Brain imaging data have repeatedly shown that the anterior cingulate cortex is an important node in the brain network mediating conflict. We previously reported that polymorphisms in dopamine receptor (DRD4) and monoamine oxidase A (MAOA) genes showed significant associations with efficiency of handling conflict as measured by reaction time differences in the Attention Network Test (ANT). To examine whether this genetic variation might contribute to differences in brain activation within the anterior cingulate cortex, we genotyped 16 subjects for the DRD4 and MAOA genes who had been scanned during the ANT. In each of the two genes previously associated with more efficient handling of conflict in reaction time experiments, we found a polymorphism in which persons with the allele associated with better behavioral performance showed significantly more activation in the anterior cingulate while performing the ANT than those with the allele associated with worse performance. The results demonstrate how genetic differences among individuals can be linked to individual differences in neuromodulators and in the efficiency of the operation of an appropriate attentional network.A popular theory of cognitive control suggests that the dorsal anterior cingulate is part of a network involved in handling conflict between neural areas (1, 2). In support of this general idea, a number of neuroimaging studies have shown activation of the dorsal anterior cingulate in tasks requiring people to respond to one dimension of a stimulus rather than a strong conflicting dimension (1-3). One task in which this has been found (1, 4) involves the person responding to the direction of a central arrow when flanking arrows could point either in the same (congruent) or the opposite (incongruent) direction.The Attention Network Test (ANT) uses the flanker task to measure conflict and shows strong activation in the dorsal anterior cingulate (4, 5). Because the cingulate is modulated by the ventral tegmental dopamine system (6-8), we previously tested 200 normal persons with the ANT and genotyped them for a number of genes related to the dopamine system (9). We found polymorphisms in two genes were significantly related to the efficiency of conflict. These were the dopamine D4 receptor gene (DRD4) and monoamine oxidase a (MAOA) genes.In the current study, we ran 16 unselected normal subjects on the ANT with event-related functional MRI (fMRI). We collected cheek cells to search for polymorphisms in the two genes which we previously found to be related to performance on the conflict network of the ANT (9). We considered only alleles possessed by at least six of our subjects, and which we thought might influence dopamine modulation within the conflict network. There were sufficient data to test one such polymorphism in each of the two previously identified genes. One of these is a 30-bp repeat polymorphism in the promoter of the MAOA gene. The other is a single-nucleotide insertion͞deletion polymorphism in the 5Ј region of the DRD4 gene.One of the a...

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Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post synaptic density 95 (PSD-95). Here we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number, and post-synaptic density size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.

Conclusion: This study solidifies the concept that both HQG and PR produce positive effects on subjective symptoms and functions among COPD patients, and also provided evidence that HQG can induce additional effects compared to conventional PR.