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Serotonin pathway gene–gene and gene–environment interactions influence behavioral stress response in infant rhesus macaques

Published online by Cambridge University Press:  26 January 2010

Erin L. Kinnally ,
Genesio M. Karere ,
Leslie A. Lyons ,
Sally P. Mendoza ,
William A. Mason  and
John P. Capitanio
Erin L. Kinnally*
Affiliation:
University of California Davis
Genesio M. Karere
Affiliation:
University of California Davis
Leslie A. Lyons
Affiliation:
University of California Davis
Sally P. Mendoza
Affiliation:
University of California Davis
William A. Mason
Affiliation:
University of California Davis
John P. Capitanio
Affiliation:
University of California Davis
*
Address correspondence and reprint requests to: Erin Kinnally, Department of Psychiatry, Division of Molecular Imaging and Neuropathology, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, Room 2917, New York, NY 10032; E-mail: [email protected].
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Abstract

A subset of serotonin (5-HT) pathway polymorphisms has been shown to confer risk for psychological dysfunction, particularly in individuals who experience early adversity. Understanding the developmental processes underlying these Gene × Environment interactions will strengthen the search for risk factors for behavioral dysfunction. We investigated the combined influence of two serotonin pathway polymorphisms and species-atypical, and possibly adverse, rearing (nursery rearing [NR]) on two dimensions of behavioral stress response in infant rhesus macaques. We hypothesized that the experience of NR and possession of both “high-risk” genotypes (genotypes that are thought to confer low 5-HT function) would predict the greatest behavioral stress response to maternal/social separation. Using a matched-pair design, the impact of early experience and the serotonin transporter (rh5-HTTLPR) and monoamine oxidase A (rhMAO-A-LPR) promoter polymorphisms on behavioral reactivity of 136 infant rhesus macaques (90–120 days of age) during a 25-hr social separation/relocation procedure was assessed. Each pair included one infant reared with mother in a large, outdoor field enclosure (field rearing) and one infant reared in a nursery (NR). Pairs were matched for putative gene activity of each polymorphism, sex, age, and weight at testing. Behavioral responses in a “human intruder” test were recorded, and activity and emotional reactivity composites were created to detect different aspects of psychological adaptation to stress. Our hypothesis that high-risk groups would be the most reactive to stress was not entirely borne out. Rh5-HTTLPR × rhMAOA-LPR interactions predicted emotional reactivity and tended to predict behavioral activity scores. Carriers of the two “low-risk” alleles exhibited the lowest behavioral activity, as might be predicted, but carriers of both “high-risk” alleles were two of four genotype groups exhibiting the highest observed Emotional Reactivity. Gene × Gene interactions were exacerbated by the experience of nursery rearing, as predicted, however. Finally, we suggest that genetic or environmental factors may mitigate the risk for behavioral dysregulation illustrated in the patterns of behavioral activity and emotional reactivity displayed by infants.

Type
Regular Articles
Information
Development and Psychopathology , Volume 22 , Issue 1 , February 2010 , pp. 35 - 44
Copyright
Copyright © Cambridge University Press 2010

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References

Ansorge, M. S., Zhou, M., Lira, A., Hen, R., & Gingrich, J. A. (2004). Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science, 306, 879–881.CrossRefGoogle ScholarPubMed
Auerbach, J., Geller, V., Lezer, S., Shinwell, E., Belmaker, R. H., Levine, J., et al. (1999). Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants. Molecular Psychiatry, 3, 369–373.CrossRefGoogle Scholar
Barr, C. S., Newman, T. K., Lindell, S., Shannon, C., Champoux, M., Lesch, K. P., et al. (2004). Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Archives of General Psychiatry, 61, 1146–1152.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
