Mingkuan Lin

Oxytocin Receptor Genetic Variation Promotes Human Trust Behavior

Given that human trust behavior is heritable and intranasal administration of oxytocin enhances trust, the oxytocin receptor (OXTR) gene is an excellent candidate to investigate genetic contributions to individual variations in trust behavior. Although a single-nucleotide polymorphism involving an adenine (A)/guanine (G) transition (rs53576) has been associated with socio-emotional phenotypes, its link to trust behavior is unclear. We combined genotyping of healthy male students (n = 108) with the administration of a trust game experiment. Our results show that a common occurring genetic variation (rs53576) in the OXTR gene is reliably associated with trust behavior rather than a general increase in trustworthy or risk behaviors. Individuals homozygous for the G allele (GG) showed higher trust behavior than individuals with A allele carriers (AA/AG). Although the molecular functionality of this polymorphism is still unknown, future research should clarify how the OXTR gene interacts with other genes and the environment in promoting socio-emotional behaviors.

BDNF mediates improvements in executive function following a 1-year exercise intervention

Executive function declines with age, but engaging in aerobic exercise may attenuate decline. One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor (BDNF), which also declines with age. The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults (mean age = 66.82). Participants were randomized to a stretching and toning control group or a moderate intensity walking intervention group. BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up. We found that age moderated the effect of intervention group on changes in BDNF levels, with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise (p = 0.036). The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy, but did so as a function of age, such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71. These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes, particularly in elderly populations.

Synergistic effects of genetic variation in nicotinic and muscarinic receptors on visual attention but not working memory

It is widely appreciated that neurotransmission systems interact in their effects on human cognition, but those interactions have been little studied. We used genetics to investigate pharmacological evidence of synergisms in nicotinic/muscarinic interactions on cognition. We hypothesized that joint influences of nicotinic and muscarinic systems would be reflected in cognitive effects of normal variation in known SNPs in nicotinic (CHRNA4 rs1044396) and muscarinic (CHRM2 rs8191992) receptor genes. Exp. 1 used a task of cued visual search. The slope of the cue size/reaction time function showed a trend level effect of the muscarinic CHRM2 SNP, no effect of the nicotinic CHRNA4 SNP, but a significant interaction between the 2 SNPs. Slopes were steepest in individuals who were both CHRNA4 C/C and CHRM2 T/T homozygotes. To determine the specificity of this synergism, Exp. 2 assessed working memory for 1–3 locations over 3 s and found no significant effects on either SNP. Interpreting these results in light of Sarters [Briand LA, et al. (2007) Modulators in concert for cognition: Modulator interactions in the prefrontal cortex. Prog Neurobiol 83:69–91] claims of tonic and phasic modes of cholinergic activity, we argue that reorienting attention to the target after invalid cues requires a phasic response, dependent on the nicotinic system, whereas orienting attention to valid cues requires a tonic response, dependent on the muscarinic system. Consistent with that, shifting and scaling after valid cues (tonic) were strongest in CHRNA4 C/C homozygotes who were also CHRM2 T/T homozygotes. This shows synergistic effects within the human cholinergic system.

Both a nicotinic single nucleotide polymorphism (snp) and a noradrenergic snp modulate working memory performance when attention is manipulated

We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues, indicating the scale of visuospatial attention has a role in forming the mental representation of the target. In one of the first studies to compare effects of two single nucleotide polymorphisms (SNPs) on the same cognitive task, we investigated the neurotransmission systems underlying interactions between attention and memory. Based on our previous report that the CHRNA4 rs#1044396 C/T nicotinic receptor SNP affected visuospatial attention, but not working memory, and the DBH rs#1108580 G/A noradrenergic enzyme SNP affected working memory, but not attention, we predicted that both SNPs would modulate performance when the two systems interacted and working memory was manipulated by attention. We found the scale of visuospatial attention deployed around a target affected memory for location of that target. Memory performance was modulated by the two SNPs. CHRNA4 C/C homozygotes and DBH G allele carriers showed the best memory performance but also the greatest benefit of visuospatial attention on memory. Overall, however, the CHRNA4 SNP exerted a stronger effect than the DBH SNP on memory performance when visuospatial attention was manipulated. This evidence of an integrated cholinergic influence on working memory performance under attentional manipulation is consistent with the view that working memory and visuospatial attention are separate systems which can interact.

Healthy aging increases the cognitive effects of two genes that influence extracellular dopamine.

