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The interplay of genotype and environment in the development of fear and anxiety

  • Review article
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e-Neuroforum

Abstract

Individual differences in fear, anxiety, and the etiology of anxiety disorders develop during ontogeny. They are due to both genetic and environmental factors. With regard to the role of the environment, the organism is most susceptible to external influences during early development. Accordingly, stressors that impinge on the maternal organism during pregnancy evoke high levels of anxiety in the offspring later in life, as does an adverse early postnatal environment. However, anxiety-related circuits in the central nervous system retain their plasticity in adulthood, i.e., levels of anxiety can also be modified by experience across the entire successive lifespan. Notably, the effects of external stressors on the individual’s level of anxiety are modulated by genotype. Such genotype-by-environment interactions are particularly well studied in relation to genetic variants that modulate the function of the serotonin transporter. Thus, this review focuses on this candidate gene to elucidate the interplay of genotype and environment in the development of fear and anxiety.

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References

  1. Barr CS, Newman TK, Shannon C et al (2004) Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol Psychiatry 55:733–738

    Article  PubMed  CAS  Google Scholar 

  2. Bateson P, Barker D, Clutton-Brock T et al (2004) Developmental plasticity and human health. Nature 430:419–421

    Article  PubMed  CAS  Google Scholar 

  3. Bayer TA, Falkai P, Maier W (1999) Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the “two hit hypothesis”. J Psychiatr Res 33:543–548

    Article  PubMed  CAS  Google Scholar 

  4. Bengel D, Murphy DL, Andrews AM et al (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655

    PubMed  CAS  Google Scholar 

  5. Bethea CL, Streicher JM, Coleman K et al (2004) Anxious behavior and fenfluramine-induced prolactin secretion in young rhesus macaques with different alleles of the serotonin reuptake transporter polymorphism (5HTTLPR). Behav Genet 34:295–307

    Article  PubMed  Google Scholar 

  6. Buwalda B, Kole MHP, Veenema AH et al (2005) Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning. Neurosci Biobehav Rev 29:83–97

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Carola V, Frazzetto G, Pascucci T et al (2008) Identifying molecular substrates in a mouse model of the serotonin transporter x environment risk factor for anxiety and depression. Biol Psychiatry 63:840–846

    Article  PubMed  CAS  Google Scholar 

  9. Caspi A, Hariri AR, Holmes A et al (2010) Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167:509–527

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Champagne DL, Bagot RC, Hasselt F van et al (2008) Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci 28:6037–6045

    Article  PubMed  CAS  Google Scholar 

  12. Champagne FA, Curley JP (2005) How social experiences influence the brain. Curr Opin Neurobiol 15:704–709

    Article  PubMed  CAS  Google Scholar 

  13. Champagne FA, Francis DD, Mar A, Meaney MJ (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav 79:359–371

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Collier DA, Stober G, Li T et al (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460

    PubMed  CAS  Google Scholar 

  16. Feder A, Nestler EJ, Charney DS (2009) Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 10:446–457

    Article  PubMed  CAS  Google Scholar 

  17. Fergus S, Zimmerman MA (2005) Adolescent resilience: a framework for understanding healthy development in the face of risk. Annu Rev Public Health 26:399–419

    Article  PubMed  Google Scholar 

  18. Glover V (2011) Annual research review: prenatal stress and the origins of psychopathology: an evolutionary perspective. J Child Psychol Psychiatry 52:356–367

    Article  PubMed  Google Scholar 

  19. Gluckman PD, Hanson MA, Beedle AS (2007) Early life events and their consequences for later disease: a life history and evolutionary perspective. Am J Hum Biol 19:1–19

    Article  PubMed  Google Scholar 

  20. Gotlib IH, Joormann J, Minor KL, Hallmayer J (2008) HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 63:847–851