Bell, R. Q. (1975). A congenital contribution to emotional response in early infancy and the preschool period. Ciba Foundation Symposium, 33, 201–212.Google Scholar
Bennett, A. J., Lesch, K. P., Heils, A., Long, J. C., Lorenz, J. G., Shoaf, S. E., et al. (2002). Early experience and serotonin transporter gene variation interact to influence primate CNS function. Molecular Psychiatry, 7, 118–122.CrossRefGoogle ScholarPubMed
Bethea, C. L., Streicher, J. M., Coleman, K., Pau, F. K., 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 (5HTTLPR). Behavior Genetics, 34, 295–307.CrossRefGoogle ScholarPubMed
Bradley, S. L., Dodelzon, K., Sandhu, H. K., & Philibert, R. A. (2005). Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 136, 58–61.CrossRefGoogle Scholar
Capitanio, J. P., Mason, W. A., Mendoza, S. P., Del Rosso, L. A., & Roberts, J. A. (2006). Nursery rearing and biobehavioral organization. In Sackett, G. P., Ruppenthal, G., & Elias, K. (Eds.), Nursery rearing of nonhuman primates in the 21st century. New York: Springer.Google Scholar
Carrel, L., & Willard, H. (2005). X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature, 434, 400–404.CrossRefGoogle ScholarPubMed
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., & Suoml, S. J. (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Molecular Psychiatry, 7, 1058–1063.CrossRefGoogle ScholarPubMed
Charney, D., & Manji, H. (2004). Life stress, genes, and depression: Multiple pathways lead to increased risk and new opportunities for intervention. Science Signaling: The Signal Transduction Knowledge Environment, 2004(225), re5.Google ScholarPubMed
Cicchetti, D., Rogosch, F. A., & Sturge-Apple, M. L. (2007). Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms: Depressive symptomatology among adolescents from low socioeconomic status backgrounds. Development and Psychopathology, 19, 1161–1180.CrossRefGoogle ScholarPubMed
Clarke, R., Murphy, D. L., & Constantino, J. N. (1999). Serotonin and externalizing behavior in young children. Psychiatry Research, 86, 29–40.CrossRefGoogle ScholarPubMed
Colder, C., Mott, J. A., & Berman, A. S. (2002). The interactive effects of infant activity level and fear on growth trajectories of early childhood behavior problems. Development and Psychopathology, 14, 1–23.CrossRefGoogle ScholarPubMed
Eley, T. C., Sugden, K., Corsico, A., Gregory, A. M., Sham, P., McGuffin, P., et al. (2004). Gene–environment interaction analysis of serotonin system markers with adolescent depression. Molecular Psychiatry, 9, 908–915.CrossRefGoogle ScholarPubMed
Falconer, D. S., & MacKay, T. F. C. (1996). Quantitative genetics. Harlow: Pearson.Google Scholar
Foley, D. L., Eaves, L. J., Wormley, B., Silberg, J. L., Maes, H. H., Kuhn, J., et al. (2004). Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder. Archives of General Psychiatry, 61, 738–744.CrossRefGoogle ScholarPubMed
Frazzetto, G., Di Lorenzo, G., Carola, V., Proietti, L., Sokolowska, E., Siracusano, A., et al. (2007). Early trauma and increased risk for physical aggression during adulthood: The moderating role of MAOA genotype. PLos ONE, 2, e486.CrossRefGoogle ScholarPubMed
Gibb, B., McGeary, J., Beevers, C., & Miller, I. W. (2006). Serotonin transporter (5-HTTLPR) genotype, childhood abuse, and suicide attempts in adult psychiatric inpatients. Suicide and Life-Threatening Behavior, 36, 687–693.CrossRefGoogle ScholarPubMed
Golub, M. S., Hogrefe, C. E., Widaman, K. F., & Capitanio, J. P. (2008). Iron deficiency anemia and affective response in rhesus monkey infants. Developmental Psychobiology, 51, 47–59.CrossRefGoogle Scholar
Gottlieb, G. (2007). Probabilistic epigenesis. Developmental Science, 10, 1–11.CrossRefGoogle ScholarPubMed
Gunthert, K., Conner, T., Armeli, S., Tennen, H., Covault, J., & Kranzler, H. (2007). Serotonin transporter gene polymorphism (5-HTTLPR) and anxiety reactivity in daily life: A daily process approach to gene–environment interaction. Psychosomatic Medicine, 69, 762–768.CrossRefGoogle ScholarPubMed
Haberstick, B. C., Lessem, J., Hopfer, C., Smolen, A., Ehringer, M., Timberlake, D., et al. (2005). Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 135B, 59–64.CrossRefGoogle ScholarPubMed
