As the saying goes, "People are light and fluttering without pressure, and they can't sleep well when they have pressure." Why do stressful people "sleep badly"? What is the mechanism behind it? What are the consequences?
At 0:00 a.m. Beijing time on January 22, 2022, the team of Wang Liping of the Institute of Brain Cognition and Brain Diseases of the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences and the Shenzhen-Hong Kong Institute of Brain Science and Innovation published the latest research results in Neurons and answered these questions.
Assistant researcher Zeng Yuting, research assistant Zhao Binghao, and doctoral student Chen Shanping are the co-first authors of the paper, and researcher Wang Liping is the corresponding author.
Normal sleep includes rapid eye movement (REM) and non-rapid eye movement (NREM). When people are in a state of RAPID eye movement sleep, they will show the eyes constantly swinging left and right, the heart rate is accelerated, the blood pressure is increased, and the muscles are relaxed. Most dreams also occur during THE SLEEP phase of REM. REM sleep has been observed since 1953, and its mechanism and function have remained a mystery for the past seven decades. In previous clinical studies, sleep disorders and stress-related mental illnesses have a high comorbidity rate, such as depression and post-traumatic stress disorder and other mental illnesses, there are significant changes in REM sleep status. However, due to the unclear mechanism and function of REM sleep, our in-depth understanding of the occurrence and intervention mechanisms of many mental illnesses that coexist with sleep disorders is greatly limited.
In the face of this important problem, the team revealed for the first time the "shared" neural circuit that regulates REM sleep and instinctive fear response, and the discovery of this "shared" loop reveals that REM sleep has a potential "defense against natural enemies", provides a possible explanation for THE DISORDER OF REM sleep in mental illness, and provides a possible target for the diagnosis and treatment of comorbid psychiatric disorders associated with sleep disorders and instinctive fear disorders.
"Not sleeping well" is related to the instinct to instinctively defend
It is often said that a night without dreams is to "sleep well", while nightmares or insomnia are considered "sleep bad". Dreaming is a normal physiological phenomenon in the sleep stage, to understand the occurrence of dreams, you need to understand the structure of sleep.
In 1966, the American psychophysiologist Frederrick Snyder proposed the hypothesis that RAPID EYE movement sleep may play a "sentinel function", which believes that periodic REM sleep is often accompanied by a short awakening, allowing animals to detect dangers in the environment, but this hypothesis has not been supported by experimental evidence.
Wang Liping's team has been working on the neural mechanism of animal instinctive fear defense behavior, and for this hypothesis, the research team designed relevant experiments to study whether the sleep stage can stimulate instinctive defense behavior in response to the threat of natural enemies, and explore the neural mechanism behind it.
Foxes are natural enemies of mice, and in a waking state, fox urine odor (TMT) can quickly cause instinctive fear-evasive behavior in mice. The researchers gave mice TMT stimulation during the REM sleep phase and found that the mice woke up significantly faster than the stimuli given during the non-REM sleep phase. Stimulating mice with a gas that smells like cinnamon bread and a smell of rotten eggs did not have this effect. This suggests that REM sleep specifically responds to predator stimuli.
There is a nervous mechanism behind the pressure to "sleep badly"
Using the team's self-developed small animal eye movement monitoring, as well as endoscopic single-neuron imaging, chemical genetic regulation and other methods, the team found that compared with non-REM sleep, giving animals natural enemy odor stimulation during REM sleep can wake up mice faster, suggesting that REM sleep has the function of potential "defense against natural enemies", and successfully parsing a mouse brain from the medial subthalamus nucleus ( mSTN) corticotropin releasing hormone (CRH) neurons project onto the neural circuits of the lateral globus pallidus (LGP) that regulate the response to predator stimuli during rapid eye movement sleep.
The team found that crH neurons in this neural circuit not only play an important role in maintaining REM sleep stability, but are particularly sensitive to dangerous information about predators. Inhibiting this group of neurons reduced the length of REM sleep, but the mice woke up more slowly under predator stimulation. In the case of animal awakening, this group of neurons is also involved in the regulation of fearful stimuli against predators.
This provides experimental evidence for the hypothesis that REM sleep may act as a "sentinel function" and provides a neural mechanism explanation for the hypothesis.
Figure 1: The mSTN-CRH-LGP neural loop regulates REM sleep and defense behavior. Source: Courtesy of the research team
"Although the instinct of instinctive defense may be one of the reasons for 'poor sleep', as society evolves and develops, humans do not need to deal with natural predators in natural conditions. Otherwise conservative natural enemy defense loops may be used to deal with external stimuli such as social stress. Similarly, the occurrence of nightmares, external pressure, improper sleeping posture, disease state, etc. will affect people's sleep", zeng Yuting, the first author of the paper, said that long-term sleep problems can lead to mental health impact, and even cause depression and other mental illnesses.
Find potential targets for the treatment of psychiatric disorders
If the function of REM sleep is related to the evasion of natural enemies, then will the structure of REM sleep change occur in mice under long-term natural enemy stress stress?
In this regard, the researchers used rats to conduct chronic long-term stress simulation experiments on mice, and found that under long-term stress stress, the remboular movement sleep structure of mice changed significantly, which was manifested by the prolongation of REM sleep time and the fragmentation of sleep. Using a chemogenetic approach, inhibiting the activity of CRH neurons in mice eliminated changes in the structure of REM sleep in mice.
"The same group of neurons regulates both sleep and instinctive defense behaviors, rather than evolving two relatively independent neural regulatory networks, which is extremely important in terms of evolution." We can assume that in natural selection, the body 'shares' optimizations of existing neural circuits to improve the efficiency of signal transmission and energy use, rather than choosing a more metabolically more resource-intensive option, such as choosing two very different loops. In other words, evolution is like architects working on an old building, rather than redesigning a building from scratch," said Wang Liping, corresponding author of the paper.
Huang Zhili, vice dean of the School of Basic Medical Sciences and head of the Department of Pharmacology at Fudan University, said that the study also suggested that this "shared" neural circuit may be the cause of depression and sleep status changes in Parkinson's patients receiving deep brain stimulation therapy for the subthalamic nucleus, providing a potential target for the treatment of comorbid sleep disorders and psychiatric disorders related to instinctive fear disorders.
Hu Zhi'an, a professor at the People's Liberation Army Military Medical University in Chinese, said that for the past half century, people have been uncertain about the function of RAPID EYE movement sleep. The study suggests that one of the important functions of REM sleep is to "equip individuals with the ability to remain alert and responsive to environmental threats while staying asleep." This is a very valuable scientific discovery that is expected to expand people's understanding of the functional mechanisms of sleep and provide an important scientific basis for understanding the mechanism of sleep disorders.
Figure 2 Group photo of the main participants of the project. Qiu Zijian/Photo
Related paper information:
https://doi.org/10.1016/j.neuron.2021.12.033