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Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.

ABSTRACT: Epigenetic mechanisms may moderate genetic and environmental risk (GxE) for mood disorders. We used an experimental rhesus macaque model of early life stress to test whether epigenetic regulation of serotonin transporter (5-HTT) may contribute to GxE interactions that influence behavior and emotion. We hypothesized that peripheral blood mononuclear cell (PBMC) DNA methylation within an 800 bp cytosine-phosphate-guanosine (CpG) island that overlaps with the 5-HTT transcription initiation start site, a hypothesized model of the same genomic region in brain tissue, would mediate or moderate the effects of early life stress and a functional 5-HTT promoter polymorphism (rh5-HTTLPR) on two outcomes: PBMC 5-HTT expression and behavioral stress reactivity. Eighty-seven infant rhesus macaques (3-4 months of age) were either mother reared in large social groups (n = 70) or nursery reared (n = 17). During a maternal/social separation, infants' blood was sampled and behavioral stress reactivity recorded. PBMC DNA and RNA samples were used to determine rh5-HTTLPR genotype, 5-HTT mRNA expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and 5-HTT CpG methylation status using sodium bisulfite pyrosequencing. Consistent with human data, carriers of the low-expressing rh5-HTTLPR alleles exhibited higher mean 5-HTT CpG methylation, which was associated with lower PBMC 5-HTT expression. Higher 5-HTT CpG methylation, but not rh5-HTTLPR genotype, exacerbated the effects of early life stress on behavioral stress reactivity in infants. 5-HTT CpG methylation may be an important regulator of 5-HTT expression early in development and may contribute to the risk for mood disorders observed in 'high-risk'5-HTTLPR carriers.

SUBMITTER: Kinnally EL

PROVIDER: S-EPMC2921011 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.

Kinnally E L EL Capitanio J P JP Leibel R R Deng L L LeDuc C C Haghighi F F Mann J J JJ

Genes, brain, and behavior 20100412 6

Epigenetic mechanisms may moderate genetic and environmental risk (GxE) for mood disorders. We used an experimental rhesus macaque model of early life stress to test whether epigenetic regulation of serotonin transporter (5-HTT) may contribute to GxE interactions that influence behavior and emotion. We hypothesized that peripheral blood mononuclear cell (PBMC) DNA methylation within an 800 bp cytosine-phosphate-guanosine (CpG) island that overlaps with the 5-HTT transcription initiation start si ...[more]

PMID: 20398062

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Project description: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 x 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 x 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 x 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.

Dataset Information

Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.

Publications

Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.

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