A DV E RT I S E M E N T FE AT U R E

A DV E RT I S E M E N T FE AT U R E

THE UEHARA INTERNATIONALSYMPOSIUM 2021
The Uehara Memorial Foundation’s most recent symposium covered brain-periphery interactions,
AN INCREASINGLY SIGNIFICANT AREA in life sciences and medicine.
The body’s homeostasis is
maintained by the interactions
between elaborate andreciprocal communication
systems between the brain andperipheral tissues and organs.
We are beginning to understandthat failure in these systems
causes abnormal homeostasisof multiple organs and tissues
and potentially leads to various
diseases, making brainperiphery interactions one of
the main emerging themes inlife sciences and medicine. This
year’s symposium provided
a showcase for cutting-edge
research on brain-peripheryinteractions in basic and clinicalmedicine by experts invitedfrom Japan and overseas. The
participants exchanged new
knowledge and views, andare expected to contributeextensively to medicine frombasic research to clinicalapplications in the near future.
The first session, ‘Brainand Metabolic Control’,launched the symposium witha wonderful presentation by
Hiroshi Inoue (Kanazawa
University, Japan). Using
sophisticated chemogenetic
and genetic approaches, heshowed that hepatic glucose
production is regulated by
the parasympathetic nervous
system, and also by the vagus
nerve through α-7 nicotinic
acetylcholine receptor in
Kupffer cells, demonstrating
the importance of the brainliver interaction. Ichiro Manabe(Chiba University, Japan)
covered a significant interaction
between the heart and kidney
through the Klf-5-regulated

international students studying
in Japan. In the 37 years since it
was established, the foundation
has provided more than 10,000
grants and other forms ofassistance, totalling about ¥33
billion ($US303 million).
Organizing international
symposia is the foundation’s
most significant activity,
sponsoring specific projects
every three years. The resultsof the projects are reported in a
special symposium, attended byleading international experts inthe field. This year’s symposium‘Brain-Periphery Interactions
in Health and Diseases’, wasrenal production of GM-CSF.
On the other hand, the renalartery sympathetic nerve plays
an important role in response
to cardiac pressure overload,
suggesting a critical functionof the brain-heart-kidney
network. Joel K. Elmquist(UT Southwestern Medical
Center, USA) focused on
the importance of SF-1 in theventromedial hypothalamus(VMH) and demonstrated that
SF-1-positive VMH neurons
control the response to exercise
in skeletal muscle through thesympathetic nervous system.
He also conducted a genetic
screen in fruit flies to identify
SF-1 target genes and foundsome interesting candidates.
In the last two talks, metabolic
interactions between the brain
and peripheral organs, mainly
the liver, were discussed. Hideki

Katagiri (Tohoku University,
Japan) introduced two typesof brain-periphery interaction
involved in metabolic regulation.
He showed that the liver
sends signals in response
to metabolic states, such as
obesity and food shortage,
to the brain via neuronal andhumoral mechanisms, causing
the proliferation of pancreatic
β cells and the suppression ofbrown adipose thermogenesis,
respectively. Jens C. Brüning
(Max Planck Institute,
Germany) presented evidence
demonstrating that insulin
action in hypothalamic agoudirelated peptide (AgRP) neurons
regulates glucose productionin the liver. In addition,
sensory food perception
primes hepatic endoplasmic
reticulum-homeostasis via
activation of hypothalamic

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Norifumi IIJIMA (NIBIOHN,
Japan)

WELCOME ADDRESSSESSION 3: GLIA
AND PERIPHERY

Akira Uehara (President, The
Uehara Memorial Foundation(CEO, Taisho Pharmaceutical
Holdings Co., Ltd.)OPENING REMARKS

LIFE SCIENCE SUPPORTThe Uehara Memorial
Foundation was establishedin 1985 to commemorate thelate Shokichi Uehara, who laid
the foundation for the Taisho
Pharmaceutical Co., Ltd. andwas its president, and later its
chairman. The foundation also
marked the company’s 70th
anniversary. Since then, it has
been supporting research inlife science fields. Its research
grants, including the Uehara
Prize, recognize outstanding
accomplishments, and further
grants are offered for overseas
study. The foundation also
provides living expenses for

