BRAIN RESEARCH INSTITUTENIIGATA UNIVERSITY 2019

Message from the Director

Our mission and challenges
Hiroyuki Nawa
Director, Brain Research Institute, Niigata University
Brain Research Institute (BRI) has its roots in Niigata University Brain
Research Laboratory which was founded in 1956 with the efforts of Dr.
Mizuho Nakata and his colleagues. Dr. Komei Ueki obtained staffing support from the School of Medicine and it became Brain Research Institutein 1967, the first affiliated research institute of a national university in Japan on the human brain and related fields. Ever since its foundation, theinstitute has been integrating basic research and clinical practice. Having
placed two clinical departments (Neurosurgery and Neurology) as its core, BRI has focused on research concerning
human brain disease including neurodegenerative disease. Embracing both basic neuroscience research branches andclinical departments of the University Hospital, BRI enables creating a seamless research environment.
BRI became one of the MEXT’s Joint Usage/Research Centers in 2009 and carried out collaborative research projects with a total of 300 research institutes across Japan during the designated period, which resulted in renewing
MEXT certification. From April 2016, BRI enhances global partnerships as the collaborative research center for brain
diseases utilizing neuropathological resources. The institute is currently striving to partner with renowned institutions in China, Russia, Scandinavia and the United States with regard to joint research, agreements on research collaborations and exchanges so as to increase its international visibility and reputation.
The institute is making its internal generation shift. It has now three new young professors following the mandatory
retirement of a professor. BRI will continue to promote the appointment of young faculty, the reorganization of theinternal departments and hiring project-based faculty members, all of which will bring new energy to the institute.
Furthermore, neuroscience research seems to have broadened and developed considerably in recent years. It isnoteworthy that artificial intelligence is now applied to decode neural structure and function of human brain. In
the era of Reiwa, more than 60 years have passed since Dr. Nakata and his colleagues opened Niigata University
Brain Research Laboratory, the nature of human brain function has now come to be understood. Hence, challenges
posed to BRI would be mounting.
While Japan’s population is graying, neurogenerative diseases such as Alzheimer’s and Parkinson’s are still unsolved
and impact the society to a great extent. BRI’s responsibility is therefore to tackle brain diseases and bring newtreatments and hope to patients and families as soon as possible. In order to maintain its reputation as a leading
research institute on the brain, BRI continues to grow and evolve to reflect the changing times. The institute’s comprehensive approach includes, but is not limited to, imparting knowledge, boosting globalization, making a generation shift, and reforming the internal structure. Despite the current fiscal pressures that national universities face,
BRI is determined to work to full capacity, with a strategic approach to win more grants to enhance the institute’s
research, to meet its mission. We appreciate your continued support and cooperation.

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 2019

Dept. of Molecular Neurobiology

Dept. of Cellular Neuropathology

Dept. of Neurophysiology

Pathological Neuroscience
BranchDept. of Pathology

Prof.

Hiroyuki Nawa

Assoc. Prof.

Nobuyuki Takei

Assist. Prof.

Hisaaki Namba

Assist. Prof.

Yuriko Iwakura
Takayasu Mikuni

Prof.
Assoc. Prof.

Motokazu Uchigashima

Assist. Prof.
Prof.

Hitoshi Uchida
Hiroyuki Nawa

Assoc. Prof.

Ryuichi Hishida

Assist. Prof.
Prof.

Kohei Yoshitake
Akiyoshi Kakita

Assoc. Prof.

Hiroshi Shimizu

Assist. Prof.

Hiroki Kitaura

Dept. of Digital Pathology
Dept. of Molecular Pathology

Prof.
Prof.

Fumiaki Mori
Yukihiko Fujii

Assoc. Prof.

Makoto Oishi

Assist. Prof.

Tetsuya Hiraishi

Assist. Prof.

Manabu Natsumeda
Osamu Onodera

Assoc. Prof.

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

Koichi Wakabayashi

Prof.
Assoc. Prof.

Masato Kanazawa

Assist. Prof.

Takuya Konno

Assoc. Prof.

Hitoshi Matsuzawa

Prof.

Hironaka Igarashi

Assoc. Prof.

Kiyotaka Suzuki

Assist. Prof.
Assoc. Prof.

