BRAIN RESEARCH INSTITUTENIIGATA UNIVERSITY 2018

Message from the Director
Hiroyuki Nawa

MEXT Joint Usage / Research Center

Director, Brain Research Institute, Niigata University

The Collaborative Research Center for Brain Diseases
Utilizing Neuropathological Resources

Brain Research Institute (BRI) has its roots in the Niigata Neurological

BRI was certified as a joint usage/research center by the Ministry of Education, Cul-

Research Society of Niigata University in the early Showa era. Its deep
interest and foresight in the field of the human brain led to establishing
Niigata University Brain Research Laboratory in 1956, which was laterture, 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 mechanism

replaced by the establishment of the Research Facility of Neurosurgeryof brain disease. Given the MEXT's recognition for such achievements, BRI has renewedat the School of Medicine. The foundation of the laboratory was large-

the certification of a joint usage/research center in FY 2016.

ly thanks to the work of Dr. Mizuho Nakata and his colleagues. Dr.

BRI has the world-class collections of neuropathological specimens and advanced

Komei Ueki obtained staffing support from the School of Medicine and the facility 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, the institute has been integrating basic research and clinical practice. Having placed two

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 neu-

clinical departments (Neurosurgery and Neurology) as its core, BRI has focused on research concerning humanrological disease. Expected outcomes include the followings: to shed light on the disease pathology, to establish early imaging diagnos-

brain disease including neurodegenerative disease. Including both basic neuroscience research branches and clini-

tics, and to discover new treatment that slows disease progression.

cal departments of the University Hospital, BRI enables creating a seamless research environment.
In 2002, the Center for Integrated Human Brain Science was established as a COE (Center of Excellence) projectby the Ministry of Education, Culture, Science, Sports and Technology (MEXT), focusing on advanced imaging diagnostics and their application. Department of Neuropathology subsequently acquired MEXT’s certificate for a
21st century COE. BRI became one of MEXT’s Joint Usage/Research Centers in 2009 and conducted collaborative
research projects with a total of 300 research institutes across Japan during the designated period, which resulted

Major Research Projects
Drug discovery for Alzheimer’s disease(MEXT Joint Usage / Research Center reinforcement project)

in renewing MEXT certification. From April 2016, BRI will enhance global partnerships as the collaborative research

20 years of research efforts at Center for Integrated Hu-

center for brain diseases utilizing neuropathological resources. BRI is currently undergoing institutional reform.

man Brain Science has successfully developed non-in-

Having had a retired professor, the institute has appointed a young faculty, reorganized the departments and hired

vasive imaging method for preclinical diagnosis of Alz-project-based faculty members. We expect this will bring new energy to the institute.

heimer’s disease (AD), and has also demonstrated that

While advanced medical technology greatly helps to overcome cancer and heart disease, the increasing number of
intractable neurological disease patients (e.g. Alzheimer’s and Parkinson’s diseases) is a significant issue in our so-

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:

ciety. BRI’s responsibility is therefore to address brain diseases to provide a cure for such diseases to introduce thetogether with establishing an early diagnostic method fortreatment to our patients and families as soon as possible.

AD using magnetic resonance imaging (MRI) and positronemission tomography (PET), the project will target discov-

In order to maintain its reputation as a leading research institute on the brain, BRI continues to grow and evolveto reflect the changing times. The institute’s comprehensive approach includes, but is not limited to, impartingknowledge, boosting globalization, training young researchers, making a generation shift, developing links bothwith the School of Medicine and University Hospital, and reforming the internal structure. Despite the current fiscalpressures that we face, we are bidding for external funds and steadily engaging in enhancing our research capacity,
self-development and contributions to medical care. We appreciate your continued support and cooperation.

ery 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.

HistoryOrganization
Basic Neuroscience Branch

Pathological Neuroscience
BranchDept. of Molecular Neurobiology

As of October 2018

Dept. of Molecular Neurobiology

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

Dept. of Cellular Neuropathology

Prof.
Assist. Prof.

Dept. of Neurophysiology

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

Dept. of Pathology

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

Hiroyuki Nawa
Nobuyuki Takei
Hisaaki Namba
Yuriko Iwakura
Takayasu Mikuni
Hitoshi Uchida
Katsuei Shibuki
Ryuichi Hishida
Hiroaki Tsukano
Kohei Yoshitake
Akiyoshi Kakita
Yasuko Toyoshima
Hiroshi Shimizu
Mari Tada
Hiroki Kitaura

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

Clinical Neuroscience Branch

Dept. of Molecular Pathology
Dept. of Neurosurgery

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

Dept. of Neurology

Center for Integrated Human
Brain ScienceProf.
Lecturer
Assist. Prof.

Dept. of Integrated Neuroscience

Assoc. Prof.
Assist. Prof.

