BRAIN RESEARCH INSTITUTENIIGATA UNIVERSITY 2020

Message from the Director

BRI in the time of coronavirus
Osamu Onodera
Director, Brain Research Institute, Niigata University
My name is Osamu Onodera, BRI professor of Neurology. I became anew director in February 2020. The coronavirus pandemic emerged
shortly after my appointment and we have been struggling to deal
with various issues arise from the pandemic ever since. I imagine wewill have to live with the coronavirus for the next few years at least.
Additionally, there seems to be no going back to a previous lifestyle
from a new normal. For better or worse, we have come to acknowledge many things in the unprecedented
experience. One is the concept of higher education. After experiencing the pandemic time, there will be aparadigm shift in the perceptions of those receiving higher education. Until now, universities have provided
a physical space for education and screened those who enter the place. But the online classes, swiftly
implemented in response to the pandemic, have virtually eliminated the limitations of the physical space on
their own. This is nothing less than the unprotected exposure of higher education, which has been secured by
the physical element of space, to the world. There is a big change that will allow students to choose any classin the world. In an age where automatic translation is possible, language barriers are no longer an issue. It’sa huge upheaval for learners. When the education providers lose the superiority of the physical space, what
can the providers use as a source of strength to maintain its form?
The nature of our learning is called into question in such a time. In this context, I believe that the importanceof learning that shares the space in which we get together will become even more important. In the newnormal, there may be an even greater screening for the education with which we share the space.
In recent neuroscience research, large-scale analysis has become the mainstream and the in-situ nature ofresearch is being lost. While some suggest building a virtual form of research like network-based laboratories,
a standard form of physically constrained institute may need to change. However, the traditional idea still
exists in me, which genuine discoveries and excitements are nurtured in the context of the physical space. I
believe that the greatest advantage of the institute is that it provides a “place” of chaos, a space for learning.
In a post-pandemic world, the way the institute is run and the way it is taught could change drastically. We
will be assessed in such a situation. I think the nature of the importance of people gathering closer to haveacademic discussion won’t go away in any era. As a research institute of brain, we will make an effort todevelop such a space in the new academic system of the post-coronavirus era.

HistoryMEXT Joint Usage / Research Center
The Collaborative Research Center for Brain Diseases
Utilizing Neuropathological Resources
BRI was certified as a joint usage/research center by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in 2010. Our extensive collection of brain
disease materials and expertise have been open to the neuroscientists' community inJapan. BRI's diverse joint researches in neuropathology and related fields have brought
out a great deal of achievement in relation to unravelling the pathological mechanismof brain disease. Given the MEXT's recognition for such achievements, BRI has renewed
the certification of a joint usage/research center in FY 2016.
BRI has the world-class collections of neuropathological specimens and advanced
imaging analysis technique. BRI is committed to tackling tasks such as neuropathological analysis on brain disorders like Alzheimer's disease, development of early diagnostic technique, and translational research on the treatment for reducing disease progression.
By utilizing the specimens of human brain disease and the animal model resources along with the underpinning of translational researchfor clinical application, BRI's collaboration with researchers across the world offers a prospect of reducing the burden of intractable neurological disease. Expected outcomes include the followings: to shed light on the disease pathology, to establish early imaging diagnostics, and to discover new treatment that slows disease progression.

Major Research Projects
Drug discovery for Alzheimer’s disease(MEXT Joint Usage / Research Center reinforcement project)
20 years of research efforts at Center for Integrated Human Brain Science has successfully developed non-invasive imaging method for preclinical diagnosis of Alzheimer’s disease (AD), and has also demonstrated that
disturbance in aquaporin-4 (AQP4) functionality, whichhinders proper clearance of β-amyloid, plays a significant
role in the pathogenesis of AD. The project aims to apply
such a developed diagnostic technique in preventing AD:
together with establishing an early diagnostic method for
AD using magnetic resonance imaging (MRI) and positronemission tomography (PET), the project will target discovery of the new drug designed to modulate AQP4 function
and prevent impairment in clearance of β-amyloid.

