Usage of the term Theory of Mind (ToM) has exploded across fields ranging from developmental psychology to social neuroscience and psychiatry research. Yet 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 critically, 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 could be recovered.

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Despite several decades of research, the epigenesis of behavioural and brain lateralization is still elusive, although its knowledge is important in understanding developmental plasticity, function and evolution of lateralization, and its relationship with developmental disorders. Over the last decades, it has become clear that behavioural lateralization is not restricted to humans, but a fundamental principle in the organization of behaviour in vertebrates. This has opened the possibility of extending descriptive studies on human lateralization with descriptive and experimental studies on other vertebrate species. In this review, we therefore explore the evidence for the role of genes and environment on behavioural lateralization in humans and other animals. First, we discuss the predominant genetic models for human handedness, and conclude that their explanatory power alone is not sufficient, leaving, together with ambiguous results from adoption studies and selection experiments in animals, ample opportunity for a role of environmental factors. Next, we discuss the potential influence of such factors, including perinatal asymmetrical perception induced by asymmetrical head position or parental care, and social modulation, both in humans and other vertebrates, presenting some evidence from our own work on the domestic chick. We conclude that both perinatal asymmetrical perception and later social modulation are likely candidates in influencing the degree or strength of lateralization in both humans and other vertebrates. However, in most cases unequivocal evidence for this is lacking and we will point out further avenues for research.

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.maternal immune activation | prenatal stress | sex differences | Cntnap2 | autism A utism spectrum disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders. The core symptoms of ASD are deficits in social communication and social interactions (Diagnostic and Statistical Manual of Mental Disorders V) and one of the most noticeable biological constants in this group of disorders is the sex difference: ∼80% of the children diagnosed with an ASD are boys (1). Many genes have been implicated in the etiologies underlying ASD in humans and ASD-like behavior in animal models. Some of these genes are located on the sex chromosomes and many of these genes may be able to affect other sex-chromosomal genes or may otherwise indirectly lead to sex-specific effects (reviewed in ref.2). However, it seems unlikely that these genes can account for the full sex bias in incidence and it is becoming increasingly clear that environmental factors play a very important role as well (3), and that these factors can interact with one another (2, 4). Moreover, prenatal testosterone (an indirect genetic factor) affects human behavior (5, 6) and may increase the risk to develop an ASD (7).Although today it is commonly proposed that many neurodevelopmental disorders result from interactions between "nature" and "nurture," studies investigating the gene-environment interaction in the development of ASD are scarce.In this study we tested whether an interaction between an ASD-related genetic mutation and an environmental factor may be a...