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Project Outline

In the human brain, there are structures that have been conserved through evolution, as well as structures that are unique to only primates, acquired through the enlargement of the cerebral cortex. The clarification of these types of structure and their fundamental brain functions is required to properly understand the normal brain functioning of humans, as well as mental health, and illnesses caused by abnormal brain functioning. Existing research on the operating principles of the brain, however, has suffered from the biases and limitations of information derived from animal experiments. Many were optimistic that the complementary nature of genetic engineering techniques, which focus on rodents and fish, and cognitive neuroscience techniques, which focus on primates, would lead to progress in this area. However, results have been disappointing, with few practical or theoretical connections between these techniques having developed.

One way to get around these difficulties is by studying neural circuits known to be conserved across species, in order to reach a better understanding of the operating principles of these circuits at the molecular level, in simpler model animals. This knowledge can then be used to evaluate whether or not the same principles are conserved in primates and humans, enabling researchers to elucidate the workings of the neural circuits involved and uncover the mechanisms underlying mental illnesses caused by abnormal brain functioning.

The possibility of developing genetically-engineered primates has attracted attention for its potential to connect these various efforts. It was against this backdrop that we succeeded in creating the world's first transgenic marmoset, expanding prospects for new research. Making use of innovative new technologies available nowhere else in the world and employing comparative analysis based on multiple experimental animal systems differing in evolutionary stage, we have set out to clarify operating principles of the neural circuits governing the human mind and the molecular mechanisms that control them.

Strategic Exploitation of Neuro-Genetics for Emergence of the Mind Development into Human Mind

Our aim is to develop a technique for creating genetically engineered marmosets using Knock-In/Knock-Out technologies, in addition to conventional techniques for injecting viruses into fertilized embryos. By combining this technique with the development of cognitive information for marmoset brain analysis, innovative MRI imaging technology and marmoset genetic analysis tools, we aim to create and analyze reporter gene transgenic marmosets, marmosets introduced with human specific genes, and cognitive impairment and mental disorder primate models. We also aim to develop marmoset models suitable for research on human diseases, neurophysiology, cognitive science and higher-order brain function, and in so doing make an innovative contribution to clarifying the biological basis for human intellectual function and the pathology of mental disease.

The neural foundations for the human mind can be understood by observing the distinctiveness among species together with the universal aspects shared across all species. Thus in attempting to clarify the mind through research using animal experiments, we are focusing our research in this project on the level of neural circuits, while at the same time also applying manipulation techniques specifically suited to each of the representative animal species used in the experiments. Neural circuit function intervention is an effective technique in research at the level of neural circuits. The animal species used in our experiments complement each other in this type of research. There is abundant research on rodents, and genetic manipulation techniques for these species are far ahead of those for other mammals. Marmosets, the only primate species amenable to transgenic techniques, are characterized by their rich social behavior. Monkeys from the macaque family of primates have a well-developed cerebral cortex, high homology with humans, and have been the subject of a great deal of research. While creating transgenic macaques is not feasible, the use of viral vectors to inject genes is now a possibility. Research on different animal species 1) enables the sharing of insights on genetic manipulation techniques, and 2) forges a shared path, from hypotheses drawn from brain region homology and experimental results, toward the development of new hypotheses. Together, these efforts serve to clarify universal mechanisms shared across all species as well as particular brain functions that have evolved only in primates.

Significance of the Project

In the human brain, there are structures that have been conserved through evolution, as well as structures that are unique to only primates, acquired through the enlargement of the cerebral cortex. Thus, to properly understand problems in normal brain functioning and mental health, and the illnesses caused by abnormal brain functioning, one must clarify both these structures and the fundamental brain functions involved. Structures conserved through evolution include the basal ganglia, the thalamus and the brain stem, and govern functions such as reward/emotion and memory; the very large cerebral cortex, on the other hand, acquired only in non-human primates and humans, governs functions including tool use, language and self-consciousness. Methods used to analyzing brain function differ in each case: in the former, a reductive approach is adopted based on gene manipulation using models such as genetically-modified fish and rodents, while in the latter the main approach is psychological and involves complex behavior analysis. Very little research has delved down to the level of molecules and cells, and thus contact points between these two approaches have been few and far between.

Recently, however, a connection has finally been made with the success of the team of Hideyuki Okano and Erika Sasaki in creating the world's first transgenic primate using marmosets. This technological breakthrough promises to trigger a huge paradigm shift by enabling researchers to analyze both brain structures that are conserved through evolution as well as brain structures, acquired through the enlargement of the cerebral cortex, that are unique to non-human primates and humans. We are confident that by pursuing this kind of cutting-edge science, which is unparalleled anywhere else in the world, Japan will take the lead in ushering in a new era in brain science.

Project Advisors

  • Takashi Gojobori, Ph.D.,
    (Professor, Center for Information Biology and DNA Data Banks of Japan, National Institute of Genetics)
  • Mariko Hasegawa, Ph.D.,
    (Professor, Hayama Center for Advanced Studies, The Graduate University for Advanced Studies)