Project description:Heterozygote advantage, or overdominance, remains a popular and persuasive explanation for the maintenance of genetic variation in natural populations in the face of selection. However, despite being first proposed more than 80 years ago, there remain few examples that fit the criteria for heterozygote advantage, all of which are associated with disease resistance and are maintained only in the presence of disease or other gene-by-environment interaction. Here we report five new examples of heterozygote advantage, based around polymorphisms in the BMP15 and GDF9 genes that affect female fecundity in domesticated sheep and are not reliant on disease for their maintenance. Five separate mutations in these members of the transforming growth factor beta (TGFbeta) superfamily give phenotypes with fitness differentials characteristic of heterozygous advantage. In each case, one copy of the mutant allele increases ovulation rate, and ultimately litter size per ewe lambing, relative to the wildtype. However, homozygous ewes inheriting mutant alleles from both parents have impaired oocyte development and maturation, which results in small undeveloped ovaries and infertility. Using data collected over many years on ovulation rates, litter size, and lambing rates, we have calculated the equilibrium solution for each of these polymorphisms using standard population genetic theory. The predicted equilibrium frequencies obtained for these mutant alleles range from 0.11 to 0.23, which are amongst the highest yet reported for a polymorphism maintained by heterozygote advantage. These are amongst the most frequent and compelling examples of heterozygote advantage yet described and the first documented examples of heterozygote advantage that are not reliant on a disease interaction for their maintenance.
Project description:Cognitive control involves allocating cognitive effort according to internal needs and task demands and the Anterior Cingulate Cortex (ACC) is hypothesized to play a central role in this process. We investigated the neural basis of cognitive control in the ACC of rats performing an adjusting-amount delay discounting task. Decision-making in this this task can be guided by using either a lever-value tracking strategy, requiring a 'resource-based' form of cognitive effort or a lever-biased strategy requiring a 'resistance-based' form of cognitive effort. We found that ACC ensembles always tightly tracked lever value on each trial, indicative of a resource-based control signal. These signals were prevalent in the neural recordings and were influenced by the delay. A shorter delay was associated with devaluing of the immediate option and a longer delay was associated with overvaluing of the immediate option. In addition, ACC theta (6-12Hz) oscillations were observed at the choice point of rats exhibiting a resistance-based strategy. These data provide candidates of neural activity patterns in the ACC that underlie the use of 'resource-based' and 'resistance-based' cognitive effort. Furthermore, these data illustrate how strategies can be engaged under different conditions in individual subjects.
Project description:Dorsolateral prefrontal areas 46 and 10 are involved in distinct aspects of cognition. Area 46 has a key role in working memory tasks, and frontopolar area 10 is recruited in complex multitask operations. Both areas are innervated by the anterior cingulate cortex (ACC), a region associated with emotions and memory but is also important for attentional control through unknown synaptic mechanisms. Here, we found that in rhesus monkeys (Macaca mulatta) most axon terminals labeled from tracers injected into ACC area 32 innervated spines of presumed excitatory neurons, but ?20-30% formed mostly large synapses with dendritic shafts of presumed inhibitory neurons in the upper layers (I-IIIa) of dorsolateral areas 10, 46, and 9. Moreover, area 32 terminals targeted preferentially calbindin and, to a lesser extent, calretinin neurons, which are thought to be inhibitory neurons that modulate the gain of task-relevant activity during working memory tasks. Area 46 was distinguished as a recipient of more (by ?40%) area 32 synapses on putative inhibitory neurons. Area 10 stood apart as recipient of significantly larger (by ?40% in volume) area 32 terminals on spines of putative excitatory neurons. These synaptic specializations suggest that area 32 has complementary roles, potentially enhancing inhibition in area 46 and strengthening excitation in area 10, which may help direct attention to new tasks while temporarily holding in memory another task.