Dept. of Biological Magnetic
Resonance

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

Dept. of Functional Neurology &Neurosurgery

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

Koichi Wakabayashi
Fumiaki Mori
Yukihiko Fujii
Makoto Oishi
Tetsuya Hiraishi
Manabu Natsumeda
Osamu Onodera
Masato Kanazawa
Takuya Konno
Hitoshi Matsuzawa
Kosuke Itoh
Hironaka Igarashi
Kiyotaka Suzuki
Masaki Watanabe
Yukimi Nakamura
Yuji Suzuki
Ken-ichi Yamada
Satoshi Ueki

Bioresource
Dept. of Molecular Genetics
Science Branch
Dept. of Bioinformatics
Dept. of Comparative & Experimental
Medicine

Brain Science
BranchCenter for Transdisciplinary
Researchpotential, social withdrawal). Currently we are addressing these questions employing all types of biological approaches
techniques. 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 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 Neurophysiology
The skull of mice is thin and transparent. Therefore, cortical activities
are easily visualized using endogenous flavoprotein fluorescence signals
reflecting the activity-dependent changes in oxidative metabolism inmice. We are investigating cortical activities in the auditory, visual andsomatosensory cortices using this technique. However, there are higher

Dept. of Digital Medicine
Center for
Bioresoucebased
Researches(3) the molecular and system neuropathology of schizophrenia and its animal modeling (hallucination, auditory-evoked
including molecular genetic, biochemical, cell biological, electrophysiological, pharmacological, and behavioral tools andDept. of Digital Pathology
Prof.
Assoc. Prof.

monoaminergic development and function (GDNF, EGF, NRG1, EGFR, ErbB4), andProf.
Assoc. Prof.
Assist. Prof.
Prof.
Prof.
Assist. Prof.
Assist. Prof.
Assist. Prof.

Dept. of Animal Model Development

Prof.
Assoc. Prof.
Assist. Prof.

Dept. of Pathology NeuroscienceProf.
Assist. Prof.

Dept. of Molecular NeuroscienceProf.
Assist. Prof.

Dept. of System Pathology for
Neurological Disorders

Tenure-track
Prof.
Tenure-track
Prof.

Dept. of Translational Research

Assoc. Prof.

Dept. of Neuroscience of Disease

Tenure-track
Assoc. Prof.
Tenure-track
Assist. Prof.

Takeshi Ikeuchi
Akinori Miyashita
Kensaku Kasuga
Takeshi Ikeuchi

association cortices between these primary sensory areas, and theirfunctions are largely unknown in mice. In general, neurons in the association

Prof.
Katsuei Shibuki

Toshikuni Sasaoka
Nobuyoshi Fujisawa
Nanaho Fukuda
Kanako Oda
Toshikuni Sasaoka
Manabu Abe
Ena Nakatsukasa
Akiyoshi Kakita
Rie Saito
Osamu Onodera
Tomohiko Ishihara

activities in the association cortices can be maintained after stimulus offset,
Integration of information and short-term memory are important elements of consciousness, so that the associative
cortices are likely related to consciousness. Generally speaking, consciousness research is not easy in the frameworkof falsifiable scientific studies in mice. Fortunately, we have found a particular strain of mice that exhibit specific andsimultaneous impairment of sensory integration and short-term memory. Using these mice, we are now challenging toinvestigate the neural mechanisms of consciousness in the framework of falsifiable scientific studies.

Dept. of Pathology / Dept. of Pathology Neuroscience
Mission: To expand our understanding of human diseasesof the nervous system, by clinical service, education, andresearch.
Clinical pathology: Over 400 surgical cases and 40 to
50 autopsy cases annually, from the Departments of

Masaki Ueno

Neurosurgery and Neurology, as well as from various otherinstitutes in Japan.

Kouichirou Okamoto

Atsushi Sugie

association (integration) of information. Another point is that some neuralsuggesting that they are related to certain types of short-term memory.

Kazuki Tainaka

Hideaki Matsui

cortices respond to various stimuli, and therefore, may be involved inProf.
Akiyoshi Kakita

Research: Clinical, translational, and basic science ofhuman disorders of the nervous system, including neurodegenerative, developmental, infections, cerebrovascular, andimmune-mediated diseases.
Education: Teach medial and graduate students, residents, and fellows.

Prof.
Yukihiko Fujii

Dept. of Neurosurgery

Dept. of Comparative & Experimental Medicine

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

Dopamine is considered to be closely related to controlling of motor function, learning and memory

Nakata, “the father of Neurosurgery in Japan”, in 1953, becoming the first independentand motivation. Our research interest is focusing on understanding of the mechanism of motor

Department of Neurosurgery in Japan. Since then, the department has led the field ofcontrol and developing of a novel therapeutic strategy regarding the motor symptoms of Parkinson’s

preclinical research and surgery for brain tumors, cerebral vascular disease, brain trauma,disease, one of the major neurological disorder. We develop various model animals such as theand functional surgery. Also, the department is unique in that it is affiliated with the Brain

genetically modified mice of dopamine receptor and related molecules and examine them by

Research Institute, enabling collaboration with many basic neuroscience laboratories

biochemical analysis of gene expression, behavioral analysis of motor and cognitive function andwithin the Institute. Answering clinical questions through basic research and using theelectrophysiological analysis of neuronal activity.

