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At the moment, anxiety,DepressionIt has become a major mental health problem that plagues many people. In addition to using drugs for intervention, more and more scientific evidence shows that exercise is an effective non-drug means of relieving anxiety. For example, in animal models, exercise training can help restore neural networks while producing anti-anxiety effects.

There are currently hypotheses on the mechanism of exercise's anti-anxiety effect, including adult neurogenesis, monoamine neurotransmitters, and neuroinflammation. In addition, lactic acid produced by exercise is also attracting the attention of scientists. As a substance produced by glycolysis of various tissues under high-intensity exercise, lactic acid is involved in various molecular regulatory processes, and in the brain, studies have found that lactic acid can play an anti-depressant role.However, there are still many unsolved mysteries about the mechanism of lactic acid anti-anxiety, such as whether the lactic acid produced after exercise can affect the brainproteinHow lactylation modifies the process and alters anxiety-like behaviors remains unclear.

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August 19, 2024, Jinan University Guangdong, Hong Kong and Macao Central Nervous System Regeneration InstitutetensionThe research group published in Cell Metabolism (Cell Metabolism) journal published online titled “Physical exercise mediates cortical synaptic protein lactylation to improve stress resilience” paper, the study foundLactic acid molecules produced after exercise can improve synaptic structure and function by enhancing the lactylation modification of specific synaptic proteins in the cortex, thereby alleviating anxiety behaviors caused by stress.Researcher Zhang Li pointed out that by focusing on the lactylation modification of a series of synaptic proteins, it may be possible toMental illnessHelps in diagnosis and prediction of therapeutic effects.

In this study, the authors first used chronic restraint stress to construct a group of mouse models, which produced anxiety-like behaviors. Subsequently, the authors allowed the mice to participate in 14 days of flat treadmill exercise to increase the level of lactate in the mouse circulatory system and brain. After the experiment, the authors also obtained brain tissue from the mice and performed proteomic quantitative analysis based on lactylation modification on protein samples of the prefrontal cortex.

The results show that14-day treadmill exercise intervention not only prevents anxiety-like behavior in mice, but also significantly changes the lactylation levels of multiple synapse-related proteinsAmong them, it is noteworthy that the lysine lactylation level of the synaptic protein SNAP91 at site 885 was significantly increased after exercise (Figure 1).

▲Figure 1: Exercise increases the lactylation of the synaptic protein SNAP91 in the cortex (Image source: Reference [1])

To further confirm the key role of SNAP91 lactylation, the research team constructed a group of special mutant mice in which the SNAP91 protein 885 site (K885) in the medial prefrontal cortex (mPFC) was mutated, which means that the lactylation ability of K885 was destroyed.

According to observations, the presynaptic vesicle density of these mutant mice decreased abnormally (Figure 2), the expression of synaptic structural proteins was downregulated, and the postsynaptic density was abnormally formed, which indicates that when the lactylation of SNAP91 protein is disrupted, the synaptic structure and function will be damaged.

▲Figure 2: Abnormal SNAP91 protein lactylation leads to ultrastructural changes in cortical synapses (Image source: Reference [1])

In subsequent experiments, these mutant mice still experienced chronic restraint stress and subsequently participated in treadmill training. This time the situation was different. Mice that lost SNAP91 protein lactylation did not suppress anxiety-like behavior due to exercise (Figure 3), and the activity of the mPFC neural network was also significantly downregulated. All of this evidence shows that exercise can maintain cortical neuronal activity and neural network activity by affecting SNAP91 protein lactylation, thereby exerting an anti-anxiety effect, which also means that the study has found a lactylation pathway involved in the regulation of brain emotional function.

▲Figure 3: Exercise exerts anxiolytic effects through SNAP91 lactylation (Image source: Reference [1])

In summary, this study revealed a key "metabolism-brain" pathway, in which the lactic acid molecules produced by exercise-stimulated tissues can improve the mPFC synaptic structure and neuronal activity and relieve anxiety-like behavior in mice by affecting the lactylation modification of synaptic proteins such as SNAP91 (Figure 4). The above results reveal a new biological mechanism of lactic acid, an energy molecule, in the brain, and also provide a reference for further research on the lactylation modification of non-histone proteins in neural tissues.

Regarding future research, researcher Zhang Li said that the more important issue is to clarify whether the metabolic pattern changes in specific locations of neural tissues (neurons, glial cells, etc.) are related to lactylation modification and its downstream molecular pathways, so as to establish a mechanism model of metabolism-brain function in both space-time dimensions.

▲Figure 4: Exercise-lactation anti-anxiety model (Image source: Reference [1])

Researcher Zhang Li is the independent corresponding author of this article; Yan Lan, a doctoral graduate from Jinan University, and Wang Yajie, a doctoral student, are the co-first authors of the paper. The paper was supported by Academician Su Guohui of Jinan University and completed based on the Ministry of Education Key Laboratory of Central Nervous System Regeneration of Jinan University.

Zhang Li's research group has focused on the scientific issue of "the peripheral-central mechanism of exercise improving brain function" and has achieved a series of results since 2019. Representative work includes: (1) Identification of peripheral factors that improve brain function through exercise, discovery of factors such as S-adenosylmethionine and clusterin from tissues such as liver and fat, and clarification of their effects on improving emotions, cognition and other behaviors (Science Advances 2023; Cell Reports 2023; Advanced Science 2022, etc.); (2) Elucidate the molecular mechanism by which exercise improves synaptic structure and function, revealing the mechanism by which exercise stimulates peripheral factors to promote synaptic structure and functional remodeling and alleviate emotional and cognitive disorders by activating the mTOR pathway and protein lactylation modification in the brain (Cell Metabolism 2024; Nature Communications 2024; Science Advances 2019, etc.); (3) Analyzing the circuit mechanism of peripheral factors improving brain function, it was found that the peripheral factors secreted by the body under environmental intervention affect emotional and social behaviors by regulating the neural circuits of the cortex, amygdala and other brain regions (National Science Review 2023; Communications Biology 2023; Molecular Psychiatry 2021, etc.).

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