Polymorphisms in the 3′ UTR of the serotonin transporter are associated with cognitive flexibility in rhesus macaques

Abstract

The serotonin system is an important neurophysiological mediator of many behavioral phenotypes. Genetic variation within this system is thought to contribute not only to the natural range of behavioral differences, but also to neuropsychiatric pathologies. Cognitive flexibility, the ability to change patterns of response as reward context shifts, is an important trait that underlies many complex social interactions. Environmental manipulations of the serotonin system have been shown to alter performance on tests measuring cognitive flexibility. Variation at the serotonin transporter promoter region (5HTTLPR) has recently been shown to associate with the performance of rhesus monkeys on an object discrimination reversal learning task [Izquierdo et al. 2007]. Here, we demonstrate that functional genetic variation at the serotonin transporter 3’ untranslated region, independent of 5HTTLPR, also associates with performance in an object discrimination reversal learning task in rhesus macaques. The polymorphisms comprising the T:G:T haplotype (T1970, G1991, and T2327) were associated with fewer errors on a reversal learning test and greater levels of cognitive flexibility. We have previously demonstrated that the T:G:T haplotype renders lower levels of gene expression in vitro, paralleling the functionality of human 3’ UTR haplotypes, as well as the short allele of 5HTTLPR found in both macaques and humans. The 3’ UTR haplotypes are independent and in linkage equilibrium with the 5HTTLPR locus. Together, these data lead to the intriguing possibility that differences observed in human cognitive flexibility, whether naturally or in pathological states, may be associated with genetic variation in the serotonin transporter 3’ untranslated region also.

Polymorphism of the serotonin transporter gene modulates brain and physiological responses to acute stress in Japanese men

“…Namely, the SS carriers might have found the mental arithmetic task harder than the SL þ LL carriers resulting in greater reactivity. Indeed, recent studies of animals (Izquierdo et al 2007;Vallender et al 2008) and humans (Fiedorowicz et al 2007;Jollant et al 2007) have shown that the S allele compared to the L allele is associated with reduced higher cognitive function. However, another study has shown no differences for basic intelligence between human 5HTTLPR genotypes (Gotlib et al 2008).…”

A natural genetic polymorphism affects retroactive interference inDrosophila melanogaster

“…Little is known about the mechanisms underlying RI. Vertebrate studies suggest the involvement of serotonin [38,39]; it is unclear whether serotonin plays a role in insect learning ( [40][41][42][43]; but see [44]). Interestingly, PKG is thought to modulate serotonin (5-hydroxytryptamine; 5-HT) transporter activity [43].…”

A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?

“…Rhesus monkeys with two copies of the short allele of the rhesus 5-HTT (i.e., the 5-HT transporter) gene-linked polymorphic region (rh5-HTTLPR) showed reduced cognitive flexibility on two tasks: object discrimination reversal learning and instrumental extinction (Izquierdo et al 2007). Genetic variation at the 5-HTT 3′ untranslated region, independent of rh5-HTTLPR, also affects performance in object discrimination reversal learning in rhesus monkeys (Vallender et al 2009). …”

“…Two rhesus monkey studies at least support a role for 5-HT in cognitive flexibility (Izquierdo et al 2007;Vallender et al 2009). In sum, these studies tend to support the hypothesis that 5-HT activates the PFC.…”