    Article  PubMed  CAS  Google Scholar 

  21. Gross C, Hen R (2004) The developmental origins of anxiety. Nat Rev Neurosci 5:545–552

    Article  PubMed  CAS  Google Scholar 

  22. Hariri AR, Mattay VS, Tessitore A et al (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403

    Article  PubMed  CAS  Google Scholar 

  23. Harlow HF, Harlow M (1962) Social deprivation in monkeys. Sci Am 207:136–146

    Article  PubMed  CAS  Google Scholar 

  24. Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:1023–1039

    Article  PubMed  CAS  Google Scholar 

  25. Heiming RS, Jansen F, Lewejohann L et al (2009) Living in a dangerous world: the shaping of behavioral profile by early environment and 5-HTT genotype. Front Behav Neurosci 3:26

    Article  PubMed  Google Scholar 

  26. Heiming RS, Bodden C, Jansen F et al (2011) Living in a dangerous world decreases maternal care: a study in serotonin transporter knockout mice. Horm Behav 60:397–407

    Article  PubMed  CAS  Google Scholar 

  27. Heiming RS, Sachser N (2010) Consequences of serotonin transporter genotype and early adversity on behavioral profile—pathology or adaptation? Front Neurosci 4:5

    Article  Google Scholar 

  28. Hennessy MB, Kaiser S, Sachser N (2009) Social buffering of the stress response: diversity, mechanisms, and functions. Front Neuroendocrinol 30:470–482

    Article  PubMed  CAS  Google Scholar 

  29. Holmes A, Lit Q, Murphy DL et al (2003) Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2:365–380

    Article  PubMed  CAS  Google Scholar 

  30. Holmes A, Yang RJ, Murphy DL, Crawley JN (2002) Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27:914–923

    Article  PubMed  CAS  Google Scholar 

  31. Holmes A, Yang RJ, Lesch KP et al (2003) Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology 28:2077–2088

    PubMed  CAS  Google Scholar 

  32. Hughes V (2012) Stress: the roots of resilience. Nature 490:165–167

    Article  PubMed  CAS  Google Scholar 

  33. Jansen F, Heiming RS, Lewejohann L et al (2010) Modulation of behavioural profile and stress response by 5-HTT genotype and social experience in adulthood. Behav Brain Res 207:21–29

    Article  PubMed  CAS  Google Scholar 

  34. Kalueff AV, Olivier JDA, Nonkes LJP, Homberg JR (2010) Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes. Neurosci Biobehav Rev 34:373–386

    Article  PubMed  CAS  Google Scholar 

  35. Kalueff AV, Fox MA, Gallagher PS, Murphy DL (2007) Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav 6:389–400

    Article  PubMed  CAS  Google Scholar 

  36. Kendler KS, Kuhn JW, Vittum J et al (2005) 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

    Article  PubMed  CAS  Google Scholar 

  37. Kofman O (2002) The role of prenatal stress in the etiology of developmental behavioural disorders. Neurosci Biobehav Rev 26:457–470

    Article  PubMed  CAS  Google Scholar 

  38. Lesch KP, Araragi N, Waider J et al (2012) Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci 367:2426–2443

    Article  PubMed  CAS  Google Scholar 

  39. Lesch KP, Bengel D, Heils A et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    Article  PubMed  CAS  Google Scholar 

  40. Lesch KP (2011) When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. Curr Top Behav Neurosci 7:251–280

    Article  PubMed  Google Scholar 

  41. Lewejohann L, Kloke V, Heiming RS et al (2010) Social status and day-to-day behaviour of male serotonin transporter knockout mice. Behav Brain Res 211:220–228

    Article  PubMed  CAS  Google Scholar 

  42. Lira A, Zhou M, Castanon N et al (2003) Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 54:960–971

    Article  PubMed  CAS  Google Scholar 

  43. Mandelli L, Serretti A, Marino E et al (2007) Interaction between serotonin transporter gene, catechol-O-methyltransferase gene and stressful life events in mood disorders. Int J Neuropsychopharmacol 10:437–447