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

Prof.
Toshikuni Sasaoka

Another mission of our group is management of the animal facility of Niigata University andimprovement of environment of animal experiments using mice, rats, rabbits, guinea pigs, dogs, pigs, Japanese monkeys, marmosets
and Japanese medaka. We perform research support activity using the reproductive and developmental engineering technologies

methods including manipulation autophagy and targeting of glioma stem cells to eradicate the deadly disease malignant glioma,

such as in vitro fertilization, cryopreservation of embryos/sperms and provide services of production of genetically modified mice by(2) developing assistive surgical technology to enable accurate simulation for complex neurosurgery cases and education of young

the rapidly evolving genome editing technique. We ensure the microbiologically-controlled environment as the SPF (specific pathogen

neurosurgeons, (3) collaboration with Nishi-Niigata Chuo National Hospital to elucidate the complex pathophysiology of epilepsy.

free) grade and contribute to facilitating progress of research by efficient production of animals using techniques described above.

Dept. of Animal Model Development

Dept. of Neurology / Dept. of Molecular Neuroscience

Our research efforts are focused on understanding of molecular mechanisms of higher brain functions such as learning

The Niigata University Brain Research Institute possesses not only a basic neuroscienceand memory. Making good use of current methods in molecular biology and developmental engineering, we are now

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,

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.

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 andDept. of System Pathology for Neurological Disorders

SMON 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 successCurrent biopsy and histology have long relied on thin-sectioned 2D images

in a new discovery. Our research is attributable to the support of patients and clinicians, and we will keep tight connection with them.

with several chemical staining methods and specific immunohistochemistry.

Neurologists need comprehensive knowledge of medicine and a wide range of social skills including communication, leadership, and problem-

Facile 3D visualization of human brain tissue with single-cell resolution would

solving skills. We actively train young doctors to acquire the knowledge and skills to become a specialist in various fields from a cutting-edge

provide a novel concept of the neuropathological diagnosis and contributebasic neuroscience to practical neurology. We are professional for brain diseases and will ensure the best possible support for our patients.

our understanding of pathological mechanisms based on comprehensive
and quantitative analysis of individual biomarker. In this laboratory, we aim atDept. of Biological Magnetic ResonanceContinuous technological development represents an indispensable

establishing a novel 3D neuropathology by developing a highly efficient clearing

Tenure-track Prof.
Kazuki Tainaka

protocol for human brain tissue and combining with a rapid 3D imaging using
light-sheet fluorescence microscopy.

component of the recent remarkable advancements in the stateof our knowledge of human brain function. Magnetic resonanceDept. of System Pathology for Neurological Disorders

i 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

Prof.
Hironaka Igarashi

function. The Department of Biological Magnetic Resonance focuses

Central nervous system injuries due to stroke or trauma disrupt neural circuits and result inon the research, development and education of magnetic resonancesevere deficits of functions. The brain and spinal cord have very limited capacity to reconstruct

technologies as well as the research and education of human brain

the circuit once it is damaged, and therefore none of effective therapeutic methods have beenfunction based on integrated knowledge of advanced engineeringdeveloped so far. We previously demonstrated that spared motor and autonomic circuits are

and non-linear computational analysis.

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

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

Tenure-track 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.

dementia including Alzheimer’s disease have been developed, clinical trials using these
disease-modifying drugs have been failed to show the clinical efficacy. Considering thatdegenerative dementia develops the symptoms after long asymptomatic silent phaseover decade, we need to establish biomarkers that enable the very early detection of theProf.
Takeshi Ikeuchi

Global Partnerships

pathological process occurring in the brain. The aim of our research is the development

Global partnerships can bring together complementa-

and clinical application of cerebrospinal fluid (CSF) biomarkers for degenerative dementia.

ry strengths and deepen the impact of joint research.

In addition to CSF biomarkers, we have explored blood-based biomarkers for Alzheimer’s

BRI is committed to forming such partnerships anddisease that is less invasive and simple to perform in clinical practice. We recently reported that desmosterol is a novel blood-

will further develop existing partnerships. The institutebased biomarker candidate for Alzheimer’s disease. The other goal of our group is to elucidate the susceptible genes for dementia

regularly welcomes scientific visitors from around theby comprehensive genome-wide analysis using next generation sequencer. In order to facilitate biomarker and genetics researches,

world and signs MOUs and agreements with overseas

we have established research consortium to collect large number of biofluid samples and genomic DNAs from patients withresearch institutions. BRI also annually hosts interna-dementia by the collaboration with many clinical sites across Japan. Thus, we are working to translate research advances into

tional symposia, which feature fascinating lectures byimproved diagnosis and therapeutics for patients with dementia and to find a way to cure and possibly prevent dementia.

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.

Brain Seminar
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 un-

Every 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.

derstanding of neuroscience. The event includes lab tours andlectures.

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 October 2018