BRAIN RESEARCH INSTITUTENIIGATA UNIVERSITY 2022

Message from the Director

MEXT Joint Usage / Research Center

BRI in the time of coronavirus

The Collaborative Research Center for Neurological andPsychiatric Disorders

Osamu Onodera
Director, Brain Research Institute, Niigata University

BRI has been certified as a joint usage/research center by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) since 2010. Its extensive collectionof brain disease resources and expertise have been open to the neuroscientists’ com-

My name is Osamu Onodera, BRI professor of Neurology. I havemunity. BRI’s diverse research collaborations in neuropathology and related fields have

served as the Director since February 2020. The coronavirus

brought out a great deal of achievement in relation to unravelling the pathologicalpandemic emerged shortly after my appointment and we havemechanism of brain disease. The institute has renewed its MEXT certification of a joint

been struggling to deal with various issues arise from the pandemic

usage/research center in 2022 as “the Collaborative Research Center for Neurologicalever since. I imagine we will have to live with the coronavirus for

and Psychiatric Disorders.”
BRI has the world-class collections of neuropathological specimens and advanced imaging analysis techniques. The institute is com-the next few years at least. Additionally, there seems to be no goingmitted to tackling tasks such as neuropathological analysis on brain disorders like Alzheimer’s disease, development of early diagnostic

back to a previous lifestyle from a new normal. For better or worse, we have come to acknowledge manytechnique, and translational research on the treatment for reducing disease progression.

things in the unprecedented experience. One is the concept of higher education. After experiencing theBy utilizing the specimens of human brain disease and the animal model resources along with the underpinning of translational research

pandemic time, there will be a paradigm shift in the perceptions of those receiving higher education. Until

for clinical application, BRI’s collaboration with researchers across the world offers a prospect of reducing the burden of intractable neurological disease.

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 limitationsof the physical space on their own. This is nothing less than the unprotected exposure of higher education,

Major Research Project

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 class in the world. In an age where automatic translation is possible, language barriers

21st Century Brodmann Areas Mapping Integrating Molecular and Functional Information

are no longer an issue. It’s a huge upheaval for learners. When the education providers lose the superiority of(MEXT Education and Research Organization Reform Project)

the physical space, what can the providers use as a source of strength to maintain its form?

The center for industry-academia-government collaboration and human resource development to complete a “brain map” integrating molecular and functional information in the brain that will serve as a
guidepost for a dementia inclusive society

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 new

Overcoming age-related diseases of the brain, such as

normal, there may be an even greater screening for the education with which we share the space.

Alzheimer’s and other types of dementia, is an urgent
issue. In order to develop treatments for these diseases,
it is important to establish diagnostic methods that can

In recent neuroscience research, large-scale analysis has become the mainstream and the in-situ nature of

accurately estimate prognosis at an early stage. To do

research is being lost. While some suggest building a virtual form of research like network-based laboratories,

so, we need a map that can serve as a guidepost to pre-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

dict the progression of the disease in the brain. This project aims to develop social implementation and humanresource development in collaboration with industry,

believe that the greatest advantage of the institute is that it provides a “place” of chaos, a space for learning.

government, and academia, starting with the creation

In a post-pandemic world, the way the institute is run and the way it is taught could change drastically. Weof a new human brain map that will serve as a guide towill be assessed in such a situation. I think the nature of the importance of people gathering closer to haveunderstanding the progression of brain diseases, and to
give back to society through a dementia inclusive soci-academic discussion won’t go away in any era. As a research institute of brain, we will make an effort toety. To achieve this aim, we are working on the estab-develop such a space in the new academic system of the post-coronavirus era.

lishment of cell dispersion technology from human brain
tissue, clearing technology and cell labeling technology
for human brain tissue, and the creation of function-related maps of brain regions using functional MRI.

History
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2022

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Research Facility of
Neurosurgery at School of
Medicine, theorigin of Brain
Research Instituteis founded.

Brain Disorder Specimen
Center is set up.

Research Facility of
Neurosurgery, School of
Medicine is transformed into
Brain Research Institute.
Faculty of Morphology isrenamed Faculty of
Neuropathology.

New Brain DisorderSpecimen Center
opens. (531m2)

Monbusho’ s Center of Excellence(COE) program starts.
Ultra-high Magnetic Field MRI
Research Building opens. (251m2)

Reorganization results in BRI’s new structure of 3 big branches: Basic Neuroscience Branch (Depts. of Molecular
Neurobiology, Cellular Neurobiology, Neurophysiology, and Developmental Neurobiology), Pathological Neuroscience
Branch (Depts. of Pathology and Molecular Neuropathology), and Clinical Neuroscience Branch (Depts. of Neurosurgery
and Neurology). Brain Disorder Specimen Center is renamed Brain Disorder Analysis Center.

