Hostname: page-component-8448b6f56d-jr42d Total loading time: 0 Render date: 2024-04-24T14:28:57.149Z Has data issue: false hasContentIssue false
  • English
  • Français

The serotonin transporter gene linked polymorphic region is associated with the behavioral response to repeated stress exposure in infant rhesus macaques

Published online by Cambridge University Press:  31 January 2012

Simona Spinelli ,
Melanie L. Schwandt ,
Stephen G. Lindell ,
Markus Heilig ,
Stephen J. Suomi ,
J. Dee Higley ,
David Goldman  and
Christina S. Barr
Simona Spinelli*
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Melanie L. Schwandt
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Stephen G. Lindell
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Markus Heilig
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Stephen J. Suomi
Affiliation:
National Institute of Child Health and Human Development
J. Dee Higley
Affiliation:
Brigham Young University
David Goldman
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
Christina S. Barr
Affiliation:
National Institute on Alcohol Abuse and Alcoholism
*
Address correspondence and reprint requests to: Simona Spinelli, Preclinical Laboratory for Translational Research Into Affective Disorders, Clinic for Affective Disorders and General Psychiatry, Psychiatric University Hospital Zurich, August Forel-Strasse 7, Zurich CH-8008, Switzerland; E-mail: spinellisimona@gmail.com.
Get access Rights & Permissions [Opens in a new window]

Abstract

The short allele of the serotonin transporter linked polymorphic region (5-HTTLPR) moderates the effects of stress on vulnerability to mood and anxiety disorders. The mechanism by which this occurs may relate to differential sensitivity to stressful life events. Here we explored whether 5-HTTLPR and sex affected behavioral responses to repeated maternal separation in infant rhesus macaques. Behaviors were collected during the acute (Day 1) and the chronic (Days 2–4) phases of the separation, and the effects of duration of separation (acute vs. chronic), genotype (long/long vs. short allele), and sex (male vs. female) on behavioral responses were analyzed across four successive separations. Males increased their levels of locomotion with repeated maternal separation, whereas females exhibited an increase in frequency of self-directed behavior, a measure of “depression-like” behavior. The short-allele predicted increased environmental exploration, particularly during the chronic phase of social separation, indicative of higher arousal. In addition, the short-allele carriers were more likely to increase their levels of self-directed behavior during the chronic phase of separation, as a function of repeated exposures. These findings suggest that the short allele may increase reactivity to repeated, chronic stressors, leaving them more vulnerable to affective psychopathology, with females particularly vulnerable.

Type
Regular Articles
Information
Development and Psychopathology , Volume 24 , Issue 1 , February 2012 , pp. 157 - 165
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Barr, C. S., & Goldman, D. (2006). Non-human primate models of inheritance vulnerability to alcohol use disorders. Addiction Biology, 11, 374–385.CrossRefGoogle ScholarPubMed
Barr, C. S., Newman, T. K., Schwandt, M., Shannon, C., Dvoskin, R. L., Lindell, S. G., et al. (2004). Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. Proceedings of the National Academy of Science of the United States of America 101, 12358–12363.CrossRefGoogle ScholarPubMed
Barr, C. S., Newman, T. K., Shannon, C., Parker, C., Dvoskin, R. L., Becker, M. L., et al. (2004). Rearing condition and rh5-HTTLPR interact to influence limbic–hypothalamic–pituitary–adrenal axis response to stress in infant macaques. Biological Psychiatry, 55, 733–738.CrossRefGoogle ScholarPubMed
