Chronic stress induces fatal organ dysfunctions via a new neural circuit

August 22, 2017
Micro inflammation developed at specific sites in the brain (top panel). Pathological analysis of the stomach showed damage to tissues in the stomach (bottom right) compared to mice not under stressful conditions (bottom left). Credit: Arima Y., et al. eLife. August 15, 2017.

Hokkaido University researchers revealed that fatal gut failure in a multiple sclerosis (MS) mouse model 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, these pathogenic CD4+ T cells can cause an MS-like when transfused intravenously to healthy mice.

In previous studies using EAE mouse models, Professor Masaaki Murakami of Hokkaido University and his colleagues revealed autoreactive CD4+ T cells cross the blood-brain 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 by regional neural activation at those sites, which is triggered by specific sensory-sympathetic interactions. They termed these phenomena as gateway reflexes and have now published on at least three: the gravity-, electric-, and pain-gateway reflexes.

In the present study, the team and their collaborators in Japan and Germany investigated the possible relations between , micro-inflammation 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 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 these symptoms. Subsequent investigations revealed a complex nerve-related mechanism behind this process.

The injected pathogenic CD4+ T accumulated around blood vessels in two specific sites at the center of the brains of the stressed mice. Micro-inflammation developed around specific blood vessels, and the inflamed sites then released a small molecule called ATP that switched on a nerve pathway that is normally turned off. This switch led to gut dysfunctions, bleeding and . Also, the bleeding led to increased levels of potassium in the blood, one of factors 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 and heart failure.

"These results demonstrate a direct link between brain micro-inflammation and fatal gastrointestinal diseases via the establishment of a new neural pathway under ," says Masaaki Murakami. "Micro-inflammation 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-inflammations and organ dysfunctions, including those within the itself, in those patients."

The study was published in the journal eLife.

Explore further: New biomarkers of multiple sclerosis pathogenesis

More information: Yasunobu Arima et al, Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit, eLife (2017). DOI: 10.7554/eLife.25517

Related Stories

New biomarkers of multiple sclerosis pathogenesis

May 22, 2017
Multiple sclerosis (MS) is a chronic debilitating inflammatory disease targeting the brain. The pathogenesis of MS remains largely unknown, though brain tissue damage in MS is likely due to immune cells attacking myelin basic ...

Immune system cells cause severe malaria complication in mouse brain

December 1, 2016
Immune system cells known as cytotoxic T cells attack blood vessels and cause fatal swelling in the brains of mice with a condition that mirrors a severe complication of malaria in humans. These are the findings of a new ...

Researchers find molecular trigger for brain inflammation

April 27, 2017
Brain inflammation is a key component of multiple sclerosis, Alzheimer's, Parkinson's, ALS, and most other major neurodegenerative diseases. How inflammation starts, how it's sustained, and how it contributes to these diseases ...

A surprising new link between inflammation and mental illness

June 14, 2017
Up to 75 percent of patients with systemic lupus erythematosus—an incurable autoimmune disease commonly known as lupus—experience neuropsychiatric symptoms. But so far, our understanding of the mechanisms underlying lupus' ...

Researchers identify how inflammation spreads through the brain after injury

March 8, 2017
Researchers have identified a new mechanism by which inflammation can spread throughout the brain after injury. This mechanism may explain the widespread and long-lasting inflammation that occurs after traumatic brain injury, ...

Experimental drug shows promise in treating Alzheimer's disease

October 25, 2016
An experimental drug shows promise in treating Alzheimer's disease by preventing inflammation and removing abnormal protein clumps in the brain that are associated with the disease, suggests a study in mice presented at the ...

Recommended for you

Brain activity buffers against worsening anxiety

November 17, 2017
Boosting activity in brain areas related to thinking and problem-solving may also buffer against worsening anxiety, suggests a new study by Duke University researchers.

Investigating patterns of degeneration in Alzheimer's disease

November 17, 2017
Alzheimer's disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. ...

Study may point to new treatment approach for ASD

November 17, 2017
Using sophisticated genome mining and gene manipulation techniques, researchers at Vanderbilt University Medical Center (VUMC) have solved a mystery that could lead to a new treatment approach for autism spectrum disorder ...

Neuroscientists find chronic stress skews decisions toward higher-risk options

November 16, 2017
Making decisions is not always easy, especially when choosing between two options that have both positive and negative elements, such as deciding between a job with a high salary but long hours, and a lower-paying job that ...

Paraplegic rats walk and regain feeling after stem cell treatment

November 16, 2017
Engineered tissue containing human stem cells has allowed paraplegic rats to walk independently and regain sensory perception. The implanted rats also show some degree of healing in their spinal cords. The research, published ...

Study shows video games could cut dementia risk in seniors

November 16, 2017
Could playing video games help keep the brain agile as we age?

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

albertmalakovdds
not rated yet Aug 22, 2017
Interesting article...would like to read more on this if anyone can suggest anything....
Albert Malakov, DDS

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.