Higley, J., & Linnoila, M. (1997). Low central nervous system serotonergic activity is traitlike and correlates with impulsive behavior. A nonhuman primate model investigating genetic and environmental influences on neurotransmission. Annals of the New York Academy of Sciences, 836, 39–56.CrossRefGoogle ScholarPubMed
Hinde, K. J., & Capitanio, J. P. (2009). Lactational programming? Mother's milk energy predicts infant behavior and temperament in rhesus macaques (Macaca mulatta). Behavioral Ecology and Sociobiology.Google Scholar
Hranilovic, D., Stefulj, J., Schwab, S., Borrmann-Hassenbach, M., Albus, M., Jernej, B., et al. (2004). Serotonin transporter promoter and intron 2 polymorphisms: Relationship between allelic variants and gene expression. Biological Psychiatry, 55, 1090–1094.CrossRefGoogle ScholarPubMed
Huang, Y. Y., Cate, S. P., Battistuzzi, C., Oquendo, M. A., Brent, D., & Mann, J. J. (2004). An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences. Neuropsychopharmacology, 29, 1498–1505.CrossRefGoogle ScholarPubMed
Jaffee, S., & Price, T. S. (2007). Gene–environment correlations: A review of the evidence and implications for prevention of mental illness. Molecular Psychiatry, 12, 432–442.CrossRefGoogle ScholarPubMed
Karere, G. M., Kinnally, E. L., Sanchez, J. N., Famula, T. R., Lyons, L. A., & Capitanio, J. P. (2009). What is an “adverse” environment? Interactions of rearing experiences and MAOA genotype in rhesus monkeys. Biological Psychiatry, 65, 770–779.CrossRefGoogle Scholar
Kaufman, J., Yang, B., Douglas-Palumberi, H., Crouse-Artus, M., Lipschitz, D., Krystal, J., et al. (2007). Genetic and environmental predictors of early alcohol use. Biological Psychiatry, 61, 1228–1234.CrossRefGoogle ScholarPubMed
Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Houshyar, S., Lipschitz, D., Krystal, J. H., et al. (2004). Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences of the United States of America, 101, 17316–17321.CrossRefGoogle ScholarPubMed
Kim-Cohen, J., Caspi, A., Taylor, A., Williams, B., Newcombe, R., Craig, I. W., et al. (2006). MAOA, maltreatment, and gene–environment interaction predicting children's mental health: New evidence and a meta-analysis. Molecular Psychiatry, 11, 903–913.CrossRefGoogle ScholarPubMed
Kraemer, G., Moore, C., Newman, T., Barr, C., & Schneider, M. (2008). Moderate level fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and limbic–hypothalamic–pituitary–adrenal axis regulation in monkeys. Biological Psychiatry, 63, 317–324.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
Lesch, K. P., Meyer, J., Glatz, K., Flügge, G., Hinney, A., Hebebrand, J., et al. (1997). The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: Alternative biallelic variation in rhesus monkeys. Journal of Neural Transmission, 104, 1259–1266.CrossRefGoogle ScholarPubMed
Manuck, S., Flory, J. D., Ferrell, R. E., & Muldoon, M. F. (2004). Socio-economic status covaries with central nervous system serotonergic responsivity as a function of allelic variation in the serotonin transporter gene-linked polymorphic region. Psychoneuroendocrinology, 29, 651–658.CrossRefGoogle ScholarPubMed
Manuck, S. B., Flory, J. D., McCaffery, J. M., Matthews, K. A., Mann, J. J., & Muldoon, M. F. (1998). Aggression, impulsivity, and central nervous system serotonergic responsivity in a nonpatient sample. Neuropsychopharmacology, 19, 287–299.CrossRefGoogle Scholar
McCormack, K., Newman, T., Higley, J., Maestripieri, D., & Sanchez, M. (2009). Serotonin transporter gene variation, infant abuse, and responsiveness to stress in rhesus macaque mothers and infants. Hormones and Behavior.CrossRefGoogle ScholarPubMed
Meyer, J., Ginovart, N., Boovariwala, A., Sagrati, S., Hussey, D., Garcia, A., et al. (2006). Elevated monoamine oxidase a levels in the brain: An explanation for the monoamine imbalance of major depression. Archives of General Psychiatry, 63, 1209–1216.CrossRefGoogle Scholar
Middeldorp, C., de Geus, E., Beem, A., Lakenberg, N., Hottenga, J., Slagboom, P., et al. (2007). Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression. Behavior Genetics, 37, 294–301.CrossRefGoogle ScholarPubMed