Barr, C. S., Schwandt, M. L., Lindell, S. G., Higley, J. D., Maestripieri, D., Goldman, D., et al. (2008). Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proceeding of the National Academy of Science of the United States of America, 105, 5277–5281.CrossRefGoogle ScholarPubMed
Becker, K., El-Faddagh, M., Schmidt, M. H., & Laucht, M. (2007). Is the serotonin transporter polymorphism (5-HTTLPR) associated with harm avoidance and internalising problems in childhood and adolescence? Journal of Neural Transmission, 114, 395–402.CrossRefGoogle ScholarPubMed
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746–754.CrossRefGoogle ScholarPubMed
Bethea, C. L., Streicher, J. M., Coleman, K., Pau, F. K. Y., Moessner, R., & Cameron, J. L. (2004). Anxious behavior and fenfluramine-induced prolactin secretion in young rhesus macaques with different alleles of the serotonin reuptake transporter polymorphism. Behavor Genetics, 34, 295–307.CrossRefGoogle ScholarPubMed
Bowlby, J. (1969). Attachment and loss. New York: Basic Books.Google Scholar
Brummett, B. H., Boyle, S. H., Siegler, I. C., Kuhn, C. M., Ashley-Koch, A., Jonassaint, C. R., et al. (2008). Effects of environmental stress and gender on associations among symptoms of depression and the serotonin transporter gene linked polymorphic region (5-HTTLPR). Behavior Genetics, 38, 34–43.CrossRefGoogle ScholarPubMed
Canli, T., & Lesch, K. P. (2007). Long story short: The serotonin transporter in emotion regulation and social cognition. Nature Neuroscience, 10, 1103–1109.CrossRefGoogle ScholarPubMed
Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010). Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167, 509–527.CrossRefGoogle Scholar
Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., et al. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851–854.CrossRefGoogle ScholarPubMed
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389.CrossRefGoogle ScholarPubMed
Champoux, M., Bennett, A., Shannon, C., Higley, J. D., Lesch, K. P., & Suomi, S. J. (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Molecular Psychiatry, 7, 1058–1063.CrossRefGoogle ScholarPubMed
Coe, C. L., Glass, J. C., Wiener, S. G., & Levine, S. (1983). Behavioral, but not physiological, adaptation to repeated separation in mother and infant primates. Psychoneuroendocrinology, 8, 401–409.CrossRefGoogle Scholar
Eme, R. F. (2007). Sex differences in child-onset, life-course-persistent conduct disorder. A review of biological influences. Clinical Psychology Review, 27, 607–627.CrossRefGoogle ScholarPubMed
Erickson, K., Gabry, K. E., Lindell, S., Champoux, M., Schulkin, J., Gold, P., et al. (2005). Social withdrawal behaviors in nonhuman primates and changes in neuroendocrine and monoamine concentrations during a separation paradigm. Development Psychobiology, 46, 331–339.CrossRefGoogle ScholarPubMed
Fanous, A. H., Neale, M. C., Aggen, S. H., & Kendler, K. S. (2007). A longitudinal study of personality and major depression in a population-based sample of male twins. Psychological Medicine, 37, 1163–1172.CrossRefGoogle Scholar
Garber, J. (2006). Depression in children and adolescents: Linking risk research and prevention. American Journal of Preventive Medicine, 6(Suppl. 1), S104–S125.CrossRefGoogle Scholar
Grabe, H. J., Spitzer, C., Schwahn, C., Marcinek, A., Frahnow, A., Barnow, S., et al. (2009). Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. American Journal of Psychiatry, 166, 926–933.CrossRefGoogle ScholarPubMed
Gross, C., & Hen, R. (2004). The developmental origins of anxiety. Nature Reviews Neuroscience, 5, 545–552.CrossRefGoogle ScholarPubMed
Hamet, P., & Tremblay, J. (2005). Genetics and genomics of depression. Metabolism, 54(Suppl. 1), 10–15.CrossRefGoogle ScholarPubMed
Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400–403.CrossRefGoogle ScholarPubMed