Masaki Watanabe
Yuji Suzuki

Assoc. Prof.

Ken-ichi Yamada

Assist. Prof.

Satoshi Ueki

Dept. of Digital Medicine
Center for
Bioresoucebased
Researches

Bioresource
Dept. of Molecular Genetics
Science Branch

Akinori Miyashita

Assist. Prof.

Kensaku Kasuga

Dept. of Bioinformatics

Prof.

Takeshi Ikeuchi

Dept. of Comparative & Experimental
MedicineProf.

Toshikuni Sasaoka

Dept. of Pathology Neuroscience

Dept. of Molecular Neuroscience

Lecturer

Dept. of System Pathology for
Neurological Disorders

Nanaho Fukuda

Assist. Prof.

Nobuyoshi Fujisawa

Assist. Prof.

Kanako Oda
Toshikuni Sasaoka

Prof.
Assoc. Prof.

Manabu Abe

Assist. Prof.

Ena Nakatsukasa
Akiyoshi Kakita

Prof.
Assoc. Prof.

Mari Tada

Assist. Prof.

Rie Saito
Osamu Onodera

Prof.
Prof.

Tomohiko Ishihara
Kazuki Tainaka

Prof.

Masaki Ueno

Assist. Prof.

Center for Transdisciplinary
ResearchTakeshi Ikeuchi

Assoc. Prof.

Dept. of Animal Model Development

Brain Science
BranchProf.

Dept. of Translational Research

Assoc. Prof.

Kouichirou Okamoto

Dept. of Neuroscience of Disease

Assoc. Prof.

Hideaki Matsui

Assist. Prof.

Atsushi Sugie

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. Our efforts have been paid to the following projects: (1) the
specificity and functionality of the intracellular signaling driven by these bioactive
proteins (BDNF, mTOR, S6 kinase, AMPK), (2) the cytokine-dependent regulation ofProf.
Hiroyuki Nawa

monoaminergic development and function (GDNF, EGF, NRG1, EGFR, ErbB4), and(3) the molecular and system neuropathology of schizophrenia and its animal modeling (hallucination, auditory-evoked
potential, social withdrawal). Currently we are addressing these questions employing all types of biological approaches
including molecular genetic, biochemical, cell biological, electrophysiological, pharmacological, and behavioral tools andtechniques. We hope these studies will lead to the understanding of how these bioactive factors control the onset andprogression of developmental brain diseases such as schizophrenia, autism, which might hint at developing new drugs.

Dept. of Neurophysiology
The skull of mice is thin and transparent. Therefore, cortical activities are easily visualizedusing endogenous flavoprotein fluorescence signals reflecting the activity-dependent changesin oxidative metabolism in mice. We are investigating cortical activities in the auditory, visualand somatosensory cortices using this technique. Recently, we’ve started to investigate higher
association cortices between these primary sensory areas, of which functions are largely unknown
in mice. Previous researches using primates such as monkeys have shown that neurons in theassociation cortices respond to various stimuli, and are involved in association (integration) of
information. The integrated information is said to be used for higher brain functions such as
cognition, attention, judgment, memory, motivation, and fine exercise, but its neural network
mechanism is hardly understood at present. Although mice have seldom been used for the
researches on the association cortices, we are now challenging to investigate the neuralmechanisms of their higher functions with using genetic tools such as transgenic mice.

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
i n m a m m a l i a n b ra i n t i s s u e ( C e l l , 2016 ) . I n a d d i t i o n , w e re c e n t l ydeveloped “vSLENDR”, a genome editing method to target virtually
any cell-types, areas and ages across the brain, widely expanding

Prof.
Takayasu Mikuni

the 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 therapeuticstrategies.