Brain Disorder Analysis
Center is transformed into 2
Centers: Center of Integrated
Human Brain Science andCenter for Bioresource-based
Researches. The lattermerges with Genetic
Research Facility of Niigata
University and Animal Testing
Facility, School of Medicine.

CIHBS PET Building opens. (416m2)

Center for Integrated Human
Brain Science (CIHBS)
Building opens. (3,969m2)
21st century COE program“Virtual University of
Neuropathology” starts.

Center for
Bioresource-based
Researches extension
is completed. (200m2)

BRI renews MEXT’s certification on the
Joint Usage/Research Center, which isrenamed “Collaborative ResearchCenter for Brain Diseases Utilizing
Neuropathological Resources”.
BRI is certified as a Joint Usage/ResearchCenter by the Ministry of Education, Culture,
Sports, Science and Technology (MEXT). (“theAdvanced Collaborative Research Center for
Brain Diseases Utilizing NeuropathologicalSpecimens”, start date: April 1, 2010)

BRI renews MEXT’ scertification on the Joint
Usage/Research Center,
which is renamed “The
Collaborative ResearchCenter for Neuropathological and Psychiatric
Disorders” .

Organization
Basic Neuroscience Branch

As of July 1 2022

Dept. of Brain Tumor Biology

Assoc. Prof
Assist. Prof

Dept. of Cellular Neuropathology

Prof.
Assoc. Prof.
Assist. Prof.
Assist. Prof.

Dept. of System Pathology for
Neurological Disorders

Prof.
Prof.
Assist. Prof.
Assist. Prof.
Assist. Prof.
Assist. Prof.

Pathological Neuroscience
BranchDept. of Pathology

Prof.
Assoc. Prof.
Assist. Prof.

Dept. of Molecular Pathology

Visiting Prof.
Visiting
Assoc. Prof.

Clinical Neuroscience Branch

Dept. of Neurosurgery

Prof.
Assoc. Prof.
Assist. Prof.
Assist. Prof.

Dept. of Neurology

Prof.
Assoc. Prof.
Assist. Prof.

Center for Integrated Human
Brain Science

Dept. of Integrated Neuroscience

Assoc. Prof.
Assist. Prof.

Dept. of Biological Magnetic
Resonance

Prof.
Assoc. Prof.
Assist. Prof.

Dept. of Functional Neurology &Neurosurgery

Prof.
Assoc. Prof.
Assist. Prof.

Center for
Bioresourcebased
Researches

Bioresource
Dept. of Molecular Genetics
Science Branch

Prof.
Assoc. Prof.
Assist. Prof.

Dept. of Comparative & Experimental
Medicine

Prof.
Assoc. Prof.
Assist. Prof.

Dept. of Animal Model Development

Prof.
Assoc. Prof.

Brain Science
BranchDept. of Pathology NeuroscienceProf.
Assoc. Prof.
Assist. Prof.

Dept. of Molecular NeuroscienceProf.
Assoc. Prof.
Assist. Prof.

Dept. of Neuroscience of Disease

Prof.
Assoc. Prof.
Assoc. Prof.
Assoc. Prof.
Assist. Prof.
Assist. Prof.

Dept. of Translational ResearchSpecially
Appointed
Prof.

Dept. of Cellular Neuropathology

Nobuyuki Takei
Yuriko Iwakura

Our goal is to understand the physiology and pathophysiology of thebrain at the cellular and molecular levels. We established “SLENDR”,

Takayasu Mikuni
Motokazu Uchigashima
Daisuke Satoh
Risa Iguchi
Kazuki Tainaka
Masaki Ueno
Hitoshi Uchida
Tokiharu Sato
Satoshi Miyashita
Takahiro Inouea 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 theapplicability of genome engineering technologies in the broad fieldProf.
Takayasu Mikuni

Dept. of System Pathology for Neurological Disorders
Current biopsy and histology have long relied on thinsectioned 2D images with several chemical staining methods

Koichi Wakabayashi
Fumiaki Mori

Osamu Onodera
Masato Kanazawa
Shintaro Tsuboguchi

and specific immunohistochemistry. Facile 3D visualization ofhuman brain tissue with single-cell resolution would provide
a novel concept of the neuropathological diagnosis andcontribute our understanding of pathological mechanisms
based

Prof.
Kazuki Tainaka

andquantitative

analysisofa novel 3D neuropathology by developing a highly efficient
clearing protocol for human brain tissue and combining withDept. of System Pathology for Neurological Disorders
Central nervous system injuries due to stroke or trauma disrupt neuralcircuits and result in severe deficits of functions. The brain and spinal cordhave very limited capacity to reconstruct the circuit once it is damaged, andtherefore none of effective therapeutic methods have been developed so far.

