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

  • Simona Spinelli (a1), Melanie L. Schwandt (a1), Stephen G. Lindell (a1), Markus Heilig (a1), Stephen J. Suomi (a2), J. Dee Higley (a3), David Goldman (a1) and Christina S. Barr (a1)...

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.

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Corresponding author

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.

References

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Barr, C. S., & Goldman, D. (2006). Non-human primate models of inheritance vulnerability to alcohol use disorders. Addiction Biology, 11, 374385.
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, 1235812363.
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, 733738.
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, 52775281.
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, 395402.
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746754.
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, 295307.
Bowlby, J. (1969). Attachment and loss. New York: Basic Books.
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, 3443.
Canli, T., & Lesch, K. P. (2007). Long story short: The serotonin transporter in emotion regulation and social cognition. Nature Neuroscience, 10, 11031109.
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, 509527.
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, 851854.
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, 386389.
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, 10581063.
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, 401409.
Eme, R. F. (2007). Sex differences in child-onset, life-course-persistent conduct disorder. A review of biological influences. Clinical Psychology Review, 27, 607627.
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, 331339.
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, 11631172.
Garber, J. (2006). Depression in children and adolescents: Linking risk research and prevention. American Journal of Preventive Medicine, 6(Suppl. 1), S104S125.
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, 926933.
Gross, C., & Hen, R. (2004). The developmental origins of anxiety. Nature Reviews Neuroscience, 5, 545552.
Hamet, P., & Tremblay, J. (2005). Genetics and genomics of depression. Metabolism, 54(Suppl. 1), 1015.
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, 400403.
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, 227230.
Hennessy, M. B. (1986). Multiple, brief maternal separations in the squirrel monkey: Changes in hormonal and behavioral responsiveness. Physiology & Behavior, 36, 245250.
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, 551556.
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, 127145.
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, 639643.
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, 853862.
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, 929937.
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, 5963.
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, 338.
Kraemer, G. W., & Clarke, A. S. (1990). The behavioral neurobiology of self-injurious behavior in rhesus monkeys. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 14, S141S168.
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, 15271531.
Levinson, D. F. (2006). The genetics of depression: A review. Biological Psychiatry, 60, 8492.
McEwen, B. S. (2007). Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews, 87, 873904.
Mineka, S., & Suomi, S. J. (1978). Social separation in monkeys. Psychological Bulletin, 85, 13761400.
Mineka, S., Suomi, S. J., & DeLizio, R. (1981). Multiple separations in adolescent monkeys: An opponent-process interpretation. Journal of Experimental Psychology: General, 110, 5685.
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, 99103.
Munafò, M. R., Brown, S. M., & Hariri, A. R. (2008). Serotonin transporter (5-HTTLPR) genotype and amygdala activation: A meta-analysis. Biological Psychiatry, 63, 852857.
Murphy, D. L., Lerner, A., Rudnick, G., & Lesch, K. P. (2004). Serotonin transporter: Gene, genetic disorders, and pharmacogenetics. Molecular Interventions, 4, 109123.
Neigh, G. N., Gillespie, C. F., & Nemeroff, C. B. (2009). The neurobiological toll of child abuse and neglect. Trauma Violence Abuse, 10, 389410.
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, 24622471.
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, 463469.
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.
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, 16581664.
Sinha, R. (2008). Chronic stress, drug use, and vulnerability to addiction. Annals of the New York Academy of Science, 1141, 105130.
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, 443449.
Sloan, D. M., & Kornstein, S. G. (2003). Gender differences in depression and response to antidepressant treatment. Psychiatry Clinic of North America, 26, 581594.
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, 977987.
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, 312319.
Suomi, S. J. (1991). Primate separation models of affective disorders. In Madden, J. I. (Ed.), Neurobiology of learning, emotion and affect (pp. 195214). New York: Raven Press.
Suomi, S. J. (1997). Early determinants of behaviour: Evidence from primate studies. British Medical Bulletin, 53, 170184.
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, 770786.
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, 411429.
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, 671676.
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, 295301.
Way, B., & Taylor, S. E. (2010). The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biological Psychiatry, 67, 487492.
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, 7288.

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

  • Simona Spinelli (a1), Melanie L. Schwandt (a1), Stephen G. Lindell (a1), Markus Heilig (a1), Stephen J. Suomi (a2), J. Dee Higley (a3), David Goldman (a1) and Christina S. Barr (a1)...

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