BBI: The team of Zhongda Hospital Affiliated to Southeast University discovered the reason why poor sleep hurts the brain!

Sleep is an indispensable physiological requirement for health and life, and plays a vital role in maintaining homeostasis in the immune, metabolic, gastrointestinal, cardiovascular and central nervous systems [1].

However, in the busy modern society, sleep deprivation or sleep disorders have become a global public health epidemic
.

According to statistics from the World Health Organization, the global rate of sleep disorders has approached 30%; The incidence of sleep disorders in Chinese adults is as high as 40%, and more than 300 million people have sleep disorders, and this number is increasing year by year [2,3].

According to the 2022 China National Healthy Sleep Survey, from 1985 to 2018, the sleep time of Chinese adults less than 6 hours is increasing year by year; 44% of young people stay up late every day until after midnight; 42% of the elderly have difficulty falling asleep, and the incidence of insomnia is high [4].

There is also growing evidence that reduced sleep can lead to cognitive dysfunction and increase the risk of Alzheimer's disease (AD) [5, 6].

Although numerous facts suggest that sleep problems are risk factors for mild cognitive impairment, preclinical AD, and the development of AD, the underlying mechanism by which sleep deprivation (SD) affects cognitive function still needs to be further explored
.

Recently, Professor Ren Qingguo's team from the Department of Neurology, Zhongda Hospital Affiliated to Southeast University, published important research results online in the internationally renowned journal Brain, behavior, and immunity, they found that chronic SD can lead to intestinal dysbacteriosis, thereby activating the intestinal and brain NLRP3 inflammasomes, destroying the intestinal and blood-brain barriers, triggering the inflammatory response of the intestine and central nervous system (CNS), and then impairing cognitive function
.

This study is the first to propose NLRP3 inflammasomes, as key regulators in the microbiome-gut-brain axis, to play an important role in SD-induced cognitive impairment, and may become a potential target for the prevention of
cognitive impairment and AD.

Screenshot of the first page of the paper

NLRP3 is the most well-defined functional inflammasome
ever found.
To explore whether inflammation plays a role in a mouse model of SD, the researchers first examined the effect of SD on the activity of NLRP3 inflammasome in the brain of
mice.

They found that IBA-1, NLRP3 inflammasome and IL-1β expression were significantly increased in the prefrontal cortex and hippocampus of SD mice, and microglia in the hippocampus were significantly activated
.
The researchers further found that the expression of markers representing the blood-brain barrier in the prefrontal cortex and hippocampus of SD mice, including Occludin, ZO-1 and Claudin-5, was significantly reduced, indicating that chronic SD disrupted the blood-brain barrier
in mice.

In order to explore the effect of SD on the intestinal flora, the researchers sequenced the 16S rRNA gene and found that the intestinal dysbacteriosis of chronic SD mice was manifested by significant changes in the composition of the intestinal flora, including decreased alpha-polymorphisms and
Beta-polymorphisms.
At the same time, chronic SD disrupts the intestinal barrier, increases the level of inflammatory factors in peripheral blood, including LPS, IL-1β and IL-6
.

Intestinal dysbacteriosis
in chronic SD mice.

By transplanting the "SD flora", the researchers were able to simulate almost all the behavioral and pathological changes caused by chronic SD in mice, including cognitive decline, disruption of the intestinal mucosal barrier and blood-brain barrier, and increased
intestinal and hippocampal NLRP3 inflammasomes.

Interestingly, when the researchers knocked out the NLRP3 gene in mice, they reversed the cognitive decline caused by chronic SD, including improvements in learning and memory in mice responded to water mazes and new object recognition tests
.
At the same time, NLRP3 knockout mice had reduced intestinal and blood-brain barrier function impairment after chronic SD, and lower levels of NLRP3 inflammasome and IL-1β levels in the gut and central nervous system compared with wild-type SD mice
.

NLRP3 knockout improves cognitive function
in SD mice.

Finally, the researchers used AAV virus to downregulate the expression
of NLRP3 inflammasome in the intestine and hippocampus, respectively.
They found that in mice with chronic SD, downregulation of NLRP3 inflammasome in the gut improved intestinal mucosal barrier function, reduced levels of peripheral blood inflammatory factors, and improved cognitive function
in SD mice.
Similarly, downregulating NLRP3 in the hippocampus can inhibit neuroinflammation and improve synaptic damage and cognitive impairment
caused by chronic SD.

The study suggests that dysbiosis of the gut is the driving factor
of chronic SD causing cognitive dysfunction.
Gut microbes can lead to intestinal barrier disruption by activating NLRP3 inflammasome in the gut, increasing peripheral blood inflammation levels, and further activating NLRP3 inflammasome in the central nervous system through the damaged blood-brain barrier, leading to synaptic damage and cognitive dysfunction
.

The study reveals how gut-brain interactions affect cognitive function
in chronic SD.
The study clarifies the damaging role of intestinal microbiota in chronic SD and highlights the important role
played by NLRP3 inflammasome as a core mediator in microbiome-gut-inflammation-brain in chronic SD-induced cognitive dysfunction.

Research mechanism diagram
.

In general, this study confirmed that intestinal flora and NLRP3 inflammasome are the key links of cognitive dysfunction caused by chronic SD, elucidated the new mechanism of chronic SD impairment of cognitive function, revealed gene and drug interventions targeting intestinal flora and NLRP3 inflammasome as new strategies for preventing cognitive impairment, and provided new ideas
for reducing the risk of cognitive impairment caused by chronic SD and preventing neurodegenerative diseases such as AD.

References

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