1.Mechanisms of Sini San in Regulation of Gut Microbiota Against Depression and Liver Injury in CUMS Rats
Junling LI ; Yan ZHANG ; Lei WANG ; Fang QI ; Zhenzhen CHEN ; Tianxing CHEN ; Yuhang LIU ; Xueying WANG ; Xianwen TANG ; Yubo LI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):33-40
ObjectiveTo explore the efficacy and mechanisms of Sini San in the treatment of depression and liver injury based on gut microbiota. MethodsThirty-two male Sprague-Dawley (SD) rats were randomly divided into a normal group, model group (M), Sini San group (MS, 2.5 g·kg-1), and fluoxetine group (MF, 2 mg·kg-1). Except for the normal group, rats in the other three groups were subjected to chronic unpredictable mild stress (CUMS). After 8 weeks, the open-field test and sucrose preference test were conducted. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing factor (CRF), lipopolysaccharide (LPS), Zonulin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), γ-aminobutyric acid (GABA) levels in the hippocampus and prefrontal cortex, and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect hippocampal BDNF mRNA expression. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using the ultraviolet lactate dehydrogenase method. The ultrastructure of the intestinal epithelium was observed by electron microscopy, and gut microbiota in rat feces were analyzed using 16S rDNA high-throughput sequencing. ResultsCompared with the normal group, the sucrose preference of rats in the model group was significantly reduced (P0.01), whereas it was significantly increased in the Sini San group compared with the model group (P0.05). Compared with the normal group, hippocampal GABA protein levels and BDNF mRNA expression in the model group were significantly decreased (P0.05), and compared with the model group, both were significantly increased in the Sini San group (P0.05, P0.01). Compared with the normal group, serum LPS and Zonulin levels in the model group were significantly increased (P0.05, P0.01), and compared with the model group, Zonulin levels in the Sini San group were significantly decreased (P0.05). No obvious changes were observed in the ultrastructure of the jejunal mucosa among groups. Compared with the normal group, widened and blurred tight junctions, sparse and shortened microvilli, and mitochondrial swelling with cristae disruption in epithelial cells were observed in the ileal and colonic mucosa of the model group, which were markedly improved in the Sini San and fluoxetine groups. The results of 16S rDNA high-throughput sequencing showed that Sini San improved CUMS-induced dysbiosis of Bacteroidetes and Proteobacteria. Correlation analysis indicated that Bacteroidetes and Proteobacteria were significantly correlated with depression-related indicators, liver function, and intestinal mucosal permeability. ConclusionSini San exerts antidepressant and hepatoprotective effects by improving Bacteroidetes and Proteobacteria and inhibiting the increase in intestinal mucosal permeability in CUMS rats.
2.Analysis of Animal Models of Retinitis Pigmentosa Based on Diagnostic Features of Chinese and Western Medicine
Xiaoyu LI ; Lina LIANG ; Jiefeng CHEN ; Xiaoxiao ZHU ; Yina QI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):198-203
Retinitis pigmentosa (RP) is the most common hereditary blinding eye disease in clinical practice, with the pathogenesis remaining unclear. Patients experience progressive apoptosis of retinal photoreceptor cells, accompanied by degeneration of retinal pigment epithelium (RPE) cells. Current Western medical treatments mainly focus on gene therapy and stem cell transplantation, showing limited efficacy. In contrast, clinical observations have confirmed the therapeutic effects of traditional Chinese medicine (TCM) treatments. Establishing an RP animal model that aligns with the diagnostic features of both TCM and Western medicine could help combine the strengths of both approaches, thereby broadening the treatment options for RP. This study categorizes and summarizes the existing RP animal models in terms of classification, types, inheritance patterns, and alignment with clinical manifestations. It is found that current RP models are primarily derived from natural animal models such as RD mice and RCS rats, transgenic animal models like RPE-65 knockout mice and rhodopsin gene knockout mice, and chemically induced models such as those created by monochromatic light exposure or N-ethyl-N-nitrosourea (ENU) administration. These three categories of models focus more on detecting RP-related histopathological, molecular biological, and cellular immunological indicators, but offer limited observation of the overall characteristics of the disease and lack insight into syndrome differentiation. Although RP is a congenital genetic disease, its progression is influenced by acquired factors such as environment, constitution, emotions, and care. Current models do not fully capture the characteristics of this disease. Therefore, establishing an RP animal model based on the diagnostic features of both TCM and Western medicine will have significant implications for future experimental and clinical research.
