Scientific Research on
Innovative Areas FY2016-2020Brain and Individuality

Message from Project leader

It has been suggested that the evolution of human specific social behavior and cognitive ability had caused psychiatric disorders. On the other hand, in many cases, these psychiatric disorders-relevant genes show allelic polymorphisms, which could contribute to a human personality. Thus, we focus on psychiatric disorders-relevant genes which have been subject to positive natural selection through evolutionary lineages from nonhuman species and these genes in which allelic polymorphisms are maintained by balancing selection in the present human population. We could understand the mechanisms of the evolution of human mental personality by examining the cause of maintenance of these alleles and the effect of the allelic differences on mental differences.

Our previous study showed that VMAT1 could be detected as a positively selected gene in human lineage. Among them, VMAT1, vesicular monoamine transporter 1, is particularly interesting since it has a human-unique polymorphism (Thr/Ile) in the 136th amino acid site compared to other mammals (Asn). This, in this project, we will try to examine the cause of the maintenance of polymorphism of VMAT1 by using Tohoku Megabank database for genomic and mental condition data. In addition, we will examine the phenotypic effects of this allelic polymorphism by creating genome editing mice.

Message from Project leader

The aims of our study are first to predict neurodevelopmental outcome by sulcal variations on MRI at term age, and second to clarify the association between sulcal pattern and perinatal variables in children born preterm.

Message from Project leader

In 1980s, in terms of the epistemology of disability, medical models that bring persons with disabilities closer to the majority was replaced by social models that aim to realize a social environment that includes diverse individualities. In recent years, ASD research based on the viewpoint of users and social model has gradually appeared. Based on the perspective of users and the social model, we have also investigated the individualities that hardly change even if the social environment changes, and clarified the communication style which is easy for ASD to participate in, by the unique approach called “tojisha-kenkyu (user-led study)”. In this project, in order to realize the platform of participatory research on ASD, or “co-production of research” (Nature 2018) of ASD, we will A. establish a training program for tojisha-kenkyu, B. enhance mutual critique between tojisha-kenkyu and academic research, and C. conduct Japanese-UK comparative research on ASD.

Message from Project leader

I have been interested in sophisticated human brain mechanisms allowing flexible adaptation to changing environments, and have examined individual differences in the relationships between behavioral characteristics and brain functions. In order to individually predict behavioral profile and elucidate underlying brain mechanisms, the current project aims to develop individualized brain mapping technique. In particular, a predictor of behavioral profile is developed by learning open resource big data of behavioral measures and functional brain images. Then, for out-sample individuals with their data collected independently, the predictor predicts behavioral characteristics and identifies underlying brain mechanisms. As such, the current technique may provide a novel approach to individualize functional mapping of the human brain.

Message from Project leader

Microexon are about 3-27 nt long short exons and alternative splicing of them results in short insertions or deletions in the amino acid sequence of protein and changes in protein function. Some of the microexons are alternatively spliced in neurons in a developmental-stage specific manner and misregulation of them is reportedly associated with neuropsychiatric diseases, such as autism. However, previous studies did not focus on the effects of genomic variations on splicing of microexons, variations in alternative splicing patterns of microexons among single cells, or the effects of stability of protein structure and protein-protein interactions. By taking advantage of recent genome and transcriptome sequencing data and protein structure data, we perform a multi-layer analysis from genome through transcriptome and protein structure to phenotype focused on microexons and contribute to filling the gap between genome and personality.

Message from Collaborator

Individual difference in cognitive functions must be underpinned by variation in neural networks of each subject. We aim to find neural bases of individual differences in cognition by electrocortical stimulation mapping and selective Wada testing in patients with intractable epilepsy. These methods are the gold standard to determine intra-hemispheric localization of cognitive functions. The location of eloquent areas must be identified in the individual patient, with the goal of sparing these regions from resection. Epilepsy surgery offers the opportunity for thorough examination prior to resection, enabling within-subject, pre- and postoperative comparisons.

Message from Project leader

The aim of our laboratory is to elucidate the biological basis of human prosocial behavior. In this project, we examine how the methylation level of the oxytocin receptor gene (OXTR) affects individual differences in prosocial behavior. In addition, we examine what social environmental factors regulate the methylation of the oxytocin receptor gene.

Message from Project leader

Schizophrenia is a commonly occurring psychiatric disorder characterized by positive symptoms, negative symptoms and cognitive dysfunction. Currently, much remains unknown about the details of the molecular and cellular etiology of this disorder. Furthermore, given that many patients still fail to achieve sufficient　remission after current drug medications, including clozapine treatment, there is a need for new drugs based on new molecular mechanisms. To achieve this, it is important to identify the molecular mechanisms behind the inter-individual　variability of response to antipsychotics. In this project, we employ the induced pluripotent stem cell-related technologies to identify the molecular mechanisms behind the inter-individual variability of response to clozapine as well as individual differences of neural functions.