Hitoshi Shimada
Yoshihiro Murakami
Masahiro Hatakeyama

We previously demonstrated that spared motor and autonomic circuits are
dynamically reorganized after injuries and influence the recovery process offunctions. These results suggest that controlling the rewiring of the circuit
would lead to make proper neuronal connections that achieve functional

Prof.
Masaki Ueno

recovery. The goal of our study is to understand the process of rewiring andits underlying molecular mechanisms and neural functions. Toward this aim,
we are analyzing neural systems of both normal and injured brain and spinal

Toshikuni Sasaoka
Nanaho Fukuda
Kanako Oda

cord, using cutting-edge techniques including, mouse genetics, viral tracers,
optogenetics, chemogenetics, and 3D behavior analysis. We believe that thisstudy paves the way to develop novel strategies to regenerate circuits andToshikuni Sasaoka
Manabu Abe

restore neural functions.

Akiyoshi Kakita
Mari Tada
Rie Saito

Dept. of Pathology / Dept. of Pathology Neuroscience
Mission:Osamu Onodera
Taisuke Kato
Akihiro Sugai

Kouichirou Okamoto

comprehensive

a rapid 3D imaging using light-sheet fluorescence microscopy.

Hironaka Igarashi
Kosuke Itoh
Masaki Watanabe

Hideaki Matsui
Ryuichi Hishida
Tomoyuki Yamanaka
Atsushi Sugie
Godfried Dougnon
Takayoshi Otsuka

onindividual biomarker. In this laboratory, we aim at establishing

Yuji Suzuki
Yukimi Nakamura

Takeshi Ikeuchi
Akinori Miyashita
Kensaku Kasuga

will explore the cellular and molecular mechanism underlying long-lasting memory, and further investigate how themechanism is impaired in memory disorders to provide new therapeutic strategies.

Akiyoshi Kakita
Hiroshi Shimizu
Asa Nakahara

Yukihiko Fujii
Makoto Oishi
Tetsuya Hiraishi
Manabu Natsumedaof neuroscience (Neuron, 2017). Using “SLENDR” and “vSLENDR”, weTo p rov i d e t h e h i g h e s t q u a l i t y p a t h o l o g y s e r v i c e s a n d s c i e n t i f i cevidence focused on the advancement of developments in the field of
neuropathology.
Vision:A s a n a c a d e m i c p at h o l o g y d e p a r t m e n t , we a i m t o d e l i ve r a h i g hdegree of professionalism in clinicopathological diagnostic services

Prof.
Akiyoshi Kakita

Genetic variations and neuropathologic features ofpatients with PRKN mutations.

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

Dept. of Molecular Genetics

Department of Neurosurgery, Niigata University was founded by Professor Mizuho Nakata,

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.

“the father of Neurosurgery in Japan”, in 1953, becoming the first independent Departmentof Neurosurgery in Japan. Since then, the department has led the field of preclinical researchand 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 Research Institute,Fig 1.

enabling collaboration with many basic neuroscience laboratories within the Institute.
Answering clinical questions through basic research and using the results to improve clinicalmedicine, is precisely what Professor Nakata envisioned when he founded the Brain Research

Prof.
Yukihiko Fujii

Institute. It is our obligation to carry on this spirit, and all staff is dedicated to discovering
new insight into neurosurgical practice. The main research areas we are currently focusing on

Fig 2.

Prof.
Takeshi Ikeuchi

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) identifying molecular makers of humanaxonal regeneration and development, (4) developing assistive surgical technology to enable accurate simulation for complex neurosurgery

Dept. of Comparative & Experimental Medicine

cases and education of young neurosurgeons, (5) the establishment of real-time intraoperative brain mapping or neuromonitoring methods(Fig 2) (6) 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,

Prof.
Toshikuni Sasaoka

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 caused by toxic reagents, making us tohave profound connections with society. Up to now, we established entities of novel brain diseases andProf.
Osamu Onodera

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

We are conducting a multicenter, investigator-initiated clinical trial forpolyglutamine disease, the most common form of hereditary spinocerebellar
ataxia.The observation period for all patients will be completed in September
2022, and we plan to start analyzing the results.

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.

