Health status is affected by not only genetic and environmental factors but also the intrauterine environment. This is the so- called Barker’s hypothesis, which is also known as the fetal origins of adult disease hypothesis. A birth cohort study is one of epidemiological methods to determine whether this hypothesis is true. We are involved not only in the Koshu Project, a regional birth cohort study that has been underway for 24 years, but also in the study titled “Japan Children’s Study,” which is a part of the “Brain- Science and Society” research and development program initiated by the JST RISTEX and the “Eco & Child Study,” which is nickname of the Ministry of the Environment’s Japan Environment and Children’s Study (JECS). On the basis of this experience, we will elaborate on the significance of combination of birth cohort studies and neuroscience research. Several issues face birth cohort studies. First, because the subjects are children in the developmental stages. Second, measuring the sentinel health events that constitute neuroscience- related outcomes requires the development of methods that enable longitudinal measurements in a repeated fashion similar to measurement of height. Third, ethical problems are a major issue facing birth cohort studies.

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For understanding the neural substrate of social interaction, it is crucial to elucidate the developmental processes under which the brain mediates interaction with the environment and the mother, other persons and the physical environment. I discuss important roles of spontaneous activity of the brain and body in the fetus and early infant period.

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The topics about emotion, decision-making and consciousness have been traditionally dealt with humanities and social sciences. However, recent advances in non- invasive neuroimaging techniques (fMRI) and cognitive sciences made these topics hot research areas in neurosciences. The emerging field of social brain research or social neuroscience will greatly contribute to clinical psychiatry. Here, I will introduce our recent interdisciplinary neuroscience approach combining molecular neuroimaging techniques (positron emission tomography : PET), cognitive sciences and economics to understand neural as well as molecular basis of altered decision- making in neuropsychiatric disorders. We found that people with low D1 receptor density in the striatum showed more non- linear probability weighting (more pronounced overestimation of low probabilities and underestimation of high probabilities). We also examined relationship between the degree of loss aversion and noradrenalin transmission by PET. Our finding was that individual with low norepinephrine transporter density in the thalamus tended to be more loss averse. We hope that understanding the molecular mechanism of extreme or impaired decision- making can contribute to the assessment and prevention of neuropsychiatric disorders.

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Much evidence indicates that patients with autism spectrum disorders (ASD) demonstrate marked social dysfunction. However, the etiology is still unknown. We have studied social dysfunctions in youth with high- functioning ASD compared with typically developing participants using functional MRI (fMRI). Firstly, individuals with ASD during self- face evaluation demonstrated relatively low self- related activity in the posterior cingulate cortex, and atypical neural responses to self- faces in the right insula. Dysfunction in these areas could contribute to the lack of self - conscious behaviors in response to self- reflection in ASD individuals. Secondly, when the subjects executed finger gestures and observed the gesture, the congruency effects in the extrastriate body area was reduced in ASD group. The finding suggests that the ASD have dysfunction in the extrastriate body area as a comparator of self and other’s action. Finally, we conducted hyper- scanning functional MRI while the subjects performed real- time joint- attention task. The findings showed that the impairment of joint attention in ASD is related to hypo- function of early visual processing. Furthermore, in ASD patients, a reduced inter- subject synchronization of the right inferior frontal cortex may be related to the difficulty in understanding shared intention through eye contact. These aberrant neuroimaging findings could be social brain marker in ASD.

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Neuroimaging techniques serve as a conduit connecting conventional social sciences and neuroscience by depicting neural substrates of human social behavior, a gateway into basic neuro- scientific investigation conducted from molecular to system level. Targeting the mechanism of breakdown of the socialization, examined is the neural basis of psychiatric disorders using animal models. Research on the neural substrates of the normal and atypical development of the socialization process will benefit from the use of experimental animals sharing common underlying genetic characteristics with psychiatric patients. Animal models will be employed to identify endophenotypes of psychiatric disorders at multiple levels. Imaging science is expected to integrate different levels of information. Knowledge obtained by experimental studies, however, should be tested in social contexts before applied to real- life social situations. Cohort studies are best suited to clarify how social competence develops. Large- scale cohort studies are necessary for in- depth examination of the factors contributing to its development. Combined with cohort studies, the validity of neuro- scientific information is to be tested in actual social contexts using input from other disciplines of human sciences, and the results to be fed back to revise hypotheses. Developmental cohort studies utilizing neuro- scientific findings will provide a suitable arena for such interdisciplinary efforts.