PROGRAM

Shuh Narumiya (Chair of
the Organizing Committee)(Professor, Kyoto University)

SESSION 1: BRAIN ANDMETABOLIC CONTROLAKIRA UEHARA
President, The Uehara
Memorial Foundation
CEO, Taisho Pharmaceutical
Holdings Co., Ltd.

scheduled for June 2020, inTokyo, but postponed until June
7 to 9, 2021 and held online, due
to the pandemic.

proopiomelanocortin (POMC)
neurons. Upon high fat-feeding,
POMC neurons are locallyinhibited by activation of arcuate
prepronociceptin (PNOC)expressing neurons, leading
to hyperphagia. Furthermore,maternal high fat-feeding
during lactation increases bodyweight and fat mass of offspring
involving impaired programmingof hypothalamic and striatum
neurocircuits.
Session 2, entitled ‘NeuroImmune Crosstalk for Mucosal
Defense,’ started with a fly
genetic study by Shoichiro
Kurata (Tohoku University,
Japan) to elucidate neuralcontrol of gut homeostasis.
Using an enhancer-trap
screening, they discoveredthat a specific type of neurons
projecting to the gut epithelium
maintains gut homeostasis

Chairperson: Ichiro Manabe &Hideki Katagiri
S1-1. Role of Brain–LiverInteraction in Hepatic Glucose
Metabolism
Hiroshi INOUE (Kanazawa
University, Japan)
S1-2. Neuro–Immune-Metabolic
Regulation of Cardiac
Homeostasis and Disease
Ichiro MANABE (Chiba
University, Japan)
S1-3. SF-1 in the Hypothalamus:
A Molecular Link between
Energy Balance and Exercise
Joel K. ELMQUIST (UTSouthwestern Medical Center,
USA)
S1-4. Neuronal Information
Highways for Systemic
Regulation of Glucose
Metabolism
Hideki KATAGIRI (Tohoku
University, Japan)
S1-5. Brain Insulin Action in
CNS-dependent Control of
Metabolism
Jens C. BRÜNING (Max Planck
Institute, Germany)

SESSION 2: NEURO–IMMUNE CROSSTALKFOR MUCOSAL DEFENSE
Chairperson: Norifumi IijimaS2-1. Neural Control of Gut
Homeostasis in Drosophila
Shoichiro KURATA (Tohoku
University, Japan)
S2-2. Neuro–Immune Control of
Mucosal Virus Infection

Chairperson: Rieko Muramatsu &Takaomi C. Saido
S3-1. Roles of Astroglial IFITM3
and MHCI in Brain Dysfunction
Associated with Systemic
Immune Activation
Kiyofumi YAMADA (Nagoya
University, Japan)
S3-2. Circulating Factors
Regulate Central Nervous
System Regeneration
Rieko MURAMATSU (National
Center of Neurology andPsychiatry, Japan)
S3-3. Physiological andPathological Functions ofMicroglia for Brain Periphery
Interactions
Hiroaki WAKE (Nagoya
University, Japan)
S3-4. Microglia at the
Crossroads of Cortical Wiringand Environmental Signals
Sonia GAREL (IBENS, France)
S3-5. The Effect of Plasmacytoid
Dendritic Cell Depletion on
Alzheimer’s Disease Pathology
Takaomi C. SAIDO (RIKEN,
Japan)
S3-6. Redox Balance in Central
Nervous System and Its Impact
on Aging-related Diseases
Hozumi MOTOHASHI (Tohoku
University, Japan)
S3-7. Novel Genetic Tools forStudying Microglia in the CNS
Marco PRINZ (University ofFreiburg, Germany)S3-8. The Immune System Holdthe Key to Defeat Alzheimer’s
Disease: The Role of
Monocyte-derived Macrophages
Michal SCHWARTZ (The
Weizmann Institute of Science,
Israel)SESSION 4: IMMUNEACTIVATION IN BRAIN
DEVELOPMENT
Chairperson: Yukiko Gotoh
S4-1. Peripheral Cytokines at

Perinatal and Prenatal Stages
Perturb Neurocognitive
Development: Implication in
Schizophrenia
Hiroyuki NAWA (Wakayama
Medical University, Japan)
S4-2. Modulatory Roles of the
Immune System in Shaping
Animal Behaviors
Jun R. HUH (Harvard Medical
School, USA)S4-3. First-line Defense
Mechanisms against Viral
Infection
Yukiko GOTOH (The Universityof Tokyo, Japan)

