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The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: Potential roles in genetic selection and Gene × Environment interactions

  • Stephen G. Lindell (a1), Qiaoping Yuan (a2), Zhifeng Zhou (a2), David Goldman (a2), Robert C. Thompson (a3), Juan F. Lopez (a3), Stephen J. Suomi (a4), J. Dee Higley (a5) and Christina S. Barr (a1)...
  • Please note a correction has been issued for this article.


In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.


Corresponding author

Address correspondence and reprint requests to: Christina S. Barr, Section of Comparative Behavioral Genomics, Laboratory of Neurogenetics, DICBR, NIAAA, NIH, 5625 Fishers Lane, Room 3S-32, Rockville, MD 20852; E-mail:


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Adamsen, D., Meili, D., Blau, N., Thony, B., & Ramaekers, V. (2010). Autism associated with low 5-HIAA in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants. Molecular Genetics, 102, 368373.
Barr, C. S. (2011). Primate models of alcohol use disorders: Genetic and environmental variables. Unpublished manuscript.
Barr, C. S., Chen, S. A., Schwandt, M. L., Lindell, S. G., Sun, H., Suomi, S. J., et al. (2010). Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the micro-opioid receptor gene locus. Biological Psychiatry, 67, 7880.
Barr, C. S., Dvoskin, R. L., Gupte, M., Sommer, W., Sun, H., Schwandt, M. L., et al. (2009). Functional CRH promoter variation drives stress-induced alcohol consumption in primates. Proceedings of the National Academy of Sciences, 106, 1459314598.
Barr, C. S., & Goldman, D. (2006). Nonhuman primate models of inheritance of vulnerability to alcohol abuse and addiction. Addiction Biology, 11, 374385.
Barr, C. S., Newman, T. K., Becker, M. L., Parker, C. C., Champoux, M., Lesch, K. P., et al. (2003). The utility of the non-human primate: Model for studying gene by environment interactions in behavioral research. Genes, Brain, and Behavior, 2, 336340.
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, 11461152.
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 Sciences, 101, 1235812363.
Barr, C. S., Newman, T. K., Shannon, C., Parker, C. 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., Chen, S. A., Suomi, S. J., Goldman, D., et al. (2007). Mu opioid receptor gene variation is associated with alcohol response and consumption in rhesus monkeys. Archives of General Psychiatry, 64, 369376.
Barr, C. S., Schwandt, M. L., Lindell, S. G., Higley, J. D., Maestripieri, D., Goldman, D., et al. (2008). A functional OPRM1 variant is associated with attachment behavior in infant rhesus macaques. Proceedings of the National Academy of Sciences, 105, 52775281.
Barr, C. S., Schwandt, M., Newman, T. K., & Higley, J. D. (2004). The use of adolescent nonhuman primates to model human alcohol intake: Neurobiological, genetic and environmental variables. Annals of the New York Academy of Sciences, 1021, 221233.
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, 118122.
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 (5HTTLPR). Behavior Genetics, 34, 295307.
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., 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.
Chamove, A. S., Rosenblum, L. A., & Harlow, H. F. (1973). Monkeys (Macaca mulatta) raised only with peers. Animal Behavior, 21, 316325.
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.
Copeland, W. E., Sun, H., Costello, E. J., Angold, A., Heilig, M. A., & Barr, C. S. (2011). Child–opioid receptor gene variant influences parent–child relations. Neuropsychopharmacology, 36, 11651170.
Crockett, M. J., Clark, L., Hauser, M. D., & Robbins, T. W. (2010). Serotonin selectively influences moral judgment and behavior through effects on harm aversion. Proceedings of the National Academy of Sciences, 107, 1743317438.
Harlow, H. F., & Suomi, S. J. (1974). Induced depression in monkeys. Behavioral Biology, 12, 273296.
Heinz, A. J., Beck, A., Meyer-Lindenberg, A., Sterzer, P., & Heinz, A. (2011). Cognitive and neurobiological mechanisms of alcohol-related aggression. Nature Reviews in Neuroscience, 12, 400413.
Herman, A. I., Conner, T. S., Anton, R. F., Gelernter, J., Kranzler, H. R., & Covault, J. (2011). Variation in the gene encoding the serotonin transporter is associated with a measure of sociopathy in alcoholics. Addiction Biology, 16, 124132.
Higley, J. D., Hasert, M. F., Suomi, S. J., & Linnoila, M. (1991). Nonhuman primate model of alcohol abuse: Effects of early experience, personality, and stress on alcohol consumption. Proceedings of the National Academy of Sciences, 88, 72617265.
Higley, J. D., Suomi, S. J., & Linnoila, M. (1996). A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcoholism: Clinical and Experimental Research, 20, 629642.
