Center for Human-Intelligence Research

Center Director: Hideyuki Okano (Professor, School of Medicine)

Primary Campus: Shinanomachi

Cognitive science, brain science, robotics, society, civilization

■ Activities Continuing from FY2019: Background, Rationale, and Goals

Following the previous fiscal year, the center's groups—"Elucidation from Molecular Biology and Developmental Engineering," "Elucidation from Comparative Cognitive Science," "Elucidation from Brain Science," and "Elucidation from Robotics Engineering"—will work together in unison to broadly explore human intelligence from the molecular to the behavioral level, using approaches not only from the natural sciences but also from the humanities and social sciences. The project items are as follows.

(01) In research on inducing human cognitive evolution through the interaction of environment, genes, and neural activity, we will continue to conduct behavioral and imaging analyses (MRI, PET) using genetically modified marmosets, a primate model of disease, to detect behavioral abnormalities related to psychiatric and neurological disorders from an early stage, and prepare to publish the results.

For items (02) through (07) from the FY2019 Business Report, we will aim to publish them as papers or establish a plan for publication as significant achievements related to human intelligence by the final fiscal year.

(07) In the development of marmoset brain function mapping technology using fMRI, we will analyze in detail the relationship between marmoset gene expression and functionally connected regions.

(08) As part of the development of brain function mapping technology using electron microscopy, we will work on developing a method to visualize neural activity with the world's fastest multi-beam scanning electron microscope.

(09) For cell-type-specific long-term imaging of the marmoset brain using fluorescent calcium imaging technology, we will use an ultra-compact two-gram fluorescence microscope to develop technology for deep brain function mapping in a free-moving environment.

(10) We will conduct correlative analysis using fluorescence and electron microscopy at the center and will compile a paper on the analysis results regarding the characteristic axonal degeneration and localization of early-stage Alzheimer's disease-related molecules in Alzheimer's model mice, using cell/tissue labeling techniques comparable between electron and light microscopy with the world's fastest multi-beam scanning electron microscope.

(11) For postmortem human brain analysis of Alzheimer's disease, we plan to obtain brains from Alzheimer's patients and conduct analyses on axonal degeneration and the localization of early-stage Alzheimer's disease-related molecules.

(12) In the project to clarify the characteristics of human intelligence by comparing the neural mechanisms of spatial cognition in eels with humans, we will identify global cues for spatial cognition and the selection of these cues, as well as consider sensory deprivation and brain lesion effects in fish.

■ New Activity Goals, Content, and Implementation Background for FY2020

The following new items will be initiated from the next fiscal year.

(13) We will conduct research aimed at elucidating the complex motor control mechanisms in the striatum using deep-brain fluorescent calcium imaging technology.

(14) We will induce neural cells from patient-derived iPS cell lines or genome-edited lines and conduct research on reproducing epilepsy-like symptoms in vitro and the pathogenic mechanisms of Alzheimer's disease using human cells.

■ Implementation Details, Research Outcomes, and Degree of Achievement for the Fiscal Year Business Plan

The research outcomes for FY2019 are described for each research item.

(01) In research on inducing human cognitive evolution through the interaction of environment, genes, and neural activity, we are continuing to conduct behavioral analyses, such as sleep behavior, and imaging analyses (MRI, PET) using genetically modified model marmosets for psychiatric and neurological disorders to detect related behavioral abnormalities from an early stage.

(02) In the development of human disease model marmosets, we have conducted histological analysis of transgenic marmosets with forced expression of alpha-synuclein, continuously analyzing early-stage changes in Parkinson's disease. Through analysis to detect disease-related changes early, we were able to identify disease-specific impairments and have submitted a paper.

(03) In the development of transgenic marmosets with human-specific genes, we are conducting phenotype analysis using the brains of mice with modified human-specific genes. In particular, we quantitatively analyzed the thickness of the cerebral cortex, which is specifically enlarged in the human brain. We have also succeeded in creating individual marmoset models with modified human-specific, developmentally important genes and are conducting histological analysis.

(04) In elucidating the neural basis of social behavior through communication, we are proceeding with the creation of autism model marmosets using new genome-editing technology.

(05) In the development of new methods for creating genetically modified primate animals, we have succeeded in increasing the efficiency of gene modification by applying new genome-editing technology to marmoset embryos, and are currently in the process of creating genetically modified individuals.

(06) As a comparative cognitive science study to identify the characteristics of human intelligence, we have developed and are currently analyzing a method for quantitative evaluation using a new system that can analyze marmoset behavior over time as a new behavioral analysis method for experimental animals.