3.Mechanisms of Sini San in Regulation of Gut Microbiota Against Depression and Liver Injury in CUMS Rats
Junling LI ; Yan ZHANG ; Lei WANG ; Fang QI ; Zhenzhen CHEN ; Tianxing CHEN ; Yuhang LIU ; Xueying WANG ; Xianwen TANG ; Yubo LI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):33-40
ObjectiveTo explore the efficacy and mechanisms of Sini San in the treatment of depression and liver injury based on gut microbiota. MethodsThirty-two male Sprague-Dawley (SD) rats were randomly divided into a normal group, model group (M), Sini San group (MS, 2.5 g·kg-1), and fluoxetine group (MF, 2 mg·kg-1). Except for the normal group, rats in the other three groups were subjected to chronic unpredictable mild stress (CUMS). After 8 weeks, the open-field test and sucrose preference test were conducted. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing factor (CRF), lipopolysaccharide (LPS), Zonulin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), γ-aminobutyric acid (GABA) levels in the hippocampus and prefrontal cortex, and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect hippocampal BDNF mRNA expression. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using the ultraviolet lactate dehydrogenase method. The ultrastructure of the intestinal epithelium was observed by electron microscopy, and gut microbiota in rat feces were analyzed using 16S rDNA high-throughput sequencing. ResultsCompared with the normal group, the sucrose preference of rats in the model group was significantly reduced (P<0.01), whereas it was significantly increased in the Sini San group compared with the model group (P<0.05). Compared with the normal group, hippocampal GABA protein levels and BDNF mRNA expression in the model group were significantly decreased (P<0.05), and compared with the model group, both were significantly increased in the Sini San group (P<0.05, P<0.01). Compared with the normal group, serum LPS and Zonulin levels in the model group were significantly increased (P<0.05, P<0.01), and compared with the model group, Zonulin levels in the Sini San group were significantly decreased (P<0.05). No obvious changes were observed in the ultrastructure of the jejunal mucosa among groups. Compared with the normal group, widened and blurred tight junctions, sparse and shortened microvilli, and mitochondrial swelling with cristae disruption in epithelial cells were observed in the ileal and colonic mucosa of the model group, which were markedly improved in the Sini San and fluoxetine groups. The results of 16S rDNA high-throughput sequencing showed that Sini San improved CUMS-induced dysbiosis of Bacteroidetes and Proteobacteria. Correlation analysis indicated that Bacteroidetes and Proteobacteria were significantly correlated with depression-related indicators, liver function, and intestinal mucosal permeability. ConclusionSini San exerts antidepressant and hepatoprotective effects by improving Bacteroidetes and Proteobacteria and inhibiting the increase in intestinal mucosal permeability in CUMS rats.
4.Analysis of Animal Models of Retinitis Pigmentosa Based on Diagnostic Features of Chinese and Western Medicine
Xiaoyu LI ; Lina LIANG ; Jiefeng CHEN ; Xiaoxiao ZHU ; Yina QI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):198-203
Retinitis pigmentosa (RP) is the most common hereditary blinding eye disease in clinical practice, with the pathogenesis remaining unclear. Patients experience progressive apoptosis of retinal photoreceptor cells, accompanied by degeneration of retinal pigment epithelium (RPE) cells. Current Western medical treatments mainly focus on gene therapy and stem cell transplantation, showing limited efficacy. In contrast, clinical observations have confirmed the therapeutic effects of traditional Chinese medicine (TCM) treatments. Establishing an RP animal model that aligns with the diagnostic features of both TCM and Western medicine could help combine the strengths of both approaches, thereby broadening the treatment options for RP. This study categorizes and summarizes the existing RP animal models in terms of classification, types, inheritance patterns, and alignment with clinical manifestations. It is found that current RP models are primarily derived from natural animal models such as RD mice and RCS rats, transgenic animal models like RPE-65 knockout mice and rhodopsin gene knockout mice, and chemically induced models such as those created by monochromatic light exposure or N-ethyl-N-nitrosourea (ENU) administration. These three categories of models focus more on detecting RP-related histopathological, molecular biological, and cellular immunological indicators, but offer limited observation of the overall characteristics of the disease and lack insight into syndrome differentiation. Although RP is a congenital genetic disease, its progression is influenced by acquired factors such as environment, constitution, emotions, and care. Current models do not fully capture the characteristics of this disease. Therefore, establishing an RP animal model based on the diagnostic features of both TCM and Western medicine will have significant implications for future experimental and clinical research.
