Sex-specific gene-environment interactions underlying ASD-like behaviors.

The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.

Etiologies underlying sex differences in Autism Spectrum Disorders.

The male predominance of Autism Spectrum Disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.

Deconstructing and reconstructing theory of mind.

Usage of the term 'theory of mind' (ToM) has exploded across fields ranging from developmental psychology to social neuroscience and psychiatry research. However, its meaning is often vague and inconsistent, its biological bases are a subject of debate, and the methods used to study it are highly heterogeneous. Most crucially, its original definition does not permit easy downward translation to more basic processes such as those studied by behavioral neuroscience, leaving the interpretation of neuroimaging results opaque. We argue for a reformulation of ToM through a systematic two-stage approach, beginning with a deconstruction of the construct into a comprehensive set of basic component processes, followed by a complementary reconstruction from which a scientifically tractable concept of ToM can be recovered.

The relation between handedness indices and reproductive success in a non-industrial society.

The evolution of handedness in human populations has intrigued scientists for decades. However, whether handedness really affects Darwinian fitness is unclear and not yet studied in a non-industrial society where selection pressures on health and handedness are likely to be similar to the situation in which handedness has evolved. We measured both hand preference and asymmetry of hand skill (speed of fine motor control, measured by a pegboard task, and accuracy of throwing), as they measure different aspects of handedness. We investigated the associations between both the direction (left versus right) and strength (the degree to which a certain preference or asymmetry in skill is manifested, independent of the direction) of handedness. We analyzed to what extent these measures predict the number of offspring and self-reported illness in a non-industrial society in Papua, Indonesia. As it is known that body height and fitness are correlated, data on body height was also collected. Due to low numbers of left-handers we could not investigate the associations between direction of hand preference and measures of Darwinian fitness. We found a positive association between strength of asymmetry of hand skill (pegboard) and the number of children men sired. We also found a positive association for men between strength of hand preference and number of children who died within the first three years of life. For women we found no such effects. Our results may indicate that strength of handedness, independent of direction, has fitness implications and that the persistence of the polymorphism in handedness may be ascribed to either balancing selection on strength of asymmetry of hand skill versus strength of hand preference, or sexual antagonistic selection. No relationships between health and handedness were found, perhaps due to disease related selective disappearance of subjects with a specific handedness.

The fighting hypothesis in combat: how well does the fighting hypothesis explain human left-handed minorities?

The strong population bias in hand preference in favor of right-handedness seems to be a typical human trait. An elegant evolutionary hypothesis explaining this trait is the so-called fighting hypothesis that postulates that left-handedness is under frequency-dependent selection. The fighting hypothesis assumes that left-handers, being in the minority because of health issues, are still maintained in the population since they would have a greater chance of winning in fights than right-handers due to a surprise effect. This review critically evaluates the assumptions and evidence for this hypothesis and concludes that some evidence, although consistent with the fighting hypothesis, does not directly support it and may also be interpreted differently. Other supportive data are ambiguous or open for both statistical and theoretical criticism. We conclude that, presently, evidence for the fighting hypothesis is not particularly strong, but that there is little evidence to reject it either. The hypothesis thus remains an intuitively plausible explanation for the persistent left-hand preference in the population. We suggest alternative explanations and several ways forward for obtaining more crucial data for testing this frequently cited hypothesis.

'Winner effect' without winning: unresolved social conflicts increase the probability of winning a subsequent contest in a cichlid fish.

Previous winning experience increases the probability of winning a subsequent contest. However, it is not clear whether winning probability is affected only by the outcome of the contest (winning or losing) or whether fighting experience itself is also sufficient to induce this effect. We investigated this question in the East African cichlid fish Pundamilia spec. To create an unresolved conflict we allowed males to fight their own mirror image prior to a real fight against a size-matched non-mirror-stimulated control male. When males fight their own mirror image, the image's response corresponds to the action of the focal animal, creating symmetrical fighting conditions without the experience of losing or winning. We found that mirror-stimulated males were more likely to win an ensuing contest than control males. Interestingly, in this species mirror stimulation also induced an increase in circulating androgens, which is consistent with the hypothesis that stimulation of these sex steroids during aggressive encounters may prepare the animal for subsequent encounters. Our results suggest that fighting experience alone coupled with an androgen response, increases the likelihood of winning, even in the absence of a winning experience.

Plasticity of lateralization: schooling predicts hand preference but not hand skill asymmetry in a non-industrial society.

Considerable variation in the frequency of left-handedness between cultures has been reported, ranging from 0.5 to 24%. This variation in hand preference may have evolved under natural or cultural selection. It has been suggested that schooling affects handedness but as in most human societies only a selected and minor part of the population does not attend school this is difficult to test. We investigated to what extent schooling affects both hand preference and asymmetry in hand skill in a non-industrial population in the highlands of New Guinea. This provided unique opportunities because of the relatively recent establishment of a primary school in this population, and where people still live a non-industrial traditional life reflecting conditions in which handedness may have evolved. We interviewed 620 inhabitants (aged 5-70 y) to collect demographic data and school history, tested hand preference on 10 ecologically relevant activities, and measured performance of each hand on three tasks (pegboard, grip force, ball throwing). Schooled individuals were overall faster in fine motor performance, had greater grip strength and greater throwing accuracy. This suggests that there is implicit selection on the fitter part of the population to enter school. Schooling is associated with hand preference, as schooled individuals were more likely to be extremely right-handed and less likely to be strongly right-handed, but not with asymmetry of hand skill (controlled for sex and age). Developmental plasticity in hand preference but not skill asymmetry, and the weak correlations between hand preference and hand skill asymmetry indicate that they represent different aspects of brain lateralization. Furthermore, the weak correlations between hand preference and hand skill asymmetry leave room for moderating factors such as schooling, sex and age to have a differential effect on hand preference and hand skill, and each needs to be studied in its own right.