Clinical research promotion project for neurologicaldisease by establishing the system neuropathology:
Establishing a platform for clinical research utilizing
neuropathological resources (MEXT education and research
activities project)
In therapeutic research of brain disease, the diagnostics bound by
the traditional theory of localization of brain function appears nolonger sufficient. In order to overcome brain disease, there has been
an increasing demand for a new academic discipline, which allows
us to understand brain disease in accordance with the functional
connectivity of each part of the brain. Niigata University launcheda project aimed at setting a new pathological assessment method,naming such neuropathology as “System Pathology for Neurological
Disorders.” Conducting interventional trials based on the knowledge will pave a way to overcome brain disease. Connecting thecollective expertise in brain at BRI, a number of research projects
on neurology at School of Medicine and the medical care system at
University Hospital together, the project aims to ensure a seamless
environment that will readily translate basic scientific findings into
therapeutic interventions for patients. The project seeks to launch aclinical research center, which will serve for translational research on
brain disease.

Organization
Basic Neuroscience Branch

As of July 1 2020

Dept. of Molecular Neurobiology
Dept. of Brain Tumor Biology
Dept. of Cellular Neuropathology

Dept. of System Pathology for
Neurological Disorders
Pathological Neuroscience
BranchDept. of Pathology
Dept. of Molecular Pathology

Clinical Neuroscience Branch

Dept. of Neurosurgery

Dept. of Neurology

Center for Integrated Human
Brain Science

Dept. of Integrated Neuroscience
Dept. of Biological Magnetic
Resonance
Dept. of Functional Neurology &Neurosurgery

Center for
Bioresoucebased
Researches

Bioresource
Dept. of Molecular Genetics
Science Branch
Dept. of Comparative & Experimental
MedicineProf.

Hiroyuki Nawa

Assist. Prof.

Hisaaki Namba

Assoc. Prof

Nobuyuki Takei

Assist. Prof

Yuriko Iwakura

Prof.
Assoc. Prof.

Motokazu Uchigashima

Assist. Prof.

Hitoshi Uchida

Prof.

Kazuki Tainaka

Prof.

Masaki Ueno

Prof.

Akiyoshi Kakita

Assoc. Prof.

Hiroshi Shimizu

Prof.

Brain Science
BranchDept. of Pathology Neuroscience

Dept. of Molecular Neuroscience

Fumiaki MoriProf.

Yukihiko Fujii

Assoc. Prof.

Makoto Oishi

Assist. Prof.

Tetsuya Hiraishi

Assist. Prof.

Manabu Natsumeda
Osamu Onodera

Prof.
Assoc. Prof.

Masato Kanazawa

Assist. Prof.

Takuya Konno

Assoc. Prof.

Hitoshi Matsuzawa

Prof.

Hironaka Igarashi

Assist. Prof.

Masaki Watanabe

Assoc. Prof.

Yuji Suzuki

Assoc. Prof.

Ken-ichi Yamada

Assist. Prof.

Satoshi Ueki

Prof.

Dept. of Translational ResearchTakeshi Ikeuchi

Assoc. Prof.

Akinori Miyashita

Assist. Prof.

Kensaku Kasuga

Prof.
LecturerProf.

Toshikuni Sasaoka
Nanaho Fukuda
Kanako Oda
Toshikuni Sasaoka

Assoc. Prof.

Manabu Abe

Assist. Prof.

Ena Nakatsukasa
Akiyoshi Kakita

Prof.
Assoc. Prof.

Mari Tada

Assist. Prof.

Rie Saito

Prof.
Assist. Prof.

Dept. of Neuroscience of Disease

Koichi Wakabayashi

Assoc. Prof.

Assist. Prof.

Dept. of Animal Model Development

Takayasu Mikuni

Osamu Onodera
Akihiro Sugai

Prof.

Hideaki Matsui

Assoc. Prof.

Ryuichi Hishida

Assoc. Prof.

Atsushi Sugie

Assoc. Prof.

Kouichirou OkamotoDept. of Molecular Neurobiology
Neurons and glial cells communicate to each other not only via neurotransmitters
but also using various bioactive proteins, namely neurotrophic factors andcytokines. Our long-term objective is to elucidate the molecular and pathologic
mechanisms of how these bioactive proteins regulate brain development
or perturb neural functions related with neuropsychiatric diseases. We haveestablished animal models for schizophrenia by perturbation of cytokine
signals during neonatal development. Using these models, we aim to clarify

Prof.
Hiroyuki Nawa

neuropathological and therapeutic mechanisms of the disease. Our efforts
have been paid to the following projects: (1) the molecular and systemneuropathology of schizophrenia and its animal modeling (hallucination,
auditory-evoked potential, social withdrawal), (2) the cytokine-dependent regulation of monoaminergic development
and function (EGF, NRG1, EGFR, ErbB4), and (3) the specificity and functionality of the intracellular signaling driven
by these bioactive proteins and their possibility as therapeutic targets for schizophrenia. Currently we are addressingthese questions employing all types of biological approaches including molecular genetic, biochemical, cell biological,
electrophysiological, pharmacological, and behavioral tools and techniques. We hope these studies will lead to theunderstanding of how bioactive factors control the onset and progression of developmental brain diseases such as
schizophrenia, which might hint at developing new drugs.