Project description:The primate dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) focus attention on relevant signals and suppress noise in cognitive tasks. However, their synaptic interactions and unique roles in cognitive control are unknown. We report that two distinct pathways to DLPFC area 9, one from the neighboring area 46 and the other from the functionally distinct ACC, similarly innervate excitatory neurons associated with selecting relevant stimuli. However, ACC has more prevalent and larger synapses with inhibitory neurons and preferentially innervates calbindin inhibitory neurons, which reduce noise by inhibiting excitatory neurons. In contrast, area 46 mostly innervates calretinin inhibitory neurons, which disinhibit excitatory neurons. These synaptic specializations suggest that ACC has a greater impact in reducing noise in dorsolateral areas during challenging cognitive tasks involving conflict, error, or reversing decisions, mechanisms that are disrupted in schizophrenia. These observations highlight the unique roles of the DLPFC and ACC in cognitive control.
Project description:Response inhibition, or the suppression of prepotent, but contextually inappropriate behaviors, is essential to adaptive, flexible responding. In autism spectrum disorders (ASD), difficulty inhibiting prepotent behaviors may contribute to restricted, repetitive behavior (RRB). Individuals with ASD consistently show deficient response inhibition while performing antisaccades, which require one to inhibit the prepotent response of looking towards a suddenly appearing stimulus (i.e., a prosaccade), and to substitute a gaze in the opposite direction. Here, we used fMRI to identify the neural correlates of this deficit. We focused on two regions that are critical for saccadic inhibition: the frontal eye field (FEF), the key cortical region for generating volitional saccades, and the dorsal anterior cingulate cortex (dACC), which is thought to exert top-down control on the FEF. We also compared ASD and control groups on the functional connectivity of the dACC and FEF during saccadic performance. In the context of an increased antisaccade error rate, ASD participants showed decreased functional connectivity of the FEF and dACC and decreased inhibition-related activation (based on the contrast of antisaccades and prosaccades) in both regions. Decreased dACC activation correlated with a higher error rate in both groups, consistent with a role in top-down control. Within the ASD group, increased FEF activation and dACC/FEF functional connectivity were associated with more severe RRB. These findings demonstrate functional abnormalities in a circuit critical for volitional ocular motor control in ASD that may contribute to deficient response inhibition and to RRB. More generally, our findings suggest reduced cognitive control over behavior by the dACC in ASD.
Project description:BackgroundSingle nucleotide polymorphisms (SNPs) within the Fat mass and obesity associated (FTO) gene have been linked with increased body weight. However, the data on an association of FTO with cardiovascular diseases remains conflicting. Therefore, we ascertained whether FTO is associated with aortic valve stenosis (AVS), one of the most frequent cardiovascular diseases in the Western world.Methods and findingsIn this population-based case-control study the FTO SNP rs9939609 was analyzed in 300 German patients with AVS and 429 German controls of the KORA survey S4, representing a random population. Blood samples were collected prior to aortic valve replacement in AVS cases and FTO rs9939609 was genotyped via ARMS-PCR. Genotype frequencies differed significantly between AVS cases and KORA controls (p = 0.004). Separate gender-analyses uncovered an association of FTO with AVS exclusively in males; homozygote carriers for the risk-allele (A) had a higher risk to develop AVS (p = 0.017, odds ratio (OR) 1.727; 95% confidence interval (CI) 1.087-2.747, recessive model), whereas heterozygote carriers for the risk-allele showed a lower risk (p = 0.002, OR 0.565, 95% CI 0.384-0.828, overdominant model). After adjustment for multiple co-variables, the odds ratios of heterozygotes remained significant for an association with AVS (p = 0.008, OR 0.565, 95% CI 0.369-0.861).ConclusionsThis study revealed an association of FTO rs9939609 with AVS. Furthermore, this association was restricted to men, with heterozygotes having a significantly lower chance to develop AVS. Lastly, the association between FTO and AVS was independent of BMI and other variables such as diabetes mellitus.