SESSION 5: EMOTIONAL
BRAIN AND PERIPHERY
Chairperson: Tomoyuki
FuruyashikiS5-1. Stress and Brain–
Gut Interactions: Role ofCorticotropin Releasing Factor
Signaling
Yvette TACHÉ (UCLA, USA)S5-2. Roles of Brain andPeripheral Inflammation in
Stress and Depression
Tomoyuki FURUYASHIKI (Kobe
University, Japan)
S5-3. Artificial Hibernation/
Life-protective State Induced byThiazoline-related Innate
Fear Odors via Sensory TRPA1
Activation
Ko KOBAYAKAWA (Kansai
Medical University, Japan)

SESSION 6:
SENSORIMOTORINTEGRATION
Chairperson: Yoshihiro Yoshihara
S6-1. Elucidation of Excitatory/
Inhibitory Imbalance in theCentral and Peripheral Systemsof Psychiatric Disorders
Shinichiro NAKAJIMA (Keio
University, Japan)
S6-2. The Claustrum
Orchestrates Cortical Slow-wave
Activity
Yoshihiro YOSHIHARA (RIKEN,
Japan)
S6-3. The Circuits Linking
Interoception, Emotion and

Pain—The Role of Parabrachioamygdaloid Network
Fusao KATO (Jikei University,
Japan)
S6-4. Dissecting the Phenotype
of Dystonia Musculorum Mice
Hirohide TAKEBAYASHI (Niigata
University, Japan)

SESSION 7:
BRAIN–PERIPHERYCOMMUNICATIONSIN AGING
Chairperson: Shin-ichiro Imai
S7-1. The NAD World 3.0: The
Importance of eNAMPT/NMNmediated Inter-tissue
Communications in Mammalian
Aging/Longevity Control
Shin-ichiro IMAI (IBRI, Japan;
Washington University (St.
Louis), USA)S7-2. The Hypothalamus andAging
Dongsheng CAI (Albert Einstein
College of Medicine, USA)S7-3. Brain Aging andRejuvenation throughCirculatory Factors
Tony WYSS-CORAY (Stanford
University, USA)SESSION 8: IMMUNECONTROL OF BRAIN
PATHOLOGY
Chairperson: Akihiko Yoshimura
S8-1. Brain-draining Lymphatics
and Neurological Disorders
Jonathan KIPNIS (Washington
University (St. Louis), USA)
S8-2. The Biochemical Dialog
between Major Physiological
Systems Mediated by Immune
Cells
Sidonia FAGARASAN (RIKEN,
Japan)
S8-3. Neural Repair after
Ischemic Brain Injury by Innate
and Adaptive Immunity
Akihiko YOSHIMURA (Keio
University, Japan)

CLOSING REMARKS
Tomoyuki Furuyashiki (Vice Chairof the Organizing Committee)(Professor, Kobe University)

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for survival. Norifumi Iijima(National Institutes ofBiomedical Innovation, Healthand Nutrition, Japan) presented
his findings on roles of cellularand humoral immunity in thevaccination against herpes
simplex virus (HSV)-2, aneurotropic virus. He discoveredthat the establishment oftissue-resident memory T cells
in vaginal tissues, rather thana systemic antibody-based
vaccine provides rapid clearanceof the virus, the finding
exploitable for the developmentof a new HSV vaccine.
Session 3, ‘Glia andPeriphery,’ introduced cuttingedge findings on the role ofglia for the brain-peripheryinteraction. Kiyofumi Yamada(Nagoya University, Japan)
presented a contributionof astrocytes to the brain
dysfunction associated with a
response to systemic immune
activation, showing functions ofan interferon-stimulated gene
IFITM3, as well as the major
histocompatibility complex class
I (H-2D). Rieko Muramatsu(NCNP, Japan) addressed
how circulating factors—
FGF21 and apelin—promoteremyelination of demyelinatedlesions in the central nervous
system by stimulating theproliferation and differentiationof oligodendrocyte precursor
cells. She suggested that a
reduced concentration of
apelin may be responsible forthe inadequate remyelination
apparent in aged mice. Hiroaki
Wake (Nagoya University,
Japan) identified dual roles of
microglia in the regulation of
permeability of the blood-brain
barrier (BBB) via in vivo imaging.
He showed that systemic
inflammation results in the
recruitment of microglia to the
cerebral vasculature, with themicroglia initially maintaining
BBB integrity by making theclaudin-5–dependent contact