We hypothesized that normal variation in genes influencing the bioavailability of dopamine in prefrontal cortex contribute to inter-individual differences in working memory (WM), particularly in healthy old age. To test this, 858 healthy young, middle-aged, and older people were tested on a spatial WM task and genotyped for catechol-O-methyltransferase (COMT VAL158MET) and dopamine betahydroxylase (DBH; C-1021T) single nucleotide polymorphisms (SNPs). Since these genes encode enzymes influencing levels of extracellular dopamine, important for WM, we reasoned that individuals with low activity alleles of each SNP (less efficient degradation of dopamine by COMT and less efficient conversion of dopamine to norepinephrine by DBH) would have higher levels of extracellular dopamine and therefore better WM performance. We predicted the poorest WM performance in people who are both COMT VAL/VAL and DBH C/C homozygotes, encoding enzymes with high activity. That prediction was borne out, but only in the older group under difficult discrimination. This suggests the high activity alleles of these 2 genes combine in reducing ability to manipulate information in WM among the old. Further, we predicted the best performance in people who inherited both low activity alleles. That prediction was not borne out. That we found genetic effects only among older people and not in midlife indicates that brain changes late in life heighten negative effects of chronically lower levels of extracellular dopamine due to normal genetic variation. We found that age increased the combined effect on WM of the COMT and DBH genes encoding enzymes controlling levels of extracellular dopamine.

Dopamine Beta Hydroxylase Genotype Identifies Individuals Less Susceptible to Bias in Computer-Assisted Decision Making

Computerized aiding systems can assist human decision makers in complex tasks but can impair performance when they provide incorrect advice that humans erroneously follow, a phenomenon known as “automation bias.” The extent to which people exhibit automation bias varies significantly and may reflect inter-individual variation in the capacity of working memory and the efficiency of executive function, both of which are highly heritable and under dopaminergic and noradrenergic control in prefrontal cortex. The dopamine beta hydroxylase (DBH) gene is thought to regulate the differential availability of dopamine and norepinephrine in prefrontal cortex. We therefore examined decision-making performance under imperfect computer aiding in 100 participants performing a simulated command and control task. Based on two single nucleotide polymorphism (SNPs) of the DBH gene, −1041 C/T (rs1611115) and 444 G/A (rs1108580), participants were divided into groups of low and high DBH enzyme activity, where low enzyme activity is associated with greater dopamine relative to norepinephrine levels in cortex. Compared to those in the high DBH enzyme activity group, individuals in the low DBH enzyme activity group were more accurate and speedier in their decisions when incorrect advice was given and verified automation recommendations more frequently. These results indicate that a gene that regulates relative prefrontal cortex dopamine availability, DBH, can identify those individuals who are less susceptible to bias in using computerized decision-aiding systems.

Interactive effects of the COMT gene and training on individual differences in supervisory control of unmanned vehicles.

Objective: We examined whether a gene known to influence dopamine availability in the prefrontal cortex is associated with individual differences in learning a supervisory control task. Background: Methods are needed for selection and training of human operators who can effectively supervise multiple unmanned vehicles (UVs). Compared to the valine (Val) allele, the methionine (Met) allele of the COMT gene has been linked to superior executive function, but it is not known whether it is associated with training-related effects in multi-UV supervisory control performance. Method: Ninety-nine healthy adults were genotyped for the COMT Val158Met single nucleotide polymorphism (rs4680) and divided into Met/Met, Val/Met, and Val/Val groups. Participants supervised six UVs in an air defense mission requiring them to attack incoming enemy aircraft and protect a no-fly zone from intruders in conditions of low and high task load (numbers of enemy aircraft). Training effects were examined across four blocks of trials in each task load condition. Results: Compared to the Val/Met and Val/Val groups, Met/Met individuals exhibited a greater increase in enemy targets destroyed and greater reduction in enemy red zone incursions across training blocks. Conclusion: Individuals with the COMT Met/Met genotype can acquire skill in executive function tasks, such as multi-UV supervisory control, to a higher level and/or faster than other genotype groups. Application: Potential applications of this research include the development of individualized training methods for operators of multi-UV systems and selecting personnel for complex supervisory control tasks.

A functional promoter variant of the human formimidoyltransferase cyclodeaminase (FTCD) gene is associated with working memory performance in young but not older adults.

Objective: The central role of working memory in IQ and the high heritability of working memory performance motivated interest in identifying the specific genes underlying this heritability. The FTCD (formimidoyltransferase cyclodeaminase) gene was identified as a candidate gene for allelic association with working memory in part from genetic mapping studies of mouse Morris water maze performance. Method: The present study tested variants of this gene for effects on a delayed match-to-sample task of a large sample of younger and older participants. Results: The rs914246 variant, but not the rs914245 variant, of the FTCD gene modulated accuracy in the task for younger, but not older, people under high working memory load. The interaction of haplotype × distance × load had a partial eta squared effect size of 0.015. Analysis of simple main effects had partial eta squared effect sizes ranging from 0.012 to 0.040. A reporter gene assay revealed that the C allele of the rs914246 genotype is functional and a main factor regulating FTCD gene expression. Conclusion: This study extends previous work on the genetics of working memory by revealing that a gene in the glutamatergic pathway modulates working memory in young people but not in older people.