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Autism is the most common neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, impaired communication, and restricted interest or repetitive behavior. Previous studies revealed that several chromosomal abnormalities are contributed to increased risk of autism. Because duplication of human chromosome 15q11- 13 is seen the most frequently in autism patients, we have generated mice with a 6. 3Mb duplication on mouse chromosome 7 that corresponds to human chromosome 15q11- 13. Mice with a paternal duplication (patDp/+) showed the abnormalities in sociality and vocalization, and behavioral inflexibility. In addition, we analyzed the brain of patDp/+ mice, and found some evidences that implicated the abnormality of serotonergic system in these mice. These results suggested that this chromosome- engineered mouse would provide a powerful tool to understand the pathophysiology of autism.

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Social behavior is crucial for our lives in the society. Alterations in social behavior are associated with numerous psychiatric disorders. Chromosome region 7q11.23 is a region whose deletion and duplication are associated with Williams-Beuren syndrome (WBS) and autism spectrum disorders, respectively, both of which show abnormal social behaviors. Therefore, genes in the region are promising candidates responsible for the formation and function of brain circuitry important for social behavior. Genotype-phenotype correlation analyses of individuals with WBS with atypical deletion have narrowed down the genes responsible for their overly friendly behavior and one of the genes is a transcription factor, Gtf2i. We found that Gtf2i heterozygous mice showed increased social behavior, reminiscent of social behavior observed in individuals with WBS. By analyzing genetically modified mice including Gtf2i heterozygous mice and BAC transgenic mice with extra one copy of Gtf2i, behaviorally and molecularly, we hope to gain insights into mechanisms of the formation and function of brain circuitry responsible for social behavior and mechanisms of how alterations in the Gtf2i copy numbers affect the brain circuitry, leading to altered social behavior.

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Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that can induce synaptic maturation through the interaction with presynaptic adhesion molecules called Neurexins (NRXNs). In recent years, mutations, deletions and copy number variations in both NLGNs and NRXNs have been discovered in the patients with autism, indicating that impairment in synapses caused by dysfunction of these molecules may be responsible for autism. To study the relevance between these mutations and autism, we generated knock-in mice recapitulating a mutation of NLGN3 called R451C identified in patients with autism. NLGN3 R451C mice had normal locomotor activities but showed impaired social interaction and enhanced spatial learning and memory in behavioral tests, which are reminiscent of the clinical features of autism. Although numbers and structure of synapses are normal, inhibitory synaptic transmission was significantly enhanced in the pyramidal neurons in somatosensory cortex in the knock-in mice. Administration of GABA blocker, picrotoxin, ameliorated the impaired social interaction suggesting that this can be the cause of the social abnormality. On the other hand, parameters indicating impaired synaptic maturation (enhancement of NMDA/AMPA ratio, NR2B function, and LTP) were observed in CA1 hippocampal pyramidal neurons in the knock-in mice and these are likely enhancing memory ability in the mutants. We speculate that enhancement of inhibitory synaptic function in cortical neurons may also be a result of impaired synaptic maturation and this creates clinical features in some types of autism.

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Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication, with delayed or altered language development, and repetitive and stereotypic behavior. Although the gene-environment interactions are thought to contribute to many case of autism, little is know about these mechanisms. To understand the gene-environment interactions in autism, we focused to analyze Secretin (Sct) and secretin receptor (Sctr) deficient mice. Sct is a member of the secretin/VIP/glucagon peptide hormone family, and Sctr is a G-protein coupled receptor. Several clinical trials on Sct administration report neurobehavioral improvement in autism and schizophrenia although the results of these trials remain controversial. Sct and Sctr deficient mice showed abnormal autism-related social and repetitive behavior with impaired synaptic plasticity in hippocampus. In addition, the mutant mice exhibited mildly diminished survival of neural progenitor cells/immature neurons. Furthermore, we identified secretin signal plays a neuroprotective role of neuronal progenitor cells against the neurotoxicity of ethanol. Our data demonstrate that Sct and Sctr mutant mice are useful animal models of autism and could identify the environ-mental risk factors that develop autismrelated phenotypes. Knowing the gene-environment interactions in neuropsychological development will shed light on the molecular mechanism of autism and potentially point toward therapeutic strategies.

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