with endothelial cells. However,
the microglia subsequently
disrupt BBB function by
mediating phagocytosis ofastrocytic endfeet. The potential
role of BBB leakage in recruiting
peripheral blood cells during thelater phases of inflammation
was also discussed. Sonia Garel(CNRS, INSERM, Université PSL,France) talked about the roleof microglia in the regulation of
the forebrain circuits. Depletionor functional perturbation of
microglia impairs the timely
positioning of specific subsets
of interneurons as well as
their subsequent functional
integration into the neocortex,
with these effects having
physiological and behaviouralconsequences. She also
showed that responses of
microglia to the microbiome
are sexually dimorphic, which
has major implications for our
understanding of sexual biases
in the occurrence of microgliarelated neurodevelopmental
disorders. The remaining talks
focused on novel glial roles andfunctions in neuroinflammationand neurodegenerative disease.
Using his original Alzheimer’s
disease (AD) mouse model(AppNL-G-F/NL-G-F), Takaomi
C. Saido (RIKEN, Japan) showeddistinct microglia subclasses
exert differential effects on
amyloid β peptide deposition. In
particular, his findings suggestthat microglia expressing sialicacid-binding immunoglobulinlike lectin (Siglec)-H contributeto amyloid β peptide deposition
and AD pathogenesis. Hozumi
Motohashi (Tohoku University,
Japan) highlighted theimportance of redox balancein the central nervous system
for age-related diseases. She
presented an interesting findingthat neuron-specific deficiency
of CARS2, a mitochondrial
sulfur metabolizing enzyme,
decreases glutathione in theliver, suggesting the presence

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A DV E RT I S E M E N T FE AT U R E

of a sulfur metabolic network
connecting the central nervous
system and the liver. MarcoPrinz (University Hospital
Freiburg, Germany) foundhexosaminidase b (Hexb), alysosomal enzyme that is stably
expressed in microglia evenunder pathological conditions.
He generated HexbtdTomato
and HexbCreERT2 mouselines and showed that they
could be novel genetic tools
useful for selectively visualizing
and targeting microglia,
respectively. Michal Schwartz(The Weizmann Institute of
Science, Israel) presented thedata relevant to immunotherapy
against Alzheimer’s disease(AD) and dementia. Immune
checkpoint blockade arrestsand even reverses cognitive loss
with reduction of inflammation

and brain pathology in several
murine models of AD andage-related dementia. The
mechanism includes monocyte
recruitment by interferon
gamma signalling in the choroid
plexus.
Session 4, ‘Immune
Activation in Brain
Development,’ illustrated
elaborate long-term
consequences and mechanismsof immune activation in brain
development and functions.
Hiroyuki Nawa (Wakayama
Medical University, Japan)
reported a range of circuit-level
alterations in a rodent modelof schizophrenia induced byneonatal injection of epidermal
growth factor (EGF), withdopaminergic aberrations
being prominent among
these alterations. Jun R. Huh© Viaframe / Getty Images

A DV E RT I S E M E N T FE AT U R E(Harvard Medical School, USA)summarized a series of studies
on the mechanisms that underlie
autism spectrum disorder(ASD) induced by maternal
immune activation (MIA). He
implicated interleukin (IL)-17a
as a key mediator of the effectsof MIA on embryos, with thiscytokine having been foundto induce aberrant laminarorganization and activationof the dysgranular zone of the
primary somatosensory cortex.
Of interest, however, expressionof IL-17a induced in adult mice bybacterial lipopolysaccaride wasfound to temporarily rescue thesocial behaviour deficits induced
by MIA, revealing a beneficial
effect of inflammation onneurodevelopmental disorders(in particular, those associatedwith a primed immune system).

