2017/9/25

Chronic Stress Induces Fatal Organ Dysfunctions Via a New Neural Circuit - Science Newsline

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6/12/14Published: August 21, 2017.
Released by Hokkaido University

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New research reveals the mechanisms behind the effects of chronic stress and tiny
inflammations in the brain on fatal gut failure.
Hokkaido University researchers revealed that fatal gut failure in a multiple sclerosis (MS) mousemodel, EAE, under chronic stress is caused by a newly discovered nerve pathway. The findings
could provide a new therapeutic strategy 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 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 MS­like disease when transfused intravenously to healthymice.
In previous studies using EAE mouse models, Professor Masaaki Murakami of Hokkaido
University and his colleagues revealed autoreactive CD4+ T cells cross the blood­brain barrier at
specific sites and cause inflammation 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 byregional neural activation at those sites, which is triggered by specific sensory­sympathetic
interactions. They termed these phenomena as gateway reflexes and have published on at leastNoninvasive Ultrasound Pulses
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StrokeMore »three, the gravity­, electric­, and pain­gateway reflexes.
In the present study, the team and their collaborators in Japan and Germany investigated thepossible relations between chronic stress, micro­inflammation in the brain, and stress­relatedorgan failures.
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 the stress caused severe symptoms such as
gastrointestinal failures and even sudden death. Cell transfer or stress alone did not cause thesesymptoms. Subsequent investigations revealed a complex nerve­related mechanism behind thisprocess.
The injected pathogenic CD4+ T cells accumulated around blood vessels in two specific sites atthe center of the brains of the stressed mice. Micro­inflammation developed around specificblood vessels, and the inflamed sites then released a small molecule called ATP that switched ona nerve pathway that is normally turned off. This switch led to gut dysfunctions, bleeding andfailure. Also, the bleeding led to increased levels of potassium in the blood, which was one offactors leading to heart failure.
The team was able to prevent gut failure by suppressing inflammation in the brain or blocking
nerve pathways from the brain to the gut. The results suggest that tiny areas of inflammation
around some specific vessels in the brain, which are known to happen in various brain diseases
including multiple sclerosis, are a risk factor for organ dysfunctions including severe gut andheart failure.

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2017/9/25

Chronic Stress Induces Fatal Organ Dysfunctions Via a New Neural Circuit - Science Newsline"These results demonstrate a direct link between brain micro­inflammation and fatal
gastrointestinal diseases via the establishment of a new neural pathway under stress," says
Masaaki Murakami. "Micro­inflammation in the brain is also seen in Alzheimer's disease andParkinson's disease. So it's of particular interest to investigate possible connections between
brain micro­inflammations and organ dysfunctions, including those within the brain itself, in thosepatients."
The study was published in the journal eLife.

Journal reference: dx.doi.org/10.7554/eLife.25517
The above story is based on materials provided by Hokkaido University.

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