Dopamine is thought to play an important role in motor control, memory, learning and motivation. We focus
on Parkinson's disease (PD), which is one of the most common neurological diseases, and as a PD model
animal, we develop a genetically modified mouse for dopamine receptors and their related molecules. By
analyzing animal behavior and neural circuit activities of the PD model mice, we aim to clarify the role ofdopamine signaling on motor control, learning and memory, leading to develop a new therapeutic approachfor PD. At the same time, we are studying RNA-binding proteins that are responsible for development andfunction of neural circuits by using mouse genetics. In collaboration with Dept. of Animal Model Development,
we are conducting research to regenerate defective organs by embryo manipulation using the blastocyst
complementation method. In addition, we are focusing on development of an innovative embryo manipulating system for the generation ofgenetically modified marmosets.
We are in charge of administration and management of core facility for animal experiments in Niigata University with mice, rats, rabbits,
guinea pigs, dogs, pigs, Japanese monkeys, marmosets, medaka etc. In addition to setting up the experimental environment, we support
researchers by providing reproductive engineering technologies such as in vitro fertilization, embryo transfer, cryopreservation of embryos
and spermatozoa, and DNA injection to oocytes. We also use genome editing technology to create genetically modified animals in a shorttime period. Using these experimental techniques, we maintain the animal facility in the Specific Pathogen Free (SPF) environment, andalso contribute to the implementation of efficient research through planned animal production.

Dept. of Animal Model Development

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.

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 Biological Magnetic ResonanceContinuous technological development represents an indispensable
component of the recent remarkable advancements in the state

Dept. of Neuroscience of Diseaseof our knowledge of human brain function. Magnetic resonance

There exist approximately 100,000,000,000 neurons in each human brain, and theis a field which provides a number of versatile non-invasive

number of glia cells is much more than that of neurons. Supposed that each neuron

methodologies applicable to the analysis of human specific brain

is a star in the Universe, we could compare the brain to a small Universe within.

function. The Department of Biological Magnetic Resonance focuses

However, things are more complicated because each neuron extends long fibers toon the research, development and education of magnetic resonanceother neurons for communicating signals. In one sense, the brain, a small Universe,
is much more complicated than the Universe itself.

technologies as well as the research and education of human brain

Prof.
Hironaka Igarashi

It is theoretically, technically and physically impossible to study all the twinkling stars in the sky. But we could estimate the characters offunction based on integrated knowledge of advanced engineeringstars or planets by carefully observing and analyzing the sun and planets in the solar system. It is also impossible to elucidate functions,and non-linear computational analysis.

Dept. of Functional Neurology & Neurosurgery
Recent development of in vivo imaging enable us to track disruptionof brain environment, such as abnormal protein deposition andanatomies and networks of all the neurons one by one, but we are able to reach a right conclusion if we handle a miniature brain andProf.
Hideaki Matsui

deduce 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.

neuroinflammation in addition to neuronal function. The aims of ourdepartment are to investigate the watershed between healthy brain
aging and brain diseases, and to reveal pathological bases of diverse
brain disorders using multimodal imaging technique including PET(positron emission tomography) and MRI (magnetic resonanceProf.
Hitoshi Shimada

Global Partnerships
Global partnerships can bring together complementarystrengths and deepen the impact of joint research. BRI is

imaging). We will execute the clinical imaging study contributing tocommitted to forming such partnerships and will further de-finding out pathological bases of neuropsychiatric disorders, leadingvelop existing partnerships. The institute regularly welcomesto the establishing novel techniques of early diagnosis, treatment

scientific visitors from around the world and signs MOUs andand prevention, by collaborating with government, industry, and academic researchers inside and outside Brain Research

agreements with overseas research institutions. BRI also an-

Institute. As a leading laboratory in this field, we have ambitious plans to cultivate human resources capable of conducting

nually hosts international symposia, which feature fascinatingtranslational study.

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 Nouken Seminarfor Neuroscience
Every year, BRI holds Niigata Nouken Seminar for Neuroscience,

Niigata Junior Doctor Training School

formerly known as Summer Seminar. The 51st meeting was held
online in February 2022 with the aim to facilitate interactions within
the institute. The event included presentations of research areas by

BRI gave online science talks in November 2021 as part of the mas-each BRI department and self-introduction time by newly added re-

ter’s program of “the Niigata Junior Doctor Training School”, a STEM

searchers. At a panel discussion held at later sessions, participants

education program aiming at fostering the budding scientists. 27

exchanged opinions openly on nurturing female researchers as wellpupils, from the 5th grade elementary school to junior high, partici-

as on projects and research initiatives that BRI engages in.

pated in a lecture session by two BRI researchers.

Science Education
Partnering with the local Super Science High Schools specified
by MEXT, BRI scientists visit local highschools to give lectures onneuro science. 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 2022