Dept. of Cellular Neuropathology
Our goal is to understand the physiology and pathophysiology of thebrain at the cellular and molecular levels. We established “SLENDR”,
a technique based on in vivo genome editing, to image endogenous
proteins with high specificity, resolution and contrast in single cells
in mammalian brain tissue (Cell, 2016). In addition, we recently
developed “vSLENDR”, a genome editing method to target virtually
any cell-types, areas and ages across the brain, widely expanding theProf.
Takayasu Mikuni

applicability of genome engineering technologies in the broad field of neuroscience (Neuron, 2017). Using “SLENDR”
and “vSLENDR”, we will explore the cellular and molecular mechanism underlying long-lasting memory, and further
investigate how the mechanism is impaired in memory disorders to provide new therapeutic strategies.

Dept. of System Pathology for Neurological Disorders
Current biopsy and histology have long relied on thin-sectioned
2D images with several chemical staining methods and specificimmunohistochemistry. Facile 3D visualization of human brain tissue
with single-cell resolution would provide a novel concept of theneuropathological diagnosis and contribute our understanding ofpathological mechanisms based on comprehensive and quantitative
analysis of individual biomarker. In this laboratory, we aim at establishing

Prof.
Kazuki Tainaka

a novel 3D neuropathology by developing a highly efficient clearing
protocol for human brain tissue and combining with a rapid 3D imaging
using light-sheet fluorescence microscopy.

Dept. of System Pathology for Neurological Disorders
Central nervous system injuries due to stroke or trauma disrupt neural circuits
and result in severe deficits of functions. The brain and spinal cord have very
limited capacity to reconstruct the circuit once it is damaged, and therefore noneof effective therapeutic methods have been developed so far. We previously
demonstrated that spared motor and autonomic circuits are dynamicallyreorganized after injuries and influence the recovery process of functions. These
results suggest that controlling the rewiring of the circuit would lead to makeProf.
Masaki Ueno

proper neuronal connections that achieve functional recovery. The goal of ourstudy is to understand the process of rewiring and its underlying molecularmechanisms and neural functions. Toward this aim, we are analyzing neuralsystems of both normal and injured brain and spinal cord, using cutting-edge
techniques including, mouse genetics, viral tracers, optogenetics, chemogenetics,
and 3D behavior analysis. We believe that this study paves the way to develop
novel strategies to regenerate circuits and restore neural functions.

Dept. of Pathology / Dept. of Pathology Neuroscience
Mission:To provide the highest quality pathology services ands c i e n t i f i c ev i d e n c e f o c u s e d o n t h e a d va n c e m e n t o fdevelopments in the field of neuropathology.
Vision:As an academic pathology department, we aim to deliver
a high degree of professionalism in clinicopathological

Prof.
Akiyoshi Kakita

diagnostic services and neuropathology research, utilizing
comprehensive and innovative approaches and building departmental competence to meet the needs of patients,
institutions, and society.
Our approach will involve taking full advantage of opportunities to advance both the science and practice ofneuropathology through individual and collaborative research, which hopefully will produce leading practitioners andresearchers.

Dept. of Neurosurgery
Department of Neurosurgery, University of Niigata was founded by Professor
Mizuho Nakata, “the father of Neurosurgery in Japan”, in 1953, becoming
the first independent Department of Neurosurgery in Japan. Since then, thedepartment has led the field of preclinical research and surgery for brain
tumors, cerebral vascular disease, brain trauma, and functional surgery.
Also, the department is unique in that it is affiliated with the Brain ResearchInstitute, enabling collaboration with many basic neuroscience laboratories

Prof.
Yukihiko Fujii

within the Institute. Answering clinical questions through basic research and using the results to improve clinical medicine, isprecisely what Professor Nakata envisioned when he founded the Brain Research Institute. It is our obligation to carry on this spirit,and all staff is dedicated in discovering new insight into neurosurgical practice.The main research areas we are currently focusing
on include: (1)establishing brain tumor cell lines and intracranial xenografts to develop the best strategies to treat each tumor, (2)diagnosing brain tumors by detecting driver mutations from cell free DNA of cerebrospinal fluid (Fig 1), (3) developing assistive
surgical technology to enable accurate simulation for complex neurosurgery cases and education of young neurosurgeons, (4)collaboration with Nishi-Niigata Chuo National Hospital to elucidate the complex pathophysiology of epilepsy.

