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.

Background: ␣7 nicotinic acetylcholine receptors are ligand-gated ion channels that bind intracellular signaling proteins. Results: A mutation in the M3-M4 loop of the ␣7 nicotinic acetylcholine receptor abolishes G␣ q activation of intracellular calcium stores. Conclusion: ␣7 nicotinic acetylcholine receptors functionally couple G proteins. Significance: Nicotinic acetylcholine receptors engage metabotropic-signaling responses.

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.

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. 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. cholinergic ͉ genetics ͉ synergism ͉ cognition

Previous investigations into whether the APOE-ε4 allele exerts cognitive effects at midlife have been inconclusive. We have advanced a “cognitive phenotype” hypothesis arguing that the ε4 allele of the apolipoprotein E gene (APOE) is associated with lower efficiency of neuronal plasticity thereby resulting in poorer cognitive performance independently of the pathology of Alzheimer’s disease (Greenwood et al., 2005). This hypothesis is best tested at midlife, prior to the neuron loss associated with AD diagnosis. This hypothesis predicts that the ε4 allele would alter cognition regardless of age through plasticity mechanisms, but would not induce longitudinal decline in midlife. The alternative “prodrome” hypothesis predicts that the APOE-ε4 allele would be associated with longitudinal cognitive decline as early as midlife due to prodromal effects of AD. We tested these hypotheses with a working memory task in a large cross-sectional sample of cognitively screened APOE-ε4 carriers and non-carriers and also in a small longitudinal sample over 3 years. The sample was divided into middle-aged (mean age 50, range 40-59) and older (mean age 69, range 60-84) individuals. Cross-sectionally, we observed that older, but not middle-aged, APOE-ε4 carriers had lower accuracy than ε4 non-carriers, mainly under the hardest discrimination condition. Longitudinally, we observed increases in accuracy in middle-aged APOE-ε4 carriers, suggesting a cognitive phenotype that includes ability to benefit from experience. We observed a longitudinal decrease in older APOE-ε4 carriers, suggesting an AD prodrome.

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.

Evidence from adult psychophysics, brain imaging, and honeybee's behaviour has been reported to support the notion that topological properties are the primitives of visual representation (Chen, 1982 Science 218 699-700). Here, we ask how the sensitivity to topological property might originate during development. Specifically, we tested 1.5- to 6-month-old infants' visual sensitivity for topological versus geometric properties with the forced-choice novelty preference technique. A disk and a ring were used in the topologically different condition (experiment 1), while a disk and a triangle were used in the geometrically different condition (experiment 2). Spontaneous preferences for the disk, the ring, and the triangle were measured pairwise using the preferential looking-time technique (experiment 3). The results showed that infants could reliably discriminate stimuli based on topological differences, but failed to do so with geometric differences. Moreover, in the generalisation task, infants showed higher novelty preference for the topologically different figure (the ring). In addition, the results of both experiments cannot be attributed to a spontaneous preference for the ring or for the disk. Further analysis on individual infants' age and performance revealed two distinct developmental trends. Infants seem to be sensitive to topological differences as young as 1.5 months, while their ability to discriminate geometric differences was at chance before 3 months and gradually improved with age. Taken together, our findings suggested an early sensitivity for topological property, at least for the detection of stimuli with or without a hole.

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.