Life science
Medical & healthcare, Drug discovery

Switching off specific brain cells protects against stress
Drug Innovation Center, Graduate School of Pharmaceutical Sciences
Associate Professor Atsushi Kasai

https://researchmap.jp/read0136710?lang=en

Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences
Professor Hitoshi Hashimoto		

https://researchmap.jp/hitoshi-hashimoto?lang=en

Brain-wide activation mapping

ClaustrumStress

A reliable marker⇒「Claustrum」
activation
Anxiety, depression▍ Background & Results
Previous research had highlighted the amygdala as center toprocessing negative emotions, but understanding the global impact of stress on the brain was limited. We advanced this by quantitatively mapping neuron activation throughout the entire brain
following stress in a mouse model, utilizing brain-wide activation
mapping and machine learning to classify the data. Our findings
revealed that stress response is characterized predominantly byactivation in the claustrum. Specific claustrum neurons, when chemogenetically activated, were found to induce anxiety-related behaviors. In contrast, their suppression diminished such behaviors,suggesting a pivotal role in stress-induced emotional regulation.
Additionally, the claustrum receives inputs from stress-activatedamygdala neurons, with targeted optogenetic activation of this circuit alone prompting anxiety behaviors, highlighting the amygdala-claustrum circuit’s significance. Repeatedly suppressing claustrum activity during stress exposure also reduced depression-likebehaviors, indicating its potential as a therapeutic target for mental
health conditions. Prior to this, the claustrum was implicated inconsciousness and brainwave modulation but its exact functionin emotional response was ambiguous. This study not only opens
avenues for mental illness treatment innovations but also enhances
our understanding of the neural underpinnings of emotions, attention, and consciousness.

▍ Significance of the research and Future perspective

Fig 1

Activation of
Inactivation of
CLA
ensemble」「CLA ensemble」「⇒anxiety behaviors ⇒ increase resilience
to repeated stress
80＊

Interaction ratio

The brain’s response to stress is vital for selecting appropriate
behaviors that ensure safety and survival. However, excessive or
repeated stress can lead to mental health issues such as anxiety
disorders. Thus, understanding the mechanisms of stress response
may help reveal the onset mechanisms of mental illnesses. In ourstudy, we used a unique whole-brain imaging system, FAST system, in conjunction with reporter mice that label activated neurons
with fluorescent proteins, to closely examine the brain immediately
after stress exposure. We analyzed this comprehensive brain activation maps with machine learning classification, and identified
that activation of the claustrum, a thin sheet-like brain regions underneath the cerebral cortex, is characteristic of a stressed brain.
Furthermore, through neuroanatomical, chemogenetic, and optogenetic techniques, we found that activation a group of cells within
the claustrum elicits anxiety-related behaviors, while their inhibition
can prevent anxiety and depression-like behaviors.

Time spentin open arms (s)Life science

Abstract

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Veh CNOhM3Dq

Elevated plus maze

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Fig 2

In this study, it has been discovered that a distinct cluster of neurons in the claustrum orchestrates the manifestation of anxiety anddepression-like behaviors following stress. These findings open
new avenues for understanding the pathogenesis of stress-related
mental illnesses and pave the way for the innovation of novel treatment strategies. This progress promises to lead to further research
into understanding the intricacies of how the mind functions.

P a t e n t
Tr e a t i s e

Niu, Misaki; Kasai, Atsushi et al. Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses. Science Advances. 2022,
Volume 8 (No.11), eabi6375. doi: 10.1126/sciadv.abi6375

URL
K e y w o r d stress, anxiety, claustrum, whole-brain imaging