​Sci Adv's Lu Hui team found that exercise training improves the motor coordination and other functions of Mecp2 mutant mice

Rett syndrome is a neurodevelopmental disorder caused by mutations in the Mecp2 gene located on the X chromosome
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The incidence rate is about 1 in 10,000, mostly women
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Patients can develop normally at the age of 1-2, and then gradually lose the skills they have learned, and develop motor, cognitive, and social barriers
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Mice lacking the Mecp2 gene after adulthood will still show motor and cognitive impairment, indicating that the Mecp2 gene is also essential for the maintenance of the function of the developed neural circuit
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Previous studies have shown that the motor cortex is not only essential for motor skills learning and motor control, but also participates in non-motor functions such as working memory, empathy, and language
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How the Mecp2 gene mutation affects the function of motor cortex neural circuits is unclear
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In addition, clinical studies have shown that exercise training can improve patients' motor dysfunction, but its neural mechanism is also unclear
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On October 22, 2021, the George Washington University Lu Hui team published a research paper titled Motor training improves coordination and anxiety in symptomatic Mecp2-null mice despite impaired functional connectivity within the motor circuit in Science Advances
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It is reported that Mecp2 gene deletion leads to dyskinesia and exercise training improves the neural circuit mechanism of dyskinesia, and it is found that giving these Mecp2 gene-deficient mice with severe motor dysfunction simple treadmill training can not only improve their anxiety symptoms, but also It can extend its lifespan by 20%
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This study uses a speed-controlled treadmill exercise behavior model (Figure 1).
Because the traditionally used running wheel and Rotarod have many shortcomings, the animals in the later stage of the onset of movement disorders have been tested.
The effect of exercise training is not good (Achilly et al.
, Nature, 2021)
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For example, both the wheel and the rotating rod training require mice to exercise autonomously, while the Mecp2 gene-deficient mice will gradually aggravate their dyskinesias with age, and their voluntary movements will gradually decrease, which will lead to insufficient training time and inter-individual mice.
The training time varies greatly
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Secondly, the sports evaluation index that can be recorded in the training of the revolver and the revolver is single
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However, speed-controlled treadmill exercise training can effectively overcome these problems
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The treadmill used in this study is driven by a speed-controllable motor.
Mice with severe dyskinesias are fixed on the treadmill with their heads fixed on top of the treadmill to help the mice follow the treadmill.
The exercise time and speed are controllable.
Ensure the intensity of sports training and eliminate training differences between mice
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Using machine learning algorithms to track and analyze mouse forelimb movement, and then evaluate and quantify the degree of movement disorder in mice
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The mice were trained to follow the treadmill movement with speed changes through 20 minutes of training once a day for two consecutive weeks
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While the mice were running on the treadmill, the two-photon microscope was used to record the activities of the second third and fifth layers of the pyramidal nerves of the motor cortex, and then the relationship between the nerve activities of the motor cortex and the behavior of the mice was analyzed
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The study found that the number of exercise steps in Mecp2 gene-deficient mice was significantly lower than that of wild-type mice, and there was no improvement after two weeks of exercise training
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However, the average stride length and the coordination degree of the left and right feet of Mecp2 gene-deficient mice gradually increased with exercise training
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It shows that although Mecp2 gene-deficient mice have dyskinesia, their motor learning ability has not completely disappeared
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Figure 1: Mice learn the skills to exercise on a treadmill with changing speed, and use two-photon calcium imaging technology to record the activity of pyramidal neurons in the second and fifth layers of the motor cortex
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The analysis of neural activity showed that although the neural activity intensity of Mecp2 gene-deficient mice was not significantly different from that of wild-type mice at rest, the neural activity of Mecp2 gene-deficient mice was significantly lower than that of wild-type mice during exercise
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This may be one of the reasons for the dyskinesia in mice lacking Mecp2 gene
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After two weeks of exercise training, the activity intensity of the 2/3 layer of the motor cortex of the Mecp2 gene-deficient mice and the wild-type mice decreased significantly as compared with the first day of training, which narrowed the gap between the two.

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In addition, compared with the early stage of exercise training, the time correlation of the activity of the pyramidal neurons in the 2/3 layer of the motor cortex of the Mecp2 gene-deficient mice was significantly decreased, but the time correlation of the direct firing activity of some neurons was significantly enhanced
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This part of the changes in neuronal firing activity patterns may be the neural basis for exercise training to improve the exercise ability of mice
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Next, the author studied whether treadmill exercise training can improve the learning of sports skills other than treadmill exercise
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After two weeks of treadmill exercise training and no exercise training Mecp2 gene-deficient mice were subjected to ladder test (Ladder test) and rotating rod test (Rotarod test), and the results showed that the mice after two weeks of treadmill exercise training performed the ladder test The scores of the test and the rotating rod test were significantly higher than those of mice without exercise training
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Next, the author studied whether exercise training has effects other than affecting motor skills, such as improving anxiety
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The results of the Open field test and the Elevated plus maze test showed that the anxiety of the mice after two weeks of exercise training was significantly improved
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In addition, the observation of survival time showed that the life span of mice after two weeks of exercise training was about 20% longer than that of mice without exercise training
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This study partially reveals the underlying neural mechanism of dyskinesia in mice lacking Mecp2 gene and exercise training to improve dyskinesia
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And found that exercise can not only improve the dyskinesia of Mecp2 gene-deficient mice, but also improve anxiety and prolong life
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This research not only provides guidance for the clinical treatment of Reiter’s syndrome, but also provides some hints on how to establish an effective exercise training model to improve the symptoms of other neurological diseases
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The first author of this study is Dr.
Yue Yuanlei of Lu Hui's team
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Dr.
Xu Pan and Dr.
Liu Zhichao are the co-first authors
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The collaborators in this study include Professor Chen Zeng, Professor Linda Kusner, Professor Rahul Slmha of George Washington University, Professor Stelios Smirnakis of Harvard Medical School and Dr.
Ryan T.
Ash of Stanford University
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Original link: http://10.
1126/sciadv.
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