The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor

Abstract

A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [ 18 F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.

From high anxiety trait to depression: a neurocognitive hypothesis

“…Work in female macaques indicates a particular susceptibility for carriers of the S allele that were, during early development, peer-only reared to develop high alcohol consumption, as compared with females from either the same genotype but reared by their mothers in social groups or with non-S allele carriers regardless of their rearing background [72]. In rhesus monkeys, a stressor context by genotype interaction was found such that the S allele influences different brain regions (including the amygdala) during exposure to different stressful situations [73]. In rodents, 5-HTT-deficient mice of at least one particular genetic background (C57BL/6J) only exhibit increased depression-related behavior after repeated exposure to uncontrollable stress [74].…”

When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

“…Although human and non-human primate functional imaging studies have begun to elucidate the neural circuits involved in the 5-HTT Â E risk factor (see Sect. 5), a molecular understanding of this phenomenon is essentially lacking (Canli et al 2006;Kalin et al 2008).…”

Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition

“…As such, 5-HTT genetic down-regulation may make an individual more vulnerable for developing anxiety-and depression-like symptoms (Caspi et al 2010). However, the same genetically linked trait may contribute to behavioral flexibility, potentially through a hyper-reactive mPFC (Heinz et al 2005) and OFC (Kalin et al 2008). 5-HTT genetic variance may therefore be an important mediator for how an individual interacts with its environment, for better and for worse.…”