Scientific Research on
Innovative Areas FY2016-2020Brain and Individuality

Message from Project leader

We know that there are individual differences in behaviors of infants as well as neonates, and even in those of fetuses. During the course of mental and physical development in infancy and toddlerhood, unique characteristics of each individual child become more apparent in the behavior, which would reflect brain function in general. In our research project, we examine how individuality of infants and toddlers emerges and appears in their behavior and brain. Cross-sectional and longitudinal data of spontaneous body movements, structural brain images and spontaneous fluctuations of brain activity will provide us promising clues to answer the question. We also focus on continuity of self in the developing period, which is critically important to form coherent characteristics of a person. Individual differences observed in the pathway of word acquisition is another main theme of the project, and we will tackle the problem by using questionnaires and brain measurements. Based on our findings in the studies of motor behaviors, brain structure, brain function, consciousness and language acquisition, we will propose a possible model of “emergence of individuality” that considers self-organized diversity of individuals, modulation of characteristics by experiences, and the constraints of physical structure.

Message from Project leader

We realize that certain individual differences exist among human beings as well as non-human animals not only biological/physical aspects but also cognitive/behavioral characteristics. However, little evidence-based research has been reported with regard to this problem. The aim of our research project is to find the fundamental dimensions of cognitive/behavioral individuality in humans and its neural/functional basis in the brain. First, we prepare a comprehensive database of multiple measures in psychological/behavioral individual differences, such as cognitive abilities, cognitive styles and behavioral characteristics (personality traits), and construct a fundamental model of individuality. Then, we measure typical individual’s cognitive/behavioral performance as well as monitor brain activation and structure with brain imaging techniques (NIRS, fMRI), and exploring neural basis of individuality through correspondences between cognitive/behavioral characteristics and neural structure/activity in the brain. Additionally, we try to find common features of individuality and its neurological basis in the brain in humans and non-human animals, such as mice based on the conditioning experiments. Our final goal is to link a model of individuality of cognitive/behavioral aspects in humans to those in non-human animals, and find a common biological basis of individuality.

Message from Project leader

Gene expression is affected not only by the DNA sequence but also by epigenetic modifications in DNA and histones around which DNA wraps. Thus, upon considering the variation of individuality, taking the epigenetic differences, in addition to differences in DNA sequence in the individual, into account is critical. We have previously fount that mice prenatally exposed to an anticonvulsant, also known as HDAC inhibitor, vaplroic acid (VPA) show impairments in the hippocampal neurogenesis, resulting in the deficit in learning and memory. These facts are well corresponds to human individuals who were born to epileptic mother with VPA prescription during pregnancy. Since VPA is a HDAC inhibitor which disturbs normal epigenome formation, we hypothesized that the disturbance could be memorized in neural stem cells (NSCs) in the hippocampus, causing the impairments described above. In this project, we aim at verifying the epigenetic memory in NSCs resulted from prenatal VPA exposure and elucidate the link between the epigenetic change and impairments of the brain functions. We also investigate whether the epigenetic memory and the brain functional deficits are modulated by other mice without prenatal VPA exposure, or vise versa, through the social interaction.

Message from Project leader

It is believed that genetic and environmental factors affect the individuality of humans as well as other species. In this project, we approach the genetic issue through analyzing the Autism susceptibility candidate 2 (AUTS2) gene. The AUTS2 protein orchestrates intracellular cytoskeleton contributing to neural network formation, while it also regulates transcription of various genes that are probably important for neural functions. Mutations in this gene cause a variety of psychiatric disorders, such as schizophrenia, autism spectrum disorders, ADHD, depression. In addition, the AUTS2 genome region is genetically very fragile. These facts suggest that a subtle mutation may change a character or individuality of a person, even though the mutation is not severer enough to lead to a psychiatric disease. In this study, we investigate the relationship between the change of individuality/character and AUTS2 mutations by using mouse models.

Evolutionally, AUTS2 is one of the most rapidly changed genome sequences since the bifurcation of Neanderthal and humans. We believe that evolutional change of AUTS2 genome may account for acquiring the human nature, such as higher brain functions. Therefore, we also investigate this gene from such an evolutional point of view.

Message from Project leader

Although mammalian neurogenesis is mostly completed by the perinatal period, new neurons are continuously generated in the subventricular zone of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus. Since the discovery of postnatal/adult neurogenesis, many extensive studies have been performed on various aspects of neurogenesis, including proliferation and fate-specification of adult neural stem cells, and the migration, maturation and synaptic integration of newly born neurons. Furthermore, recent research has shed light on the intensive contribution of postnatal/adult neurogenesis to olfactory-related and hippocampus-mediated brain functions. New neurons are continuously generated in the postnatal mammalian brain, and may contribute to diversity of the brain. In this research project, we will analyze roles of postnatal neurogenesis in the establishment of individuality.