Dept. of Neurology / Dept. of Molecular Neuroscience
The Niigata University Brain Research Institute possesses not only a basic neuroscience
branch but also a clinical neuroscience branch: Departments of Neurology and
Neurosurgery. Thus, the aim of our Institute is to overcome brain diseases. We study awide variety of brain diseases by using genetic, biochemical, cell biological, histological,
and imaging approaches, in collaboration with other departments in the Institute.
In the past 50 years, we have produced favorable results of clinical and basic research.
In the beginning, we revealed Niigata Minamata and SMON diseases, which are causedProf.
Osamu Onodera

by toxic reagents, making us to have profound connections with society. Up to now, we established entities of novel brain diseases and elucidated
their etiologies and disease mechanisms by genetic, biochemical, and histological approaches.
We have also educated a large number of neurologists. Careful observation of patients by the excellent neurologists brought us fruitful success in a
new discovery. Our research is attributable to the support of patients and clinicians, and we will keep tight connection with them.
Neurologists need comprehensive knowledge of medicine and a wide range of social skills including communication, leadership, and problemsolving skills. We actively train young doctors to acquire the knowledge and skills to become a specialist in various fields from a cutting-edge basic
neuroscience to practical neurology. We are professional for brain diseases and will ensure the best possible support for our patients.

Dept. of Biological Magnetic ResonanceContinuous

technologicaldevelopment

representsanindispensable component of the recent remarkable advancementsin the state of our knowledge of human brain function. Magnetic
resonance is a field which provides a number of versatile noninvasive methodologies applicable to the analysis of humanspecific brain function. The Department of Biological Magnetic
Resonance focuses on the research, development and education

Prof.
Hironaka Igarashi

of magnetic resonance technologies as well as the research andeducation of human brain function based on integrated knowledgeof advanced engineering and non-linear computational analysis.

Dept. of Molecular Genetics

Prof.
Takeshi Ikeuchi

Recent research and development of dementia has drastically changed. Therapeutic approachto dementia has shifted from symptomatic drugs to disease-modifying drug. More attention has
been paid in dementia to pathophysiological diagnosis based on biomarker rather than symptombased diagnosis. Prospering in research by virtue of paradigm shift, we have pioneered researchthat will bring revolution in clinical practice of dementia. Our mission has two elements; one isbiomarker development, and the other is genome research of dementia. We attempt to see
through pathological changes occurring in the brain affected with dementia using blood andcerebrospinal fluid samples from preclinical phase to symptomatic phase. We have establishedlarge sample collection of genomic DNA for dementia disorders. Whole genome/exosome
analyses have been applied in the genome analysis of dementia to explore novel genetic factors in Japan. We have provided a clinical sequence
examination for physicians across Japan for genetic diagnosis of dementia. By this effort, we will contribute to the realization of genome medicine
of dementia in Japan. Even though the environmental surrounding of dementia research has been drastically moving, we keep pioneering thedementia research without forgetting our mission that we will deliver a bright future to patients with dementia.

Dept. of Comparative & Experimental Medicine

Prof.
Toshikuni Sasaoka

Dopamine is thought to play an important role in motor control, memory, learning and motivation. We focus
on motor symptoms of Parkinson's disease (PD) which is one of the important neurological diseases, and as
a PD model animal, develop a genetically engineered mouse for dopamine receptors and related moleculesthat convey dopamine information. By analysis of animal behavior regarding learning and memory andanalysis of the function of neural circuit, we aim to clarify mechanism of motor control, learning and memory,and develop therapeutic method for PD. At the same time, we are conducting research into the search andanalysis of RNA-binding proteins that are responsible for development and maintenance of neural circuitas well as function of neural circuit. Recently, we are focusing on development of an innovative embryo
manipulating system for the generation of genetically modified marmosets in collaboration with Dept. of Animal Model Develoment.
Simultaneously, we are in charge of administration and management of core facility for animal experiments in Niigata University withmice, rats, rabbits, guinea pigs, dogs, pigs, Japanese monkeys, marmosets, medaka etc as experimental animals to promote advanced
animal experiments. In addition to setting up the experimental environment, we support research using developmental and reproductiveengineering technologies such as in vitro fertilization, embryo transfer, cryopreservation of embryos and spermatozoa. In addition, weare rapidly advancing the creation of genetically modified animals by incorporating rapidly progressing genome editing technology. Using
these experimental techniques, we maintain the animal experiment environment in the Specific Pathogen Free (SPF) environment, andalso contribute to the implementation of efficient research through planned animal production.