Message from Project leader

The purpose of this study is to establish reliable measures for animal personality and compare them across species. In several animal species we plan to identify fundamental dimensions of individual differences in behavior based on data such as behavior observations and ratings. We will also apply the same methods of measuring personality to humans. This will enable us to extract dimensions common to personality differences in humans and animals. By obtaining molecular markers that may be related to personality, i.e., genotypes and hormone levels, we will pursue three topics: 1) the comparison of different ways of assessing personality, 2) the comparison of the relationships between personality and the markers, and 3) identifying a common model of personality across species.

Message from Project leader

In this study, we will elucidate neuro-cognitive basis of individuality of the embodiment, which is linked to be each speciality and inaptness in daily life. From previous our studies, touch perception could not be allocated outside the body in part of individuals with autism spectrum disorder (ASD), and the embodiment of tools tend to be difficult in them. Thus, cognitive style of the embodiment, as a kind of individuality, might be linked to speciality and inaptness about tool use or ball games in daily life. However, it doesn’t mean simple categories such as ASD and the others, because we have observed large individual differences in various experiments. That is, neurodiversity related to sensorimotor processing about the body seems to produce individuality of the embodiment. In this study, we will investigate the sensorimotor systems that are connected to the individuality of the embodiment by using psychophysics, neuroimaging and interviews.

Message from Project leader

It is commonly accepted that genetic and environmental factors establish “individuality.” However, there are a few tools and technologies available to elucidate individuality. We will establish molecular and neural bases to define individuality of spatial pattern separation using model mice and evaluate environmental factors to influence pattern separation.

Message from Project leader

Stressful events during adulthood are potent adverse environmental factors that can predispose individuals to psychiatric disorders, including depression; however, many individuals exposed to stressful events can adapt and function normally. Thus, individuals exposed to chronic stress display wide-ranging, heterogeneous responses. While stress susceptibility may influence depression, the molecular mechanisms underlying the susceptibility and resilience to chronic stress within the brain remain to be elucidated. In this study, we focus on the epigenetic regulation of gene transcription as a key mechanism underlying individual differences in stress susceptibility.

Message from Project leader

From our current work, it is suggested that whole image of an episodic memory is represented as orchestrated activities of cell ensembles in brain. However, it remains unclear whether the ensemble representation is specific to each individual subject. To address brain individuality of cognitive function, we will propose to project preference of cognitive information in each subject by cell ensemble activities during episodic memory processing.

Message from Project leader

Social interactions such as parent-child interaction and sexual interaction, have fundamental effects on the development of animal personality. As in group-living vertebrates, social insects such as ants and bees often develop behavioral variation based on social interactions. Interestingly, such behavioral variation is considered to be functional in colony-level activities. We focus on the behavioral variability of ants in this project. First, we quantify social interaction and behavioral variability among nest-mates using the automated behavioral tracking. Second, molecular basis of behavioral variation is analyzed by examining the brain gene expression patterns. We will try to integrate the ultimate and proximate factors and that generate the personality and social organization.

Message from Project leader

Individuality is created by molecules that are responsible for formation of specific neural circuits. We are focusing on clustered protocadherins (Pcdh) as a candidate for individuality creator. In this study, we are addressing following questions using fluorescent protein knock-in mice: (a) Quantification of Pcdh dynamism, (b) Identifying underlying mechanism of Pcdh expression, (c) Analyzing relationship between Pcdh dynamism and the individuality modulation. These experiments will answer how to modulate individuality.

Message from Project leader

Courtship ultrasonic vocalizations (USVs) of male mice have been well documented and are thought to have an important role in male-female communication, functioning as a type of sexual behavior known as precopulatory behavior. Since the recent discovery of their song-like structure, USVs have attracted numerous research interest (Holy and Guo, PLOS Biol, 2005). USVs have often been used to study biolinguistics, social behaviors, vocal communication, and disorders that involve abnormalities in social behavior, especially autism spectrum disorders (ASDs).
Because singing in some songbirds is acquired by vocal learning, it was hypothesized that a similar learning process may occur in mice; however, several studies revealed that vocalizations in mice are mainly determined genetically. Mice use specific call types depending on their genetic strain. However, we observed that the number of calls and types of call repertories differ among individual mice, even among mice from the same inbred strain, such as C57BL/6. We are now focusing on the individuality observed in mouse vocalizations and the neural and hormonal mechanisms underlying this process.