Message from Project leader

The origin of individual can be traced back to fertilization, i.e., fusion of egg and sperm, a stage when the genetic and epigenetic information of the individual is established. We have a great interest how genetic and epigenetic information is transmitted to the next generation. To challenge this issue, we focus on paternal factors that affect specific traits in offspring because maternal factors are more complex and difficult to distinguish transgenerational effect from environmental effect within the uterus. The paternal factors we would like to investigate during this Individuality Project are aging and nutrition. We have paid keen attention to epigenetic changes during spermatogenesis such as DNA methylation and histone modification. We would like to elucidate how epigenetic changes in the sperm influences on gene regulation of the offspring during development and how such changes result in difference in behavior. We also hope that our findings will unveil pathogenesis of neurodevelopmental diseases such as autism spectrum disorder that has been incureased during these decades.

Message from Project leader

During the last decade, rapid progress of technological innovation in the field of life science have emerged. In genome science, reference genome sequence has been determined in the early 2000s, and subsequent exploration of whole genome sequencing have been extensively going on by using the next-generation sequencer (NGS), resulting in existence more than 100K human whole genome data (perhaps more). Moreover, the rise of single cell biology can facilitate the demand of high precision quantitative measurement tools for the transcriptional and epigenetic dynamics of each cell. Similarly, in neuroscience, next-generation of imaging tools have been developed including innovative microscopy methods, CT, MRI, and PET, and we can then decode neural activity, structural/functional brain imaging, molecular dynamics in vivo. Using these innovative technical advances, we aim to develop the high-precision quantitative tools for measuring "individuality," and aim to understand the molecular basis of individuality by the multidisciplinary approach in this project.

Message from Project leader

The aim of the study is to develop a method to explore the neural circuit mechanism that generates individuality in the brain and provide it to other groups that do research in the area of "Kosei-Souhatsu-Nou." One must significantly increase the power and precision of the current measurement methods of the function of neural circuits to detect subtle differences that have led to the emergence of profound variety of individuality. Our strategy to reduce the difficulty in developing such methods is by introducing animal models with a distorted character as test subjects to develop analysis methods. We have already shown that exposure to certain chemicals in the early stage of development can induce an alteration of behavior related to higher brain functions such as learning and memory (Collaboration with Prof. Nakashima and Prof. Tanemura; Stem Cell Rep, 2015). We planned to use such animals as the evaluation axis for individuality. We have observed that the distortion accompanied overall dynamics of neural circuit activity rather than the changes in particular cells and synapses. A method to "see" the changes in neural circuit dynamics would be necessary to measure the shift. We plan to employ a voltage-sensitive dye imaging method to visualize the circuit dynamics (PI: Tominaga). To establish the measurements in neural circuit functions as a change in individuality, we will also employ a comprehensive high-throughput behavior analysis system for mice (Co-PI: Tanemura). Correlating the imaging data and the behavioral profiles of each mouse should reveal the neural basis of the individuality.

Message from Project leader

Data are accumulating rapidly in various scientific fields today. However, it is difficult to extract information concerning individuality just by applying existing analyzing methods to big data because traditional methods tend to focus on typical data rather than outliers.

Mathematical models (or statistical models) play key roles to extract information concerning individuality from big data. Statistical models have various parameters to be adjusted and are more flexible than rigid models such as governing equations in physics, although statistical models are also built by incorporating scientific knowledge.

We formulate data concerning human and animal behavior as superposition of individuality, exterior effects, and additional noises. We extract information concerning individuality from data by using analyzing methods based on the developed mathematical models. Statistically verified models are useful for understanding of underlying phenomena generating observed data.

Message from Project leader

In this team, we are developing a system that can record markerless phenotypes for identifying personality, targeting rodents such as mice. As a phenotype, not only the individual's gait but also 3-dimensional information on other body parts, and social behavior are also in our research scope. The developed system is planned to be used by the other A02 teams and also for international collaborations. The international collaboration support group enhances this activity with the development and operation of a data sharing platform. The international collaboration support group plans to build a large database of rodents’ phonotypes. We are developing data mining algorithms such as self-organization (visualization) of data, clustering, anomaly detection, etc. and a user interface easy for the researcher to use to discover "individuality" in cooperation with researchers and machines. By applying these algorithms to the large database, it is expected that we will discover novel "Individuality" indices. Furthermore, since our system could be applied to human data, we also plan to collaborate with the other A01 teams.