He suggested that the role of
IL-17a as a neuromodulator
may be evolutionarily older
than its function as an
immunomodulator. Finally, heshowed that MIA activates anintegrated stress response in
an IL-17a-dependent manner,
resulting in a global reduction
in mRNA translation and thedevelopment of behaviouralabnormalities, only in maleoffspring. Although themechanism underlying thissex-specific difference remains
unclear, this phenomenon
may account for the higher
incidence of ASD in males.
Yukiko Gotoh (The Universityof Tokyo, Japan) reported novel
defense mechanisms against
viral infection within the brain,
specifically regarding the switch
between type I interferon

expression and apoptosis.
Session 5, entitled‘Emotional Brain and Periphery,’elaborated on central andperipheral mechanisms forstress responses contributing
to survival and diseases.
Yvette Taché (UCLA, USA)demonstrated central andperipheral roles of corticotropinreleasing factor (CRF)
receptors for the brain-gut
interaction under stress. She
discovered that CRF and CRF
receptor subtype 1 (CRFR1) indistinct brain areas mediate
stress-related colonic motor
stimulation and visceral
hyperalgesia via the autonomic
nervous system. Besides,
peripheral CRF and CRF-R1 play
crucial roles for stress-relatedcolonic secretomotor activationand visceral hyperalgesia. Thesefindings may be relevant to thepathology of irritable bowel
syndrome, a stress sensitive
functional bowel disorder.
Tomoyuki Furuyashiki (Kobe
University, Japan) demonstrated
roles of inflammation for chronicsocial stress-induced emotional
disturbance. He discoveredthat chronic stress activates
microglia through innate
immune receptors, leading to
prefrontal neuronal atrophyand depressive-like behaviour
via proinflammatory cytokines.
In parallel, chronic stressmobilizes myeloid cells in an
adrenergic receptor-dependent
mechanism, contributing toemotional disturbance. Ko
Kobayakawa (Kansai Medical
University, Japan) revealed
novel life-protective roles ofinnate fear odors throughinducing an artificial hibernation
state. He discovered that
sensory presentation ofthiazoline-related fear odoursorchestrates hypothermia,
hypometabolism, anti-hypoxia,
and anti-inflammatory immune
enhancement through Trpa1mediated signals via trigeminal

and vagal afferents, promoting
survival under lethal conditions.
These findings could be
exploited to develop effective
sensory interventions.
Session 6, entitled‘Sensorimotor Integration,’covers new attempts tounderstand how the brain
integrates multimodal peripheral
information in healthy anddisease conditions. Shinichiro
Nakajima (Keio University,
Japan) presented his ongoingclinical studies collecting
multidimensional datacomprising of symptoms, brain
connectivity, and brain andperipheral metabolic changes
from various psychiatricpatients. Multivariate analysesof these data will pave theway towards elucidating theheterogeneity and comorbidityof psychiatric disorders torebuild the diagnostic systemand develop rational treatments
for mental illnesses. Yoshihiro
Yoshihara (RIKEN, Japan)
demonstrated crucial roles of
the claustrum, a thin, sheetlike neural structure locatedbetween the insular cortex
and the striatum, in shaping
the pattern of cortical activity.
He discovered that claustrum
neurons fire during sleep anddrowsy states and orchestrateslow-wave cortical activity
by synchronous interneuron
firing that leads to prolonged
silencing of neocortical neurons.
Fusao Kato (Jikei University
School of Medicine, Japan)
identified crucial roles ofneuronal projections from thelateral parabrachial nucleus(LPB) to the central amygdala(CeA) and their plasticity asa hub for aversive sensory
information and defensive/
survival responses. He
demonstrated that inflammatory
pain potentiates LPB-CeA
synaptic transmission via
the neuropeptide CGRP,
contributing to widespread

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A DV E RT I S E M E N T FE AT U R E

tactile sensitization, a typicalsymptom of chronic pain
patients. Hirohide Takebayashi(Niigata University, Japan)
explained neuroanatomicalmechanisms for neural andnon-neural phenotypes ofgenetic dystonia mice with adystonin mutation. He showedthat the disruption of distinct
dystonin isoforms underlies theabnormality in the movement,
skin, and heart, and that thedefective sensory feedback
circuit is responsible for their
dystonia-like movements.
Session 7, ‘Brain-Periphery
Communications in Ageing,’
started with a remarkable
presentation by Shin-ichiro
Imai (Washington University,
USA; Institute of Biomedical
Research and Innovation,
Japan). He emphasized theimportance of the inter-tissuecommunication between the
hypothalamus and adipose
tissue through the secretionof extracellular nicotinamide
phosphoribosyltransferase(eNAMPT) in mammalianageing/longevity control. He
also presented the most recent
findings from the first humanclinical trial on nicotinamidemononucleotide (NMN), a
key NAD+ intermediate anda product of the NAMPT
reaction. The importance ofthe hypothalamic function was