Message from Project leader

Social discrimination is an essential and basic component of social behaviors. However, mechanisms controlling social discrimination still remain unclear. In this study, we will try to identify neural circuits controlling social discrimination and understand mechanisms of social discrimination at the cellular and molecular levels in mice. Furthermore, we will try to understand brain systems to generate individuality from the view of social behaviors.

Message from Project leader

Spermatogonial stem cells are the only stem cells in the gremline that have self-renewal potential. We have succeeded in genetically modifying the male germline using cultured SSCs, designated as gremline stem (GS) cells.This technology based on GS cells and spermatogonial transplantation provides an alternative approach in genetic manipulation of many animal species, in which conventional ES cell-based approach is not applicable (Nat Med 19: 958, 2013; Neuron 86: 617, 2015; A 19: 1124, 2016).

On the other hand, the impact of manipulating SSCs on the health of offspring has not been analyzed to date. Recent studies suggest several lines of evidence regarding the epigenetic inheritance. Given such new studies, it is possible that offspring derived from transplantation of genetically manipulated GS cells may not be normal, which may become an important impediment for future application of this technology to other animal species.
In this project, we will perform behavioral analysis of offspring derived from cultured SSCs and assess the impact of GS cell culture on the next generation.

Message from Project leader

Social contact to the conspecifics is essential for building personal relationships, and it elicits stress responses such as increased heart rate and expression of positive and negative emotion. To understand the diversity in interpersonal distance, it is important to focus on the individual difference in emotional responses. NPBWR1, a receptor binds with neuropeptide B/W has reported to be involved in fear, autonomic response and social behavior. Investigating the physiological role of NPBWR1 and neural circuit it governs could reveal the individual difference in emotional response which affects interpersonal distance to regulate social contact.

Message from Project leader

Many animals, including man, live in groups. They socially interact with each other, establish long-term relationships between individuals, and form a complicated social network. Here we define “social individuality” as social behavioral traits, including the position in the social hierarchy and the social role, that are acquired through social interactions. In this project, using a new tracking system that allows us to monitor mouse social behavior over several days and neuroscientific techniques such as optogenetic and chemogenetic tools that allow us to manipulate neuronal activities of a specific cell type in a reversible manner, we will test the hypothesis that a history of social interactions shapes “social individuality”. Specifically, we will examine the role of oxytocin on the emergence of “social individuality”.

Message from Project leader

We humans are inherently social and therefore our behaviors are modulated by rewards not only to oneself (self-rewards) but also to others (other-rewards). The degree of behavioral modulation varies across individuals, which could be attributed to variable degree of sensitivity in response to other-rewards. Our previous study using monkeys unraveled the neural representation and computation of self- and other-rewards in the brain (Noritake et al., 2018); (1) the self-reward information and other-reward information were monitored in different subpopulations in the medial prefrontal cortex (MPFC), a core node in the processing of social information; (2) a subjective reward (anintegration of self- and other-rewards) was encoded in the dopaminergic (DA) midbrain nuclei, a crucial node in the processing of reward information; and (3) a causal analysis of local field potentials revealed that the neuronal information flow was predominantly from the MPFC to the DA midbrain nuclei, suggesting the computation of subjective rewards as an integration of self- and other-rewards. However, it remains to be answered what neural substrates cause such individual variability in sensitivity to other-rewards. The proposed study extends our previous findings by investigating how the neuronal modulations in the MPFC and the DA midbrain nuclei reflect individual differences in sensitivity to other-rewards. Further, we hypothesize that the processing of other-rewards is impaired in autistic individuals, and hence focus on neural differences between monkeys with normal development and monkeys with an autistic phenotype. Our study has potential to elucidate the neural mechanisms underlying individual differences in sensitivity to other-rewards and to bridge a gap between the microscopic mechanism (molecular and genetic studies using rodents) and the macroscopic understanding (behavioral, cognitive, and brain functional imaging studies in humans).

Message from Collaborator

Although one of the criteria for classification of long non-coding RNA is that no ORF should encode more than 100 amino acids, short predicted ORFs (less than 100 amino acids) can be found in many lncRNA molecules. Recently, we have identified a set of novel polypeptides that are expressed from short predicted ORFs within putative lncRNAs by mass-spectrometry, and found the biological functions for one of the polypeptides [Matsumoto et al., Nature 541: 228-232 (2017)].
We have identified more novel polypeptides by applying in silico approach. Interestingly, many of the polypeptides specifically expressed in the brain, and exist only in mammals. We thus hypothesized that these brain- and mammal-specific polypeptides are required for higher brain functions and the formation of individual differences.

Message from Project leader

We aim at elucidating how genetic and environmental factors shape male sexual orientation in the fruit fly Drosophila, with special reference to the social-experience-dependent plasticity in neurons.