Homberg, J. R., & Lesch, K. P. (2011). Looking on the bright side of serotonin transporter gene variation. Biological Psychiatry, 69, 513519.
Hu, X. Z., Lipsky, R. H., Zhu, G., Akhtar, L. A., Taubman, J., Greenberg, B. D., et al. (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder. American Journal of Human Genetics, 78, 815826.
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter polymorphism (5-HTTLPR), stress and depression meta-analysis revisited. Archives of General Psychiatry, 68, 444454.
Kinnally, E. L., Capitanio, J. P., Leibel, R., Deng, L., Leduc, C., Haghighi, F., et al. (2010). Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes, Brain, and Behavior, 9, 575582.
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 tradeoffs in health and disease. Neuroscience & Biobehavioral Reviews, 29, 338.
Kraemer, G. W., Moore, C. F., Newman, T. K., Barr, C. S., & Schneider, M. L. (2008). Moderate levels of fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and LHPA axis regulation in monkeys. Biological Psychiatry, 63, 317324.
Krawczak, M., Trefilov, A., Berard, J., Bercovitch, F., Kessler, M., Sauermann, U., et al. (2005). Male reproductive timing in rhesus macaques is influenced by the HTTLPR promoter polymorphism of the serotonin transporter gene. Biology of Reproduction, 72, 11091113.
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, 12591266.
Lin, E., Chen, P. S., Chang, H. H., Gean, P.-W., Tsai, H. C., Yang, Y. K., et al. (2009). Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder. Progress in Neuropsychopharmacology and Biological Psychiatry, 33, 11671172.
Lindell, S. G., Schwandt, M. L., Sun, H., Sparenborg, J. D., Bjoerk, K., Kasckow, J. W., et al. (2010). Functional NPY variation as a factor in stress resilience in rhesus macaques. Archives of General Psychiatry, 67, 423431.
Lopez, J. F., & Higley, J. D. (2002). The effect of early experience on brain corticosteroid and serotonin receptors in rhesus monkeys. Biological Psychiatry, 51, 294.
Mazzanti, C. M., Lappalainen, J., Long, J. C., Bengel, D., Naukkarinen, H., Eggert, M., et al. (1998). Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Archives of General Psychiatry, 55, 936940.
McEwen, B. S. (2006). Protective and damaging effects of stress mediators: Central role of the brain. Dialogues in Clinical Neuroscience, 8, 367381.
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.
Schwandt, M. L., Lindell, S. G., Sjoberg, R. L., Chisholm, K. L., Higley, J. D., Suomi, S. J., et al. (2010). Gene–environment interactions and response to social intrusion in male and female rhesus macaques. Biological Psychiatry, 67, 323330.
Sinha, R. (2007). Chronic stress, drug use, and vulnerability to addiction. Annals of the New York Academy of Sciences, 1141, 105130.
Smith, M. J., & Price, G. R. (1973). The logic of animal conflict. Nature, 246, 1518.
Spinelli, S., Chefer, S., Carson, R. E., Jagoda, E., Lang, L., Heilig, M., et al. (2010). Effects of early-life stress on serotonin 1A receptors in juvenile rhesus monkeys measured by PET. Biologial Psychiatry, 67, 11461153.
Spinelli, S., Chefer, S., Suomi, S. J., Higley, J. D., Barr, C. S., & Stein, E. (2009). Early life stress induces long-term morphologic changes in primate brain. Archives of General Psychiatry, 66, 658665.
Spinelli, S., Schwandt, M. L., Lindell, S. G., Heilig, M., Suomi, S. J., Higley, J. D., et al. (2012). The serotonin transporter gene linked polymorphic region is associated with the behavioral response to repeated stress exposure in infant rhesus macaques. Development and Psychopathology, 24, 157165.
Spinelli, S., Schwandt, M. L., Lindell, S. G., Newman, T. K., Heilig, M., Higley, J. D., et al. (2007). Association between the rh-5HTTLPR polymorphism and behavior in rhesus macaques during social separation stress. Developmental Psychopathology, 19, 977987.
Suomi, S. J. (1982). Abnormal behavior in nonhuman primates. In Fobes, J. D. & King, J. E. (Eds.), Primate behavior. New York: Academic Press.
Veenstra-Vanderweele, J., Jessen, T. N., Thompson, B. J., Carter, M., Prasad, H. C., Steiner, J. A., et al. (2009). Modeling rare gene variation to gain insight into the oldest biomarker in autism: Construction of the serotonin transporter Gly56Als knock-in mouse. Journal of Neurodevelopmental Disorders, 1, 158171.
Wendland, J. R., Lesch, K. P., Newman, T. K., Timme, A., Gachot-Neveu, H., Thierry, B., et al. (2005). Differential functional variability of serotonin transporter and monoamine oxidase A genes in macaque species displaying contrasting levels of aggression-related behavior. Behavior Genetics, 30, 110.
Yuan, Q., Zhou, Z., Lindell, S. G., Higley, J. D., Ferguson, E., Thompson, R. C., et al. (2012). The rhesus macaque is three times as diverse but more closely equivalent in “damaging” coding variation as compared to the human. BMC Genetics, 13, 52.
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