Hayden, E. P., Dougherty, L. R., Maloney, B., Olino, T. M., Sheikh, H., Durbin, C. E., et al. (2008). Early-emerging cognitive vulnerability to depression and the serotonin transporter promoter region polymorphism. Journal of Affective Disorder, 107, 227–230.CrossRefGoogle ScholarPubMed
Hennessy, M. B. (1986). Multiple, brief maternal separations in the squirrel monkey: Changes in hormonal and behavioral responsiveness. Physiology & Behavior, 36, 245–250.CrossRefGoogle ScholarPubMed
Higley, J. D., Suomi, S. J., & Linnoila, M. (1991). CSF monoamine metabolite concentrations vary according to age, rearing, and sex, and are influenced by the stressor of social separation in rhesus monkeys. Psychopharmacology (Berlin), 103, 551–556.CrossRefGoogle ScholarPubMed
Higley, J. D., Suomi, S. J., & Linnoila, M. (1992). A longitudinal assessment of CSF monoamine metabolite and plasma cortisol concentrations in young rhesus monkeys. Biological Psychiatry, 32, 127–145.CrossRefGoogle ScholarPubMed
Hugo, C., Seier, J., Mdhluli, C., Daniels, W., Harvey, B. H., Du Toit, D., et al. (2003). Fluoxetine decreases stereotypic behavior in primates. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 27, 639–643.CrossRefGoogle ScholarPubMed
Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves, L. J. (1993). A longitudinal twin study of personality and major depression in women. Archives of General Psychiatry, 50, 853–862.CrossRefGoogle ScholarPubMed
Kendler, K. S., Prescott, C. A., Myers, J., & Neale, M. C. (2003). The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry, 60, 929–937.CrossRefGoogle ScholarPubMed
Koller, G., Zill, P., Skoruppa, T., Bondy, B., Preuss, U. W., & Soyka, M. (2008). Low level of harm avoidance is associated with serotonin transporter functional haplotype in alcohol-dependent individuals. Psychiatric Genetics, 18, 59–63.CrossRefGoogle ScholarPubMed
Korte, S. M., Koolhaas, J. M., Wingfield, J. C., & McEwen, B. S. (2005). The Darwinian concept of stress: Benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neuroscience and Biobehavioral reviews, 29, 3–38.CrossRefGoogle ScholarPubMed
Kraemer, G. W., & Clarke, A. S. (1990). The behavioral neurobiology of self-injurious behavior in rhesus monkeys. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 14, S141–S168.CrossRefGoogle ScholarPubMed
Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527–1531.CrossRefGoogle ScholarPubMed
Levinson, D. F. (2006). The genetics of depression: A review. Biological Psychiatry, 60, 84–92.CrossRefGoogle ScholarPubMed
McEwen, B. S. (2007). Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews, 87, 873–904.CrossRefGoogle ScholarPubMed
Mineka, S., & Suomi, S. J. (1978). Social separation in monkeys. Psychological Bulletin, 85, 1376–1400.CrossRefGoogle ScholarPubMed
Mineka, S., Suomi, S. J., & DeLizio, R. (1981). Multiple separations in adolescent monkeys: An opponent-process interpretation. Journal of Experimental Psychology: General, 110, 56–85.CrossRefGoogle ScholarPubMed
Monteleone, P., Santonastaso, P., Mauri, M., Bellodi, L., Erzegovesi, S., Fuschino, A., et al. (2006). Investigation of the serotonin transporter regulatory region polymorphism in bulimia nervosa: Relationships to harm avoidance, nutritional parameters, and psychiatric comorbidity. Psychosomatic Medicine, 68, 99–103.CrossRefGoogle ScholarPubMed
Munafò, M. R., Brown, S. M., & Hariri, A. R. (2008). Serotonin transporter (5-HTTLPR) genotype and amygdala activation: A meta-analysis. Biological Psychiatry, 63, 852–857.CrossRefGoogle ScholarPubMed
Murphy, D. L., Lerner, A., Rudnick, G., & Lesch, K. P. (2004). Serotonin transporter: Gene, genetic disorders, and pharmacogenetics. Molecular Interventions, 4, 109–123.CrossRefGoogle ScholarPubMed