Message from Project leader

The boldness and the shyness were studied as personality traits in many animals from insects to mammalians. However, the gene regulating this personality have not been identified in any species. To address this issue, we did the open-field test and measured boldness among several novel closed-colony medaka established from wild population in western Setouchi area. The greatest difference in the boldness was detected between two population, #1 and #2. Therefore, using these medaka, we aim to find novel gene required for emerging individuality of the boldness. As the genome size of medaka is only a quarter of those of mice and humans, we expect that it is easier to identify such genes in medaka than in mammalians. Our study may shed light on the evolutional origin of molecular/neural basis underlying individual differences in the boldness.

Message from Project leader

Individual differences in vocal learning ability are widely acknowledged, yet little is known about the factors that underlie them. Learning is influenced by not only the environment but also the genetical feature in individuals. Although offspring carry two chromosomal sets from two-parents, which are not sequentially identical, recently, increasing evidences point the existence of uneven parental genomic contribution to the offspring’s phenotypic development. However, it remains unknown how two-parental genetic features interact and further affect offspring’s learning. Here we investigate the parental genetic contribution to offspring’s vocal learning using hybrid songbirds, of which two-parental species produce distinctive species-specific songs.

Message from Project leader

Recently, epitranscriptomics, a term representing >150 natural RNA modifications in all life domains and their regulation have come into intense research focus as a largely unexplored post-transcriptional regulatory mechanism. In this project, we will utilize a rich toolbox including the most advanced RNA modification detection methods with next-generation sequencing techniques, bioinformatics, biochemical analysis, cell biology, transgenic techniques, and behavior analysis, to identify a new mechanistic interface between genes and experience, to understand the emergence of cognitive individual differences.

Message from Project leader

The development of the personality of an animal is influenced both by intrinsic and extrinsic factors. Transcription factors regulate the expression of the genetic information according to postnatal experience, thus, may function as a molecular hub to integrate the influence of intrinsic and extrinsic factors. Through using the original method that allows quantitative analysis of the activity of the transcription factors in the brain, this research aims to reveal the mechanisms that affect the development of personalities in animals.

Message from Project leader

For our integrative research project toward understanding individuality, model animals play an essential role to examine the effects of changes in genetic/environmental factors on brain activity and behavior. We focus on a peptide hormone, oxytocin, and manipulate its receptor gene in mouse brains via CRISPR/Cas9 genome editing technology to elucidate the relationship between individual genetic variations and social behavior. We also share our genome editing techniques with the group members by rapidly generating genome-edited mouse models.

Message from Project leader

Substantial individual differences in behavioral tendency have been observed in wide-range of animal species as well as in humans. Recently, such behavioral individuality is reported to emerge even with identical genetic and environmental conditions. In addition, there are often qualitative, rather than quantitative, individual differences in behavioral tendencies. In this project, we investigate the adaptive function of such behavioral individuality through theoretical consideration based on mathematical modeling of behavior and evolution.

Message from Project leader

Recent advances in non-invasive neuroimaging reveal some relationships between ‘individuality' of human brain and behavioral characteristics and psychological traits. However, at present, it is not easy to approach neural bases behind human personality from such indirect measurements of brain activities. In this project, we will further develop machine learning methods to extract latent components of brain activities for two neuroimaging data: electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI). Through the analyses of the latent structures obtained by the developed methods from EEG Microstates and fMRI Common Neural Modes shared among varous brain states, we aim at creating a novel ‘individuality'index based on neuroimaging data.

Message from Project leader

As a new technique to elucidate the mechanism of individuality formation, we will develop an imaging method to observe synaptic activity of neurons during postnatal developmental period.

Message from Project leader

Stress-induced responses in animals considerably differ across individuals. We are studying how cortical-wide functional correlations are associated with such individual differences in stress-induced dysfunctions of the peripheral organs. We expect the evidence will advance the understanding of the neurophysiological correlates of mind-body associations in health and disease from the viewpoint of individual differences.

Message from Project leader

Chronic stress exposure is one of the risk factor for depression; however, vulnerability to stress differs among individuals and its neuronal mechanisms are less understood. Although the neuronal phenotypes and mechanisms underlying stress-resiliency have been identified using animal models after chronic stress exposure, it is unknown whether or how the potential difference of brain function before stress exposure contributes to acquisition of stress-resiliency. The goal of this study is to develop an imaging and analysis method to investigate correlation relationships between individual differences of neuronal activity before stress exposure and depression-like behavior after chronic stress exposure. To achieve this, we employ our whole-brain microscopic imaging technology: FAST (block-FAce Serial microscopy Tomography) to obtain the whole-brain activation data at single cell level, and explore the brain regions contributing to individual differences of stress resilience.