Project description:We investigated afferent inputs from all areas in the frontal cortex (FC) to different subregions in the rostral anterior cingulate cortex (rACC). Using retrograde tracing in macaque monkeys, we quantified projection strength by counting retrogradely labeled cells in each FC area. The projection from different FC regions varied across injection sites in strength, following different spatial patterns. Importantly, a site at the rostral end of the cingulate sulcus stood out as having strong inputs from many areas in diverse FC regions. Moreover, it was at the integrative conjunction of three projection trends across sites. This site marks a connectional hub inside the rACC that integrates FC inputs across functional modalities. Tractography with monkey diffusion magnetic resonance imaging (dMRI) located a similar hub region comparable to the tracing result. Applying the same tractography method to human dMRI data, we demonstrated that a similar hub can be located in the human rACC.
Project description:The dorsal anterior cingulate cortex (dACC) is a core structure for the governing of cognitive control, and recent studies have shown that interindividual differences in dACC anatomy are associated with corresponding differences in the ability for cognitive control. However, individuals differ not only in anatomical features of dACC, but also exhibit substantial variability regarding the biochemical characteristics of the dACC. In this study, we combined magnetic resonance spectroscopy ((1)H-MRS) and functional magnetic resonance imaging (fMRI), finding that interindividual differences of glutamate levels in the dACC during resting-state predict the strength of the blood-oxygen level-dependent (BOLD) response to a task requiring cognitive control. This relationship was observed in the retrosplenial cortex, the orbitofrontal cortex, the inferior parietal lobe, and the basal ganglia. More specifically, individuals with low resting-state glutamate levels in the dACC showed an increased BOLD response when the task demands were high, whereas high-glutamate individuals showed the opposite pattern of an increased BOLD response when the task demands were low. Thus, we show here that individual variability of glutamate levels is directly related to how the brain implements cognitive control.
Project description:Whereas neuroimaging studies of healthy subjects have demonstrated an association between the anterior cingulate cortex (ACC) and cognitive control functions, including response monitoring and error detection, lesion studies are sparse and have produced mixed results. Due to largely normal behavioral test results in two patients with medial prefrontal lesions, a hypothesis has been advanced claiming that the ACC is not involved in cognitive operations. In the current study, two comparably rare patients with unilateral lesions to dorsal medial prefrontal cortex (MPFC) encompassing the ACC were assessed with neuropsychological tests as well as Event-Related Potentials in two experimental paradigms known to engage prefrontal cortex (PFC). These included an auditory Novelty Oddball task and a visual Stop-signal task. Both patients performed normally on the Stroop test but showed reduced performance on tests of learning and memory. Moreover, altered attentional control was reflected in a diminished Novelty P3, whereas the posterior P3b to target stimuli was present in both patients. The error-related negativity, which has been hypothesized to be generated in the ACC, was present in both patients, but alterations of inhibitory behavior were observed. Although interpretative caution is generally called for in single case studies, and the fact that the lesions extended outside the ACC, the findings nevertheless suggest a role for MPFC in cognitive control that is not restricted to error monitoring.
Project description:The persistence of intrapopulation phenotypic variation typically requires some form of balancing selection because drift and directional selection eventually erode genetic variation. Heterozygote advantage remains a classic explanation for the maintenance of genetic variation in the face of selection. However, examples of heterozygote advantage, other than those associated with disease resistance, are rather uncommon. Across most of its distribution, males of the aposematic moth Arctia plantaginis have two hindwing phenotypes determined by a heritable one locus-two allele polymorphism (genotypes: WW/Wy = white morph, yy = yellow morph). Using genotyped moths, we show that the presence of one or two copies of the yellow allele affects several life-history traits. Reproductive output of both males and females and female mating success are negatively affected by two copies of the yellow allele. Females carrying one yellow allele (i.e., Wy) have higher fertility, hatching success, and offspring survival than either homozygote, thus leading to strong heterozygote advantage. Our results indicate strong female contribution especially at the postcopulatory stage in maintaining the color polymorphism. The interplay between heterozygote advantage, yellow allele pleiotropic effect, and morph-specific predation pressure may exert balancing selection on the color locus, suggesting that color polymorphism may be maintained through complex interactions between natural and sexual selection.