Scholar 

  37. Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Canli, T. et al. Neural correlates of epigenesis. Proc. Natl. Acad. Sci. USA 103, 16033–16038 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Rao, H. et al. Genetic variation in serotonin transporter alters resting brain function in healthy individuals. Biol. Psychiatry, published online 3 May 2007 (doi:10.1016/j.biopsych.2006.11.028).

    CAS  PubMed  Google Scholar 

  40. Baas, D., Aleman, A. & Kahn, R.S. Lateralization of amygdala activation: a systematic review of functional neuroimaging studies. Brain Res. Brain Res. Rev. 45, 96–103 (2004).

    PubMed  Google Scholar 

  41. Kendler, K.S. et al. The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Arch. Gen. Psychiatry 52, 374–383 (1995).

    CAS  PubMed  Google Scholar 

  42. Wellman, C.L. et al. Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J. Neurosci. 27, 684–691 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Thapar, A. & McGuffin, P. Anxiety and depressive symptoms in childhood–a genetic study of comorbidity. J. Child Psychol. Psychiatry 38, 651–656 (1997).

    CAS  PubMed  Google Scholar 

  44. Gusnard, D.A. & Raichle, M.E. Searching for a baseline: functional imaging and the resting human brain. Nat. Rev. Neurosci. 2, 685–694 (2001).

    CAS  PubMed  Google Scholar 

  45. Shulman, G.L. et al. Common blood flow changes across visual tasks: II. Decreases in cerebral cortex. J. Cogn. Neurosci. 9, 648–663 (1997).

    CAS  PubMed  Google Scholar 

  46. Raichle, M.E. et al. A default mode of brain function. Proc. Natl. Acad. Sci. USA 98, 676–682 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Heinz, A. et al. Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation. Biol. Psychiatry 61, 1011–1014 (2007).

    CAS  PubMed  Google Scholar 

  48. Videbech, P. & Ravnkilde, B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957–1966 (2004).

    PubMed  Google Scholar 

  49. Amat, J. et al. Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala. Neuroscience 129, 509–519 (2004).

    CAS  PubMed  Google Scholar 

  50. Forster, G.L. et al. Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience 141, 1047–1055 (2006).

    CAS  PubMed  Google Scholar 

  51. David, S.P. et al. A functional genetic variation of the serotonin (5-HT) transporter affects 5–HT1A receptor binding in humans. J. Neurosci. 25, 2586–2590 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fisher, P.M. et al. Capacity for 5–HT1A-mediated autoregulation predicts amygdala reactivity. Nat. Neurosci. 9, 1362–1363 (2006).

    CAS  PubMed  Google Scholar 

  53. Higley, J.D., Suomi, S.J. & Linnoila, M. CSF monoamine metabolite concentrations vary according to age, rearing, and sex, and are influenced by the stressor of social separation in rhesus monkeys. Psychopharmacology (Berl.) 103, 551–556 (1991).

    CAS  Google Scholar 

  54. Bennett, A.J. et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol. Psychiatry 7, 118–122 (2002).

    CAS  PubMed  Google Scholar 

  55. Champoux, M. et al. Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol. Psychiatry 7, 1058–1063 (2002).

    CAS  PubMed  Google Scholar 

  56. Barr, C.S. et al. Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcohol. Clin. Exp. Res. 27, 812–817 (2003).

    CAS  PubMed  Google Scholar 

  57. Barr, C.S. et al. Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Arch. Gen. Psychiatry 61, 1146–1152 (2004).

    CAS  PubMed  Google Scholar 

  58. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003).

    CAS  PubMed  Google Scholar 

  59. Kendler, K.S., Kuhn, J.W., Vittum, J., Prescott, C.A. & Riley, B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch. Gen. Psychiatry 62, 529–535 (2005).

    CAS  PubMed  Google Scholar 

  60. Kaufman, J. et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proc. Natl. Acad. Sci. USA 101, 17316–17321 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Eley, T.C. et al. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol. Psychiatry 9, 908–915 (2004).

    CAS  PubMed  Google Scholar 

  62. Grabe, H.J. et al. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol. Psychiatry 10, 220–224 (2005).

    CAS  PubMed  Google Scholar 

  63. Surtees, P.G. et al. Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biol. Psychiatry 59, 224–229 (2005).

    PubMed  Google Scholar 

  64. Gillespie, N.A., Whitfield, J.B., Williams, B., Heath, A.C. & Martin, N.G. The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychol. Med. 35, 101–111 (2005).

    PubMed  Google Scholar 

  65. McEwen, B.S. & Sapolsky, R.M. Stress and cognitive function. Curr. Opin. Neurobiol. 5, 205–216 (1995).

    CAS  PubMed  Google Scholar 

  66. Campbell, S., Marriott, M., Nahmias, C. & MacQueen, G.M. Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am. J. Psychiatry 161, 598–607 (2004).

    PubMed  Google Scholar 

  67. Frodl, T. et al. Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch. Gen. Psychiatry 61, 177–183 (2004).

    CAS  PubMed  Google Scholar 

  68. Hastings, R.S., Parsey, R.V., Oquendo, M.A., Arango, V. & Mann, J.J. Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29, 952–959 (2004).

