Early experience and serotonin transporter gene variation interact to influence primate CNS function

Abstract

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

Early maternal rejection affects the development of monoaminergic systems and adult abusive parenting in rhesus macaques (Macaca mulatta).

“…The causes of naturally occurring individual differences in serotonergic function, however, are not well understood. A previous study of rhesus monkeys found no significant variation in CSF 5-HIAA concentrations in relation to serotonin transporter gene polymorphism but reported that the individuals with the s allele were more vulnerable to the effects of early social deprivation on later neuroendocrine and behavioral responsiveness than the individuals with the l allele (Bennett et al, 2002). The sample size of our study was too small to permit investigation of a similar Genotype ϫ Environment interaction, but nevertheless, our results suggest that early interactions with the mother are an important source of developmental variation in monoaminergic function.…”

“…Some of these studies have shown that individual differences in vulnerability to adverse early experience are modulated by genetic factors, such as the polymorphism in the serotonin transporter gene. In rhesus monkeys, a 21-base pair insertion/deletion polymorphism analogous to the human 5-hydroxytryptamine transporter gene (5-HTT) length variant of the gene-linked polymorphic region (rh5-HTTLPR) has been found in the same transcriptional region, resulting in similar allelic variation and reductions in transcriptional efficiency (Bennett et al, 2002). Rhesus monkeys with the short (s) allele are more vulnerable to the developmental dysregulation of the HPA axis induced by early social deprivation than are monkeys with the long (l) allele (Barr, Newman, Lindell, et al, 2004;Bennett et al, 2002).…”

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

“…82 In rhesus macaques, with an SERTLPR analogous to that of humans, the short allele is associated with decreased serotonergic function among monkeys reared in stressful conditions, but not among normally reared monkeys. 83 In humans, individuals with one or two copies of short allele of the SERT promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele; however, no direct association between the SERT gene and depression was observed. 84 Taken together, these studies show that there may not be a direct relationship between SERTLPR and a variety of biochemical and clinical phenotypes; yet, intriguing results do imply a role for SERTLPR in behavioral disorders when environmental factors are taken into account.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…9 The less active s-allele interacts with adverse early rearing conditions (peer rearing) to result in more distress, less activity, stronger neuroendocrine responses to stress, higher consumption of alcohol and lower serotonin turnover in the central nervous system. 8,9,26,27 During peerrearing, animals homozygous for the l allele develop more socially acceptable playful behaviours but sl heterozygotes tend to become aggressive, suggesting that the ll homozygous status confers an adaptive potential for adverse environment. 28 In conclusion, the non-human primate experiments support the G Â E hypothesis by showing that the s allele is associated with a vulnerability to early life adverse circumstances leading to multiple adverse outcomes resembling human psychiatric disorders.…”

“…2,3 Quantitative human population genetics studies indicate that G Â E plays a role in the development of depression. [4][5][6][7] In the last five years, G Â E involving specific gene polymorphisms has been identified in animals 8,9 and humans. [10][11][12][13] Encouragingly, replications 14,15 and a positive metaanalysis 16 indicate that measuring environment improves the reliability of genetic research.…”