    Article  PubMed  CAS  Google Scholar 

  44. McEwen BS (2003) Mood disorders and allostatic load. Biol Psychiatry 54:200–207

    Article  PubMed  Google Scholar 

  45. Meaney MJ (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci 24:1161–1192

    Article  PubMed  CAS  Google Scholar 

  46. Monk C, Spicer J, Champagne FA (2012) Linking prenatal maternal adversity to developmental outcomes in infants: the role of epigenetic pathways. Dev Psychopathol 24:1361–1376

    Article  PubMed  Google Scholar 

  47. Narayanan V, Heiming RS, Jansen F et al (2011) Social defeat: impact on fear extinction and amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice. PLoS One 6:e22600

    Article  PubMed  CAS  Google Scholar 

  48. Nietzer SL, Bonn M, Jansen F et al (2011) Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas. Behav Brain Res 220:42–54

    Article  PubMed  CAS  Google Scholar 

  49. Oitzl MS, Champagne DL, Veen R van der, Kloet ER de (2010) Brain development under stress: hypotheses of glucocorticoid actions revisited. Neurosci Biobehav Rev 34:853–866

    Article  PubMed  CAS  Google Scholar 

  50. Prior H, Sachser N (1995) Effects of enriched housing environment on the behaviour of young male and female mice in four exploratory tasks. J Exp Anim Sci 37:57–68

    Google Scholar 

  51. Sachser N, Kaiser S, Hennessy MB (2013) Behavioural profiles are shaped by social experience: when, how and why. Philos Trans R Soc Lond B Biol Sci 368:20120344

    Article  PubMed  Google Scholar 

  52. Sachser N, Hennessy MB, Kaiser S (2011) Adaptive modulation of behavioural profiles by social stress during early phases of life and adolescence. Neurosci Biobehav Rev 35:1518–1533

    Article  PubMed  Google Scholar 

  53. Schmidt MV (2011) Animal models for depression and the mismatch hypothesis of disease. Psychoneuroendocrinology 36:330–338

    Article  PubMed  Google Scholar 

  54. Spinelli S, Schwandt ML, Lindell SG et al (2007) Association between the recombinant human serotonin transporter linked promoter region polymorphism and behavior in rhesus macaques during a separation paradigm. Dev Psychopathol 19:977–987

    Article  PubMed  Google Scholar 

  55. Tjurmina OA, Armando I, Saavedra JM et al (2002) Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 143:4520–4526

    Article  PubMed  CAS  Google Scholar 

  56. Walker AK, Nakamura T, Byrne RJ et al (2009) Neonatal lipopolysaccharide and adult stress exposure predisposes rats to anxiety-like behaviour and blunted corticosterone responses: implications for the double-hit hypothesis. Psychoneuroendocrinology 34:1515–1525

    Article  PubMed  CAS  Google Scholar 

  57. Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086

    Article  PubMed  CAS  Google Scholar 

  58. Welberg LA, Seckl JR, Holmes MC (2000) Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Eur J Neurosci 12:1047–1054

    Article  PubMed  CAS  Google Scholar 

  59. Wellman CL, Izquierdo A, Garrett JE et al (2007) Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci 27:684–691

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Rebecca Heiming, Vanessa Kloke and Sylvia Kaiser for their valuable help in the preparation of this manuscript.

Compliance with ethical guidelines

Conflict of interest. N. Sachser and K.-P. Lesch state that there are no conflicts of interest.

All national guidelines on the care and use of laboratory animals have been followed and the necessary approval was obtained from the relevant authorities.

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Authors and Affiliations

  1. Department of Behavioural Biology, Institute for Neuro- and Behavioural Biology, University of Münster, Badestr. 13, 48149, Münster, Germany

    N. Sachser

  2. Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomantics, and Psychotherapy, University of Würzburg, Fuchsleinstr. 15, 97080, Würzburg, Germany

    K.-P. Lesch

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Correspondence to N. Sachser or K.-P. Lesch.

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This manuscript was translated by Neele Meyer, MSc.

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Sachser, N., Lesch, KP. The interplay of genotype and environment in the development of fear and anxiety. e-Neuroforum 4, 57–62 (2013). https://doi.org/10.1007/s13295-013-0045-1

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