    PubMed  Google Scholar 

  69. Rusch, B.D., Abercrombie, H.C., Oakes, T.R., Schaefer, S.M. & Davidson, R.J. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol. Psychiatry 50, 960–964 (2001).

    CAS  PubMed  Google Scholar 

  70. Sheline, Y.I., Gado, M.H. & Kraemer, H.C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

    PubMed  Google Scholar 

  71. Dranovsky, A. & Hen, R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59, 1136–1143 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Warner-Schmidt, J.L. & Duman, R.S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16, 239–249 (2006).

    CAS  PubMed  Google Scholar 

  73. Philibert, R. et al. Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 144, 101–105 (2007).

    Google Scholar 

  74. Weaver, I.C. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004).

    CAS  PubMed  Google Scholar 

  75. Morales, J.C. & Melnick, D.J. Phylogenetic relationships of the macaques (Cercopithecidae: Macaca), as revealed by high resolution restriction site mapping of mitochondrial ribosomal genes. J. Hum. Evol. 34, 1–12 (1998).

    CAS  PubMed  Google Scholar 

  76. Thierry, B. Covariation of conflict management patterns across macaque species. In Natural Conflict Resolution (eds. Aureli, F. & de Waal, F.B.M.) 106–128 (University of California Press, Berkeley, California, USA, 2000).

    Google Scholar 

  77. Thierry, B., Iwaniuk, A.N. & Pellis, S.M. The influence of phylogeny on the social behaviour of macaques (primates: Cercopithecidae, genus Macaca). Ethology 106, 713–728 (2000).

    Google Scholar 

  78. Wendland, J.R. et al. Differential functional variability of serotonin transporter and monoamine oxidase a genes in macaque species displaying contrasting levels of aggression-related behavior. Behav. Genet. 36, 163–172 (2006).

    PubMed  Google Scholar 

  79. Baumeister, R.F. & Tice, D.M. Anxiety and social exclusion. J. Soc. Clin. Psychol. 9, 165–195 (1990).

    Google Scholar 

  80. Nakamura, T. et al. Serotonin transporter gene regulatory region polymorphism and anxiety-related traits in the Japanese. Am. J. Med. Genet. 74, 544–545 (1997).

    CAS  PubMed  Google Scholar 

  81. Carr, L., Iacoboni, M., Dubeau, M.C., Mazziotta, J.C. & Lenzi, G.L. Neural mechanisms of empathy in humans: a relay from neural systems for imitation to limbic areas. Proc. Natl. Acad. Sci. USA 100, 5497–5502 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Amodio, D.M. & Frith, C.D. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7, 268–277 (2006).

    CAS  PubMed  Google Scholar 

  83. Rizzolatti, G. & Craighero, L. The mirror-neuron system. Annu. Rev. Neurosci. 27, 169–192 (2004).

    CAS  PubMed  Google Scholar 

  84. Uddin, L.Q., Kaplan, J.T., Molnar-Szakacs, I., Zaidel, E. & Iacoboni, M. Self-face recognition activates a frontoparietal “mirror” network in the right hemisphere: an event-related fMRI study. Neuroimage 25, 926–935 (2005).

    PubMed  Google Scholar 

  85. Allman, J.M., Watson, K.K., Tetreault, N.A. & Hakeem, A.Y. Intuition and autism: a possible role for Von Economo neurons. Trends Cogn. Sci. 9, 367–373 (2005).

    PubMed  Google Scholar 

  86. Dapretto, M. et al. Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nat. Neurosci. 9, 28–30 (2006).

    CAS  PubMed  Google Scholar 

  87. Moerk, K.C. & Klein, D.N. The development of major depressive episodes during the course of dysthymic and episodic major depressive disorders: a retrospective examination of life events. J. Affect. Disord. 58, 117–123 (2000).

    CAS  PubMed  Google Scholar 

  88. Weaver, I.C., Meaney, M.J. & Szyf, M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc. Natl. Acad. Sci. USA 103, 3480–3485 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kovas, Y. & Plomin, R. Generalist genes: implications for the cognitive sciences. Trends Cogn. Sci. 10, 198–203 (2006).

    PubMed  Google Scholar 

  90. Herrmann, M.J. et al. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb. Cortex 17, 1160–1163 (2006).

    PubMed  Google Scholar 

  91. Zapala, M.A. & Schork, N.J. Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables. Proc. Natl. Acad. Sci. USA 103, 19430–19435 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wessel, J., Zapala, M.A. & Schork, N.J. Accommodating pathway information in expression quantitative trait locus analysis. Genomics 90, 132–142 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank G. Lesch for designing graphics and artwork. The writing of this article and the authors' related research were supported by grants from the European Commission (NEWMOOD LSHM-CT-2003-503474), Bundesministerium für Bildung und Forschung (IZKF 01 KS 9603) and the Deutsche Forschungsgemeinschaft (SFB 581, KFO 125) to K.-P.L. and by grants from the General Clinical Research Center (5-MO1-RR-10710) and the US National Science Foundation (BCS-0224221) to T.C.

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Canli, T., Lesch, KP. Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10, 1103–1109 (2007). https://doi.org/10.1038/nn1964

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