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 deliverProf.
Akiyoshi Kakita

a high degree of professionalism in clinicopathologicaldiagnostic 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, the department has led the field ofpreclinical 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
Research Institute, enabling collaboration with many basic neuroscience laboratories
within the Institute. Answering clinical questions through basic research and using the

Prof.
Yukihiko Fujii

results to improve clinical medicine, is precisely 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 investigating include: (1) developing new treatment
methods including manipulation autophagy and targeting of glioma stem cells to eradicate the deadly disease malignant glioma,(2) developing assistive surgical technology to enable accurate simulation for complex neurosurgery cases and education of young
neurosurgeons, (3) 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 andSMON diseases, which are caused by toxic reagents, making us to have profound connections with society. Up to now, we established entities

Prof.
Osamu Onodera

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 successin 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 technological development represents an indispensable
component of the recent remarkable advancements in the stateof our knowledge of human brain function. Magnetic resonancei s a f i e l d w h i c h p rov i d e s a n u m b e r o f ve rs at i l e n o n - i nva s i ve
methodologies applicable to the analysis of human specific brain
function. The Department of Biological Magnetic Resonance focuseson the research, development and education of magnetic resonanceProf.
Hironaka Igarashi

technologies as well as the research and education of human brain
function based on integrated knowledge of advanced engineeringand non-linear computational analysis.

Dept. of Molecular Genetics / Dept. of Bioinformatics
During the last decade, there has been significant progress in understanding thepathophysiology of dementia. Although several candidate disease-modifying drugs
against dementia including Alzheimer’s disease have been developed, clinical trials using
these disease-modifying drugs have been failed to show the clinical efficacy. Consideringthat degenerative dementia develops the symptoms after long asymptomatic silent
phase over decade, we need to establish biomarkers that enable the very early
detection of the pathological process occurring in the brain. The aim of our research

Prof.
Takeshi Ikeuchi

is the development and clinical application of cerebrospinal fluid (CSF) biomarkers fordegenerative dementia. In addition to CSF biomarkers, we have explored blood-based
biomarkers for Alzheimer’s disease that is less invasive and simple to perform in clinical practice. The other goal of our group is
to elucidate the susceptible genes for dementia by comprehensive genome-wide analysis using next generation sequencer. In
order to facilitate biomarker and genetics researches, we have established research consortium to collect large number of biofluid
samples and genomic DNAs from patients with dementia by the collaboration with many clinical sites across Japan. Thus, we areworking to translate research advances into improved diagnosis and therapeutics for patients with dementia and to find a way tocure and possibly prevent dementia.

Dept. of Comparative & Experimental Medicine
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 thegeneration of genetically modified marmosets in collaboration with Dept. of Animal Model Develoment.

Prof.
Toshikuni Sasaoka

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 System Pathology for Neurological Disorders
Current biopsy and histology have long relied on thin-sectioned 2D images
with several chemical staining methods and specific immunohistochemistry.
Facile 3D visualization of human brain tissue with single-cell resolution would
provide a novel concept of the neuropathological diagnosis and contribute
our understanding of pathological mechanisms based on comprehensive
and quantitative analysis of individual biomarker. In this laboratory, we aim atestablishing a novel 3D neuropathology by developing a highly efficient clearing

Prof.
Kazuki Tainaka

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 insevere deficits of functions. The brain and spinal cord have very limited capacity to reconstruct
the circuit once it is damaged, and therefore none of effective therapeutic methods have beendeveloped so far. We previously demonstrated that spared motor and autonomic circuits are
dynamically reorganized after injuries and influence the recovery process of functions. These
results suggest that controlling the rewiring of the circuit would lead to make proper neuronalconnections that achieve functional recovery. The goal of our study is to understand the process

Prof.
Masaki Uenoof rewiring and its underlying molecular mechanisms and neural functions. Toward this aim, weare analyzing neural systems 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 todevelop novel strategies to regenerate circuits and restore neural functions.

Global Partnerships
Global partnerships can bring together complementary strengths and deepen the impact of joint research.
BRI is committed to forming such partnerships andwill further develop existing partnerships. The instituteregularly welcomes scientific visitors from around theworld and signs MOUs and agreements 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

World Brain Awareness Week:

Let’s examine
the human brain and mind
Brain Awareness Week is the global campaign to increase publicawareness of the progress and benefits of brain research. Oncea year, BRI stages an event to stimulate student interest and understanding of neuroscience. The event includes lab tours andEvery summer, BRI offers a three-day seminar for young researchers across Japan to learn and explore topics at the forefront ofneuroscience. Participants learn cutting-edge knowledge on specific topics from both BRI and external scientific experts at theforefront of neuroscience research through lectures and discussions. The seminar also features an on-site training course thatprovides an opportunity to participate in current experiments.

lectures.

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 2019