Munafò, M., Durrant, C., Lewis, G., & Flint, J. (2009). Gene × environment interactions at the serotonin transporter locus. Biological Psychiatry, 65, 211–219.CrossRefGoogle ScholarPubMed
Nemeroff, C. (2004). Early-life adversity, CRF dysregulation, and vulnerability to mood and anxiety disorders. Psychopharmacology Bulletin, 38, 14–20.Google Scholar
Newman, T., Syagailo, Y. V., Barr, C. S., Wendland, J. R., Champoux, M., Graessle, M., et al. (2005). Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys. Biological Psychiatry, 57, 167–172.CrossRefGoogle ScholarPubMed
Nilsson, K. W., Sjöberg, R. L., Wargelius, H. L., Leppert, J., Lindström, L., & Oreland, L. (2007). The monoamine oxidase A (MAO-A) gene, family function and maltreatment as predictors of destructive behaviour during male adolescent alcohol consumption. Addiction, 102, 389–398.CrossRefGoogle ScholarPubMed
Nordquist, N., & Oreland, L. (2007). Monoallelic expression of MAO-A in skin fibroblasts. Journal of Neural Transmission—General Section, 114, 713–716. [Retracted article]CrossRefGoogle ScholarPubMed
Olson, S., Bates, J. E., Sandy, J. M., & Schilling, E. M. (2002). Early developmental precursors of impulsive and inattentive behavior: From infancy to middle childhood. Journal of Child Psychology and Psychiatry, 43, 435–447.CrossRefGoogle ScholarPubMed
Reif, A., Rösler, M, Freitag, C. M., Schneider, M., Eujen, A., Kissling, C., et al. (2007). Nature and nurture predispose to violent behavior: Serotonergic genes and adverse childhood environment. Neuropsychopharmacology, 32, 2375–2383.CrossRefGoogle ScholarPubMed
Rogers, J., Shelton, S., Shelledy, W., Garcia, R., & Kalin, N. (2008). Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. Genes Brain and Behavior, 7, 463–469.CrossRefGoogle ScholarPubMed
Sabol, S., Hu, S., & Hamer, D. (1998). A functional polymorphism in the monoamine oxidase A gene promoter. Human Genetics, 103, 273–279.CrossRefGoogle ScholarPubMed
Spinelli, S., Schwandt, M. L., Lindell, S. G., Newman, T. K., Heilig, M., Suomi, S. J., et al. (2007). Association between the recombinant human serotonin transporter linked promoter region polymorphism 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
Sullivan, E. C., & Capitanio, J. P. (2008). Consistency in behavioral responsiveness from infancy to adulthood. Paper presented at the American Society for Primatologists, West Palm Beach, FL.Google Scholar
Suomi, S. (2006). Risk, resilience, and gene × environment interactions in rhesus monkeys. Annals of the New York Academy of Sciences, 1094, 52–62.CrossRefGoogle ScholarPubMed
Surtees, P. G., Wainwright, N. W., Willis-Owen, S. A., Luben, R., Day, N. E., & Flint, J. (2006). Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biological Psychiatry, 59, 224–229.CrossRefGoogle ScholarPubMed
Taylor, A., & Kim-Cohen, J. (2007). Meta-analysis of gene–environment interactions in developmental psychopathology. Development and Psychopathology, 19, 1029–1037.CrossRefGoogle ScholarPubMed
Vanyukov, M., Maher, B., Devlin, B., Kirillova, G., Kirisci, L., Yu, L., et al. (2007). The MAOA promoter polymorphism, disruptive behavior disorders, and early onset substance use disorder: Gene–environment interaction. Psychiatric Genetics, 17, 323–332.CrossRefGoogle ScholarPubMed
Weinstein, T., & Capitanio, J. (2008). Individual differences in infant temperament predict social relationships of yearling rhesus monkeys, Macaca mulatta. Animal Behaviour, 76, 455–460.CrossRefGoogle ScholarPubMed
Wendland, J., Hampe, M., Newman, T. K., Syagailo, Y., Meyer, J., Schempp, W., et al. (2006). Structural variation of the monoamine oxidase A gene promoter repeat polymorphism in nonhuman primates. Genes Brain and Behavior, 5, 40–45.CrossRefGoogle ScholarPubMed
Williams, R., Marchuk, D., Gadde, K., Barefoot, J., Grichnik, K., Helms, M., et al. (2003). Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology, 28, 533–541.CrossRefGoogle ScholarPubMed
Zalsman, G., Huang, Y. Y., Oquendo, M. A., Burke, A. K., Hu, X. Z., Brent, D. A., et al. (2006). Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. American Journal of Psychiatry, 163, 1588–1593.CrossRefGoogle ScholarPubMed