PRESS RELEASE
Chiba, October 20, 2021
New Study Helps in Finally Breaking the “Silence” on the Brain Network
Scientists chemically suppress areas of the brain and then image brain activity to reveal how
this triggers other complex operational networks
Studying the complex network of operations in the brain not only helps us understand its
working better, but also provides avenues for potential treatments for brain disorders.
But linking the brain network to actual behavior is challenging. In a new study,
researchers have discovered that pinpointed suppression or “silencing” of certain areas ofmonkey brains using genetically engineered drugs can be used to reveal changes to theiroperational network and the subsequent behavioral effects.
Scientists have been studying the human brain for centuries, yet they have only scratched
the surface of all there is to know about this complex organ. In 1990, the face ofneuroscience changed with the invention of functional magnetic resonance imaging (fMRI).
fMRI works on the idea that when a certain area of the brain is being used, it experiences anincrease in blood flow. This technique has been used to study neurological activity in thebrains of myriad animals and humans as well, providing valuable information on cognitiveand movement-based functions.
fMRI has also revealed that “activating” a certain part of the brain has effects on otheranatomically or functionally connected regions. Trying to solve this “network” of operationsin the brain is one of the key issues in neuroscience.
In a recent study (https://doi.org/10.1016/j.neuron.2021.08.032), a research team—including Toshiyuki Hirabayashi and Takafumi Minamimoto from the National Institutes forQuantum Science and Technology (QST)—has shown that gene-targeting drugs in macaquemonkeys can cause multifaceted behavioral effects via the altered operation of relevant
brain networks, thus opening a critical path towards understanding the network ofoperations underlying higher functions in primates (monkeys, humans etc.). “Our techniquewill allow us to study how disturbances to the functional brain network lead to certain
symptoms. This will help us to work backwards to clarify the network mechanisms behindbrain disorders with similar symptoms, thus leading to new treatments,” reveals Dr.
Toshiyuki Hirabayashi, principal researcher at QST, who led the study.
Conventional approaches to activating or suppressing areas of the brain include electricalstimulation or the injection of a psychoactive substance called muscimol, but recent
research has focused on using genetic techniques of targeting due to how specific they are.
Called chemogenetics, these techniques rely on artificial drugs that are designed to
specifically bind to genetically induced artificial protein called “receptors.” The drugs bind to
the receptors, and thus influence physiological and neurological processes in the brain,spinal cord, and other parts of the body where the receptors are genetically expressed.
Combining chemogenetics with fMRI enables non-invasive visualization of network-levelchanges induced by local activity manipulation. But, unlike the recent study, chemogenetic
fMRI studies so far have focused on a resting state, which might not provide the most useful
results when trying to study task-related or sensory-related activities.
For their investigation into functional brain networks, the research team studied the effects
of fMRI guided chemogenetics on hand-grasping in macaques. To do this, they first studied
the part of the brain that is responsible for precise finger movement, and then silenced(suppressed) it for one hand using a “designer receptor exclusively activated by designerdrugs” (DREADD). They then gave the monkeys with silenced hand-grasping skills a task thatinvolved picking up food pellets from a board consisting of small slots. They found that themonkeys could pick up pellets well with the non-silenced hand, which was on the same sideof the body as the silenced brain region. But they struggled with using the affected hand,which was on the opposite side. The scientists also saw that the designer drug caused a
reduced fMRI signal from “downstream” areas of the monkey brains, providing insight into
the rest of the network dysfunction underlying the altered hand-grasping behavior. Finally,
they saw that silencing the hand sensory region caused unexpectedly elevated activity in thefoot sensory region with an increased sensitivity in the foot on the opposite side of the body,which further suggested that portions of the network have inhibitory effects on other partsof the system.
These findings demonstrate that targeted chemogenetic silencing in macaques can cause
stimulatory and inhibitory, i.e., bidirectional changes in brain activity, which can be
identified using fMRI. Furthermore, chemogenetics offer a minimally invasive way torepeatedly manipulate the same location on the brain without causing damage to the brain
tissue, making the approach beneficial for the study of the functional brain network.
According to Dr. Hirabayashi, “Applying chemogenetic fMRI to higher brain functions inmacaques like memory or affection will lead to translational understanding of causal
network mechanisms for those functions in the human brain.”With developments like these, it is easy to see humankind having a clearer picture of theworkings of the human brain soon!

Schematic representation of the targeted silencing experiment.
The scientists found that silencing the brain area (SI) for hand sensation surprisingly increased activity in thebrain area for foot sensation.
Image courtesy: Toshiyuki Hirabayashi from National Institutes for Quantum Science and Technology

Research Article“Chemogenetic dissection of the primate prefronto-subcortical pathways for working
memory and decision-making”
ToshiyukiHirabayashi1,5, YujiNagai1, YukikoHori1, Ken-ichiInoue2,3, IchioAoki4,
MasahikoTakada2, TetsuyaSuhara1, MakotoHiguchi1, TakafumiMinamimoto1“Neuron”: October 20, 2021
DOI: https://doi.org/10.1016/j.neuron.2021.08.032

About National Institutes for Quantum Science and Technology, JapanThe National Institutes for Quantum Science and Technology (QST) was established in April
2016 to promote quantum science and technology in a comprehensive and integrated
manner. The new organization was formed from the merger of the National Institute ofRadiological Sciences (NIRS) with certain operations that were previously undertaken by theJapan Atomic Energy Agency (JAEA).

QST’s mission is to raise the level of quantum and radiological sciences and technologies
through its commitment to research and development into quantum science andtechnology, the effect of radiation on humans, radiation emergency medicine, and themedical use of radiation.
To ensure that research and development delivers significant academic, social and economic
impacts, and to maximize benefits from global innovation, QST is striving to establish worldleading research and development platforms, explore new fields, and serve as a center forradiation protection and radiation emergency medicine.

Website: https://www.qst.go.jp/site/qst-english/

About Dr. Toshiyuki Hirabayashi from National Institutes for Quantum Science andTechnology, JapanDr. Toshiyuki Hirabayashi is a Principal Researcher in the Department of Functional Brain
Imaging at the National Institutes for Quantum Science and Technology (QST), Japan. He
obtained his Ph.D. from the University of Tokyo School of Medicine in 2006. He then joined
his alma mater as a research associate in 2007, continuing to university lecturer by 2013. In2015, he became a senior researcher at the National Institute of Radiological Sciences (NIRS),
which later became QST. Dr. Hirabayashi’s research interests include functional neuralcircuits, memory retrieval, and fMRI/electrophysiology with chemogenetics in macaques. In
2014, he was awarded a Japan Neuroscience Society Young Investigator Award.

Funding information
This study is supported by MEXT/JSPS KAKENHI (JP15H05917 and JP20H05955 to T.M. and
JP17H02219 to T.H.), by AMED (17dm0107066h to I.A., JP18dm0207003 to M.T.,
JP18dm0307021 Q14 to K.I., JP21dm0307007 to T.H., and JP20dm0107146 to T.M.), by thecooperative research program at PRI, Kyoto University, and by National Bio-Resource
Project “Japanese Monkeys” of MEXT, Japan.
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Tel: +81-43-206-3026 Email: info@qst.go.jp