further emphasized in the next
presentation by Dongsheng
Cai (Albert Einstein College ofMedicine, USA). He -showedthat hypothalamic neural stem/
progenitor cells (htNSCs)
are important in producing
exosomes that contain many
microRNA species and convey
significant anti-ageing effects
in mice. Interestingly, his lab
employed an htNSC subclone
to derive- neurospheres which
are able to mimic pancreatic
islets, secreting microRNA-rich
exosomes as well as multiple
peptides, and when peripherally
implanted in vivo, these
spheres can lead to enhanced
survival and an amelioration of
hyperglycemia in mouse modelsof streptozotocin-induced severe
diabetes. Tony Wyss-Coray(Stanford University, USA)revealed the power of blood tomodulate ageing. He conducteda plasma proteome labelling
experiment and found a numberof plasma proteins whose uptake
was correlated or anti-correlated
to endothelial transcription. He
showed that with age, brains
reduced the uptake of plasma
proteins, most likely due to“specific” and “non-specific”
changes (increases in caveolindriven uptake and decreases
in clathrin-driven uptake). He
also showed that selective lossof matrix pericytes contributed

to changes in plasma protein
uptake in Alzheimer’s disease.
Presentations in this session
firmly demonstrated theimportance of brain-peripherycommunications in mammalianageing and gave critical insights
into the development of antiageing interventions.
Session 8, entitled ‘Immune
Control of Brain Pathology,’
started with ground-breaking
discoveries by Jonathan Kipnis(Washington University, USA)on brain-draining lymphatics,
its functions, and the relevanceto neurological disorders. He
discovered that meningeal
myeloid cells sample brain
interstitial fluids for antigen
presentation for immune cells
and that the lymphatics drain
brain molecules and cells tocervical lymph nodes, work that
contributes to antibody-based
therapeutics of Alzheimer’s
disease. He also identified a
new entry route of meningeal
myeloid cells that migrate
directly from the skull bonemarrow through dural channels
surrounding blood vessels.
Sidonia Fagarasan (RIKEN
IMS, Kyoto University, Japan)
elucidated an unexpected
systemic metabolic effect ofsustained activation of adaptive
immunity. She discovered thatthe deletion of the inhibitory
receptor PD-1 induces serum

depletion of some aminoacids, particularly tryptophan,due to their accumulation in
activated T cells, leading tobrain monoamine deficiency
and anxiety and fear responses.
She also introduced a novel
immunoregulatory role ofthe local metabolic shift in
the lymph node for adaptive
immune responses. Lastly,
Akihiko Yoshimura (Keio
University, Japan) presented
his phenomenal discoveries on
innate and adaptive immunity
not only for the progressionof brain ischemia-reperfusion
injury but also for neurologicalrepair. He demonstrated thatextracellular damage-associatedmolecular patterns (DAMPs)
activate infiltrated macrophages
through a TLR2/TLR4dependent mechanism but arecleared by macrophages throughtype A scavenger receptors.
During the chronic phase,
regulatory T cells accumulate
in the brain, regulate astrocyte
activation, and reduce neuraldamages by Amphiregulin.
This three-day symposium
attracted 463 participants,
who enjoyed these excellent
presentations and discussions.

The Uehara Memorial Foundation

ORGANIZING COMMITTEESHUH NARUMIYA
Chair, Kyoto University
Graduate School of Medicine

TOMOYUKIFURUYASHIKI
Vice-Chair, Kobe University
Graduate School of Medicine

SHIN-ICHIRO IMAIHIDEKI KATAGIRIYUKIKO GOTOH

Washington University
School of Medicine in
St. Louis; Foundation for
Biomedical Research andInnovation at Kobe

Tohoku University
Graduate School of Medicine

The University of Tokyo
Graduate School of
Pharmaceutical Sciences

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