2017/9/25

Chronic stress induces fatal organ dysfunctions via a new neural circuit | EurekAlert! Science News
PUBLIC RELEASE: 21-AUG-2017

Chronic stress induces fatal organ dysfunctions
via a new neural circuit
HOKKAIDO UNIVERSITY
New research reveals the mechanisms behind the e ects ofchronic stress and tiny in ammations in the brain on fatal
gut failure.
Hokkaido University researchers revealed that fatal gut
failure in a multiple sclerosis (MS) mouse model, EAE, underchronic stress is caused by a newly discovered nerve
pathway. The ndings could provide a new therapeuticstrategy for the intractable disease, particularly progressiveMS, which has no therapeutic strategy at present.
MS a ects an estimated 2.5 million people worldwide andcauses motor dysfunction, impaired vision andgastrointestinal failures. It is an autoimmune condition of
the central nervous system (CNS) mediated by immune cells
called autoreactive CD4+ T cells. In EAE mouse models, thesepathogenic CD4+ T cells can cause a MS-like disease whentransfused intravenously to healthy mice.
In previous studies using EAE mouse models, Professor

IMAGE: MICRO INFLAMMATION DEVELOPED AT
SPECIFIC SITES IN THE BRAIN (TOP PANEL).
PATHOLOGICAL ANALYSIS OF THE STOMACHSHOWED DAMAGE TO TISSUES IN THE STOMACH(BOTTOM RIGHT) COMPARED TO MICE NOTUNDER... view more ą
CREDIT: ARIMA Y., ET AL. ELIFE. AUGUST 15, 2017.

Masaaki Murakami of Hokkaido University and hiscolleagues revealed autoreactive CD4+ T cells cross the blood-brain barrier at speci c sites and cause
in ammation in the CNS including the brain and spinal cord. The emergence of a "gateway" for autoreactive
CD4+ T cells to cross the barrier was caused by regional neural activation at those sites, which is triggered by
speci c sensory-sympathetic interactions. They termed these phenomena as gateway re exes and havepublished on at least three, the gravity-, electric-, and pain-gateway re exes.
In the present study, the team and their collaborators in Japan and Germany investigated the possible
relations between chronic stress, micro-in ammation in the brain, and stress-related organ failures.
They put healthy mice under stress by disturbing their sleep or by rearing them on wet bedding. The transferof pathogenic CD4+ T cells under the stress caused severe symptoms such as gastrointestinal failures andeven sudden death. Cell transfer or stress alone did not cause these symptoms. Subsequent investigations
revealed a complex nerve-related mechanism behind this process.
The injected pathogenic CD4+ T cells accumulated around blood vessels in two speci c sites at the center ofthe brains of the stressed mice. Micro-in ammation developed around speci c blood vessels, and thein amed sites then released a small molecule called ATP that switched on a nerve pathway that is normallyturned o . This switch led to gut dysfunctions, bleeding and failure. Also, the bleeding led to increased levelsof potassium in the blood, which was one of factors leading to heart failure.
The team was able to prevent gut failure by suppressing in ammation in the brain or blocking nerve pathways
from the brain to the gut. The results suggest that tiny areas of in ammation around some speci c vessels inthe brain, which are known to happen in various brain diseases including multiple sclerosis, are a risk factor
for organ dysfunctions including severe gut and heart failure.
"These results demonstrate a direct link between brain micro-in ammation and fatal gastrointestinal diseases
via the establishment of a new neural pathway under stress," says Masaaki Murakami. "Micro-in ammation in
the brain is also seen in Alzheimer's disease and Parkinson's disease. So it's of particular interest to investigate
possible connections between brain micro-in ammations and organ dysfunctions, including those within thebrain itself, in those patients."
The study was published in the journal eLife.
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https://www.eurekalert.org/pub_releases/2017-08/hu-csi082117.php

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2017/9/25

Chronic stress induces fatal organ dysfunctions via a new neural circuit | EurekAlert! Science NewsMedia Contact
Naoki Namba
81-117-062-185¬ @hokkaido_uni
https://www.global.hokudai.ac.jp/ https://www.eurekalert.org/pub_releases/2017-08/hu-csi082117.php

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