Dept. of Animal Model Development
Our research efforts are focused on understanding of molecular mechanisms of higher brain functions such as learningand memory. Making good use of current methods in molecular biology and developmental engineering, we are now
engaged in the following projects: 1) functional assay of neurotransmitter receptors and related molecules with genetargeting techniques, 2) generation and analysis of animal models for human nervous diseases, 3) establishment of germ line-competent embryonic stem cells
derived from rat embryos, and 4) development of basic methods for generation of gene-modified animals using gene-editing technology.

Dept. of Neuroscience of Disease
There exist approximately 100,000,000,000 neurons in each human brain, and thenumber of glia cells is much more than that of neurons. Supposed that each neuron
is a star in the Universe, we could compare the brain to a small Universe within.
However, things are more complicated because each neuron extends long fibers toother neurons for communicating signals. In one sense, the brain, a small Universe,
is much more complicated than the Universe itself.
It is theoretically, technically and physically impossible to study all the twinkling stars in the sky. But we could estimate the characters ofstars or planets by carefully observing and analyzing the sun and planets in the solar system. It is also impossible to elucidate functions,Prof.
Hideaki Matsui

anatomies and networks of all the neurons one by one, but we are able to reach a right conclusion if we handle a miniature brain anddeduce common principles from the mini-brain.
This is the way that we have followed. We will disclose the phenomenon occurring in human brain by studying Fish brain. Especially ouraim is to elucidate the mechanism of neurological diseases and disorders, deepening scientific and social understanding for some, or
finding a drug for others. We human beings have evolved exactly from Fish, and most of the functions and structures in the human brain
are preserved in Fish brain. Our laboratory has tried uncovering the physiological functions and pathophysiology of the human brain bycomparing Fish and human brains, and we will surely find therapies for neurological diseases and disorders.

Global Partnerships
Global partnerships can bring together complementarystrengths and deepen the impact of joint research. BRI iscommitted to forming such partnerships and will further develop existing partnerships. The institute regularly welcomes
scientific visitors from around the world and signs MOUs andagreements with overseas research institutions. BRI also annually hosts international symposia, which feature fascinating
lectures by distinguished scientists from across the world.

Medical Practice and Education
BRI’s mission is to advance scientific research on the nervous system of the brain. BRI has a historical backgroundthat has developed through the clinical care of neurosurgical cases in the School of Medicine. BRI offering an integrated approach to its research, along with clinical and educational activities, is therefore a great strength. The
research at BRI covers a wide spectrum from Basic Neuroscience to Clinical Neuroscience related research to human brain disease. Pathological Neuroscience that bridges these two areas and the integrated research of thesethree areas brings greater progress, making BRI one of the most desirable institutes for research on brain diseasein Japan. In order to continue to engage in cutting-edge research, BRI is dedicated to training competent researchers. BRI is also dedicated to research in the clinical area to advance medicine.

Niigata Summer Seminarfor Neuroscience
NU Junior Doctor Training School

Every summer, BRI offers a seminar for young researchers acrossJapan to learn and explore topics at the forefront of neurosci-

BRI hosted a hands-on science experience class in August 2019 as theence. Participants learn cutting-edge knowledge on specific top-

4th session of the master’s program of “the Niigata University Juniorics from both BRI and external scientific experts at the forefront

Doctor Training School”, a STEM education program aiming at foster-of neuroscience research through lectures and discussions. The

ing the budding scientists. 41 pupils, from the 5th grade of elementaryseminar also features an on-site training course that provides anschool to junior high, participated in BRI lab tours and lectures.

opportunity to participate in current experiments.

Science Education
Partnering with the local Super Science High Schools specified
by MEXT, BRI provides opportunities including study tours at theinstitute and lectures that BRI scientists travel to the schools to
give. BRI is working to nurture the next generation of global researchers by introducing the attractive world of neuroscience.

BRAIN RESEARCH INSTITUTENIIGATA UNIVERSITY
1-757 Asahimachidori, Chuo-ku, Niigata 951-8585 Japanwww.bri.niigata-u.ac.jp/en/

Published July 2020