Neigh, G. N., Gillespie, C. F., & Nemeroff, C. B. (2009). The neurobiological toll of child abuse and neglect. Trauma Violence Abuse, 10, 389–410.CrossRefGoogle ScholarPubMed
Risch, N., Herrell, R., Lehner, T., Liang, K. Y., Eaves, L., Hoh, J., et al. (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis. Journal of the American Medical Association, 301, 2462–2471.CrossRefGoogle ScholarPubMed
Rogers, J., Shelton, S. E., Shelledy, W., Garcia, R., & Kalin, N. H. (2008). Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. Genes, Brain and Behavior, 7, 463–469.CrossRefGoogle ScholarPubMed
Schwandt, M. L., Erickson, K., Barr, C. S., Lindell, S. G., Suomi, S. J., & Higley, J. D. (2006). Effects of early experience and lack of social support on the endocrine and behavioral responses of rhesus macaques (Macaca mulatta) to separation stress. Neuropsychopharmacology, 31(Suppl. 1), 147.Google Scholar
Shannon, C., Schwandt, M. L., Champoux, M., Shoaf, S. E., Suomi, S. J., Linnoila, M., et al. (2005). Maternal absence and stability of individual differences in CSF 5-HIAA concentrations in rhesus monkey infants. American Journal of Psychiatry, 162, 1658–1664.Google ScholarPubMed
Sinha, R. (2008). Chronic stress, drug use, and vulnerability to addiction. Annals of the New York Academy of Science, 1141, 105–130.CrossRefGoogle ScholarPubMed
Sjöberg, R. L., Nilsson, K. W., Nordquist, N., Ohrivik, J., Leppert, J., Lindström, L., et al. (2006). Development of depression: Sex and the interaction between environment and a promotor polymorphism of the serotonin trarnsporter gene. International Journal of Neuropsychopharmacology, 9, 443–449.CrossRefGoogle Scholar
Sloan, D. M., & Kornstein, S. G. (2003). Gender differences in depression and response to antidepressant treatment. Psychiatry Clinic of North America, 26, 581–594.CrossRefGoogle ScholarPubMed
Spinelli, S., Schwandt, M. L., Lindell, S. G., Newman, T. K., Heilig, M., Suomi, S. J., et al. (2007). Association between the serotonin transporter linked polymorphic region and behavior in rhesus macaques during a separation paradigm. Development and Psychopathology, 19, 977–987.CrossRefGoogle ScholarPubMed
Stein, M. B., Schork, N. J., & Gelernter, J. (2008). Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology, 33, 312–319.CrossRefGoogle ScholarPubMed
Suomi, S. J. (1991). Primate separation models of affective disorders. In Madden, J. I. (Ed.), Neurobiology of learning, emotion and affect (pp. 195–214). New York: Raven Press.Google Scholar
Suomi, S. J. (1997). Early determinants of behaviour: Evidence from primate studies. British Medical Bulletin, 53, 170–184.CrossRefGoogle ScholarPubMed
Suomi, S. J., Mineka, S., & De Lizio, R. D. (1983). Short- and long-term effects of repetitive mother–infant separations on social development in rhesus monkeys. Developmental Psychology, 19, 770–786.CrossRefGoogle Scholar
Taylor, S. E., Klein, L. C., Lewis, B. P., Gruenewald, T. L., Gurung, R. A., & Updegraff, J. A. (2000). Biobehavioral responses to stress in females: Tend-and-befriend, not fight-or-flight. Psychological Review, 107, 411–429.CrossRefGoogle Scholar
Taylor, S. E., Way, B. M., Welch, W. T., Hilmert, C. J., Lehman, B. J., & Eisenberger, N. I. (2006). Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology. Biological Psychiatry, 60, 671–676.CrossRefGoogle ScholarPubMed
Trefilov, A., Berard, J., Krawczak, M., & Schmidtke, J. (2000). Natal dispersal in rhesus macaques is related to serotonin transporter gene promoter variation. Behavior Genetics, 30, 295–301.CrossRefGoogle ScholarPubMed
Way, B., & Taylor, S. E. (2010). The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biological Psychiatry, 67, 487–492.CrossRefGoogle ScholarPubMed
Wood, J. J., Cowan, P. A., & Baker, B. L. (2002). Behavior problems and peer rejection in preschool boys and girls. Journal of Genetic Psychology, 163, 72–88.CrossRefGoogle ScholarPubMed