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

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 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.

SUBMITTER: Kinnally EL

PROVIDER: S-EPMC3170845 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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

Kinnally Erin L EL Karere Genesio M GM Lyons Leslie A LA Mendoza Sally P SP Mason William A WA Capitanio John P JP

Development and psychopathology 20100101 1

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 dimen ...[more]

PMID: 20102645

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Project description:In many countries where tuberculosis (TB) is endemic, the Bacillus Calmette-Guérin (BCG) vaccine is given as close to birth as possible to protect infants and children from severe forms of TB. However, BCG has variable efficacy and is not as effective against adult pulmonary TB. At present, most animal models used to study novel TB vaccine candidates rely on the use of adult animals. Human studies show that the infant immune system is different to that of an adult. Understanding how the phenotypic profile and functional ability of the immature host immune system compares to that of a mature adult, together with the subsequent BCG immune response, is critical to ensuring that new TB vaccines are tested in the most appropriate models. BCG-specific immune responses were detected in macaques vaccinated within a week of birth from six weeks after immunization indicating that neonatal macaques are able to generate a functional cellular response to the vaccine. However, the responses measured were significantly lower than those typically observed following BCG vaccination in adult rhesus macaques and infant profiles were skewed towards the activation and attraction of macrophages and monocytes and the synthesis in addition to release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α. The frequency of specific immune cell populations changed significantly through the first three years of life as the infants developed into young adult macaques. Notably, the CD4:CD8 ratio significantly declined as the macaques aged due to a significant decrease in the proportion of CD4+ T-cells relative to a significant increase in CD8+ T-cells. Also, the frequency of both CD4+ and CD8+ T-cells expressing the memory marker CD95, and memory subset populations including effector memory, central memory and stem cell memory, increased significantly as animals matured. Infant macaques, vaccinated with BCG within a week of birth, possessed a significantly higher frequency of CD14+ classical monocytes and granulocytes which remained different throughout the first three years of life compared to unvaccinated age matched animals. These findings, along with the increase in monokines following vaccination in infants, may provide an insight into the mechanism by which vaccination with BCG is able to provide non-specific immunity against non-mycobacterial organisms.

Project description:BackgroundMaternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.MethodsA total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods.ResultsGestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test.ConclusionsAlthough the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

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

Publications

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

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