2017/9/25

Chronic stress induces fatal organ dysfunctions via a new neural circuit -- ScienceDaily

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Chronic stress induces fatal organ dysfunctions via a new neural circuit
Date:­August 21, 2017
Hokkaido University
New research reveals the mechanisms behind the eﬀects ofchronic stress and tiny inﬂammations in the brain on fatal gut
failure.

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Pathological analysis of the stomach showed damage to tissues in thestomach (bottom right) compared to mice not under stressful conditions(bottom left).
Credit: Copyrighted image; Arima Y., et al. eLife, August 15, 2017.

New research reveals the mechanisms behind the eﬀects ofchronic stress and tiny inﬂammations in the brain on fatal gut
failure.
Hokkaido University researchers revealed that fatal gut failure in a multiple
sclerosis (MS) mouse model, EAE, under chronic stress is caused by a new‐ly discovered nerve pathway. The ﬁndings could provide a new therapeuticstrategy for the intractable disease, particularly progressive MS, which has
no therapeutic strategy at present.
MS aﬀects an estimated 2.5 million people worldwide and causes motor
dysfunction, impaired vision and gastrointestinal failures. It is an autoim‐
mune condition of the central nervous system (CNS) mediated by immune
cells called autoreactive CD4+ T cells. In EAE mouse models, these path‐ogenic CD4+ T cells can cause a MS-like disease when transfused intra‐
venously to healthy mice.
In previous studies using EAE mouse models, Professor Masaaki Murakami
of Hokkaido University and his colleagues revealed autoreactive CD4+ Tcells cross the blood-brain barrier at speciﬁc sites and cause inﬂammationin the CNS including the brain and spinal cord. The emergence of a "gate‐way" for autoreactive CD4+ T cells to cross the barrier was caused by re‐gional neural activation at those sites, which is triggered by speciﬁc senso‐

https://www.sciencedaily.com/releases/2017/08/170821102733.htm

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Chronic stress induces fatal organ dysfunctions via a new neural circuit -- ScienceDaily
ry-sympathetic interactions. They termed these phenomena as gateway re‐
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In the present study, the team and their collaborators in Japan and Ger‐
many investigated the possible relations between chronic stress, micro-in‐
ﬂammation in the brain, and stress-related organ failures.

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They put healthy mice under stress by disturbing their sleep or by rearing
them on wet bedding. The transfer of pathogenic CD4+ T cells under thestress caused severe symptoms such as gastrointestinal failures and evensudden death. Cell transfer or stress alone did not cause these symptoms.
Subsequent investigations revealed a complex nerve-related mechanism
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The injected pathogenic CD4+ T cells accumulated around blood vessels in
two speciﬁc sites at the center of the brains of the stressed mice. Micro-in‐
ﬂammation developed around speciﬁc blood vessels, and the inﬂamed sites
then released a small molecule called ATP that switched on a nerve path‐way that is normally turned oﬀ. This switch led to gut dysfunctions, bleed‐ing and failure. Also, the bleeding led to increased levels of potassium in theblood, which was one of factors leading to heart failure.
The team was able to prevent gut failure by suppressing inﬂammation in thebrain or blocking nerve pathways from the brain to the gut. The results sug‐gest that tiny areas of inﬂammation around some speciﬁc vessels in thebrain, which are known to happen in various brain diseases including multi‐
ple sclerosis, are a risk factor for organ dysfunctions including severe gut
and heart failure.
"These results demonstrate a direct link between brain micro-inﬂammationand fatal gastrointestinal diseases via the establishment of a new neuralpathway under stress," says Masaaki Murakami. "Micro-inﬂammation in thebrain is also seen in Alzheimer's disease and Parkinson's disease. So it's ofparticular interest to investigate possible connections between brain microinﬂammations and organ dysfunctions, including those within the brain it‐
self, in those patients."
The study was published in the journal eLife.

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Story Source:
Materials provided by Hokkaido University. Note: Content may be edited
for style and length.

Marĳuana May Produce PsychoticLike Effects in High-Risk
Individuals
Looking Stressed
Can Help Keep thePeace

Journal Reference:
1. Yasunobu Arima, Takuto Ohki, Naoki Nishikawa, Kotaro Higuchi, Mitsu‐toshi Ota, Yuki Tanaka, Junko Nio-Kobayashi, Mohamed Elfeky, Ryota
Sakai, Yuki Mori, Tadafumi Kawamoto, Andrea Stofkova, Yukihiro
Sakashita, Yuji Morimoto, Masaki Kuwatani, Toshihiko Iwanaga,
Yoshichika Yoshioka, Naoya Sakamoto, Akihiko Yoshimura, Mitsuyoshi
Takiguchi, Saburo Sakoda, Marco Prinz, Daisuke Kamimura, Masaaki
Murakami. Brain micro-inﬂammation at speciﬁc vessels dysregu‐lates organ-homeostasis via the activation of a new neural circuit.
eLife, 2017; 6 DOI: 10.7554/eLife.25517

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Hokkaido University. "Chronic stress induces fatal organ dysfunctions via a
new neural circuit." ScienceDaily. ScienceDaily, 21 August 2017.
<www.sciencedaily.com/releases/2017/08/170821102733.htm>.

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