(07) In the development of brain function mapping technology using fMRI, we are applying the fMRI brain function mapping technology conducted in an awake state to perform fMRI analysis on genetically modified animals.

(08) As part of the development of marmoset brain function mapping technology using electron microscopy, we have succeeded in completing a function mapping method by enabling the acquisition of serial section images over a vast area with a multi-beam scanning electron microscope capable of high-speed imaging over an ultra-wide range.

(09) For cell-type-specific long-term imaging of the marmoset brain using fluorescent calcium imaging technology, we have succeeded in visualizing neural activity with fluorescent probes in free-moving marmosets using the recently developed two-gram ultra-compact fluorescence microscope, nVista, and are conducting task-based imaging.

(10) We conducted correlative analysis using fluorescence and electron microscopy at the center. This fiscal year, by applying tissue labeling techniques usable for both electron and light microscopy, we published a paper on some of the results regarding the characteristic axonal degeneration and localization of early-stage Alzheimer's disease-related molecules in Alzheimer's model mice. We are achieving our goals and obtaining results smoothly, generally as planned.

(11) For postmortem human brain analysis of Alzheimer's disease using electron microscopy to analyze axonal degeneration and the localization of early-stage Alzheimer's disease-related molecules in Alzheimer's patients, we contacted the person in charge of the human brain bank, determined the brain regions, prepared the necessary documents, and completed the procedures.

(12) Regarding the experiment to clarify the characteristics of human intelligence by comparing the neural mechanisms of spatial cognition in eels with humans, we established an experimental system for eels and reported the results in the journal *Animal Cognition*.

Number of published papers: 18

01. Tanaka H et al. Nat Commun. 2020 in press.

02. Khazaei M et al. Sci Transl Med. 2020

03. Saeki T, Hosoya M, Shibata S et al. Neurosci Lett. 2020

04. Mohan S et al. J Neuropathol Exp Neurol. 2019

05. Serizawa T et al. Development. 2019

06. Ariyasu D et al. Endocrinology. 2019

07. Hoshino Y et al. Scientific Reports. 2019

08. Li Y, Kanzaki S, Shibata S et al. Neurosci Res. 2019

09. Shibata S, et al. Front Neural Circuits, 2019

10. Kirihara T, et al. iScience 2019

11. Yamazaki Y, Abe Y, Shibata S, et al. J Neurosci. 2019

12. Kinugasa Y, et al. Journal of Cell Science, 2019

13. Abe Y et al. Neurochem Int. 2019

14. Miki F, et al. Biol Reprod. 2019

15. Watanabe,S. Learning and Motivation, 2019

16. Watanabe S & Shinozuka K, Animal Cognition 2020

17. Watanabe S Learning and Behavior (in press)

18. Shigeru Watanabe, "Do Animals Need a Mind? Confronting Anthropomorphism" (University of Tokyo Press)

Number of invited lectures at academic conferences, etc. (domestic and international): (5 domestic, 1 international)

Achievements in social contributions such as events: 3

01. "Brain Gakumon no Susume," World Brain Week 2019, Keio University Shinanomachi Campus (Hosted by the Japan Brain Century Promotion Conference, a tour for high school students and others nationwide where researchers introduce the front lines of brain research), November 2, 2019

02. "Let's Explore the Inside of the Body with the World's Fastest Electron Microscope," Keio University Shinanomachi Campus (Lab tour during the school festival for local residents, high school students, etc.), October 19, 2019

03. Edogawa Library Civic Lecture, "Understanding the Human Mind Through Birds," May 12, 2019

To date, with researchers from the Center for Human-Intelligence Research—established based on the comprehensive agreement between Keio University and RIKEN—at its core, Keio University has been recognized for playing a crucial research role as a member institution in the "Project for Elucidating the Entirety of Brain Function Networks through Innovative Technologies" by the Japan Agency for Medical Research and Development (AMED), which started in FY2014. As a result, a multi-beam scanning electron microscope with 61 beams for the world's fastest wide-area imaging—one of only three such units in regular operation worldwide—was installed at Keio University in 2016, and a state-of-the-art super-resolution fluorescence microscope equipped with 64 detectors was installed at Keio University in FY2017. Various results utilizing these instruments are now being reported. Furthermore, to carry out the project item of cell-type-specific long-term imaging of the marmoset brain using fluorescent calcium imaging technology, the newly developed two-gram ultra-compact fluorescence microscope nVista and the nVoke microscope, which also allows for optical stimulation, were introduced in 2017 and 2018, respectively. An upgrade, including the addition of an autofocus function, was implemented in February 2019. This has made it possible to visualize neural activity in the living primate brain with fluorescent probes and to artificially induce neural activity through optical stimulation, with the results now being prepared for publication.