5.Textual Research and Application of Famous Classical Formula Huopo Xialingtang
Miao YU ; Huikang ZHANG ; Xiaofan QI ; Fuping LI ; Jichun ZHOU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(3):192-200
Huopo Xialingtang is a famous classical formula for treating dampness and warmth, which is included in the Catalogue of Ancient Famous Classical Formulas(The First Batch). In this paper, bibliometric methods was used to collect the literature related to Huopo Xialingtang, and 16 items of related literature were retrieved, involving five medical books, which were used to textual research on the origin, name, composition, drug dosage, preparation method, processing and main treatment symptoms of this formula. The results indicated that Huopo Xialingtang was originated from Yiyuan written by Shi Funan in the Qing dynasty, and and was later named and extended by He Lianchen. The composition of the proposed formula was consistent with the record of Yiyuan, and the origin of each Chinese materia medica was basically clear. Houpo was the dried bark and root bark of Magnolia officinalis, Zexie was the dried tubers of Alisma orientale, Kuxingren was the dried mature seeds of Prunus armeniaca, Doukou was the dried mature fruits of Amomum kravanh, the origin of Tuhuoxiang was consistent with the 2018 edition of Shanghai Standards of Processing Chinese Crud Drugs, and the origins of the remaining Chinese medicines were consistent with the 2020 edition of Chinese Pharmacopoeia. The converted dose of each Chinese medicine was 7.46 g for Agastache rugosa, 3.73 g for Magnoliae Officinalis Cortex, 8.39 g for Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine, 11.19 g for Poria, 11.19 g for Armeniacae Semen Amarum, 14.92 g for Coicis Semen, 2.61 g for Amomi Fructus Rotundus, 5.60 g for Polyporus, 5.60 g for Alismatis Rhizoma, 14.92 g for Tetrapanacis Medulla. Huopo Xialingtang was initially used for the treatment of dampness and warmth at the beginning of the disease, and was later expanded to treat dampness obstruction, dampness-warming dysentery and so on, but always with the dampness-heat in the lungs and spleen as the pathogenesis. In modern times, the clinical application is more extensive, used in digestive, respiratory, endocrine, nervous system and other types of diseases, especially for chronic gastritis, stomach pain and fever. By combing the ancient literature of Huopo Xialingtang, we verified the origin of the formula and determined the key information of the prescription, which can provide literature reference for the clinical application and drug development of this formula.
6.Pharmacological Effect of Berberine on Alzheimer's Disease: A Review
Xuejing WANG ; Guangcheng ZHONG ; Shuting LI ; Qian ZHANG ; Bojie LUO ; Qi WANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(2):286-294
Alzheimer's disease (AD), a degenerative disease of the central nervous system, is characterized by progressive degradation of learning, memory, and cognitive functions. Currently, few drugs are available for treating AD, and their effects are limited. Berberine (BBR) is a natural isoquinoline (quaternary ammonium-like) with a wide range of pharmacological effects. Studies have proven that BBR has good potential in the treatment of AD. Specifically, BBR can inhibit the generation, aggregation, and neurotoxicity of amyloid-β and the hyperphosphorylation of Tau protein, promote the clearance of phosphorylated Tau protein, reduce the cholinesterase activity, neuroinflammation, and oxidative stress, regulate neuronal apoptosis, improve the mitochondrial function and glucose and lipid metabolism, suppress the monoamine oxidase activity, and modulate gut microbiota. In addition, researchers have ameliorated the low bioavailability of BBR. Probing into the potential targets is hoped to provide a reference for further research on the prevention and treatment of AD by BBR.
7.Epidemiological characteristics of pertussis in Jiaxing City from 2004 to 2023
LI Rui ; QI Yunpeng ; WANG Yuanhang ; ZHA Yiwei ; FU Xiaofei
Journal of Preventive Medicine 2025;37(2):139-142
Objective:
To investigate the epidemiological characteristics of pertussis in Jiaxing City from 2004 to 2023 and spatio-temporal clustering characteristics from 2022 to 2023, so as to provide insights into formulation of pertussis control measures.
Methods:
Data of pertussis cases in Jiaxing City from 2004 to 2023 were collected through the Infectious Disease Report Information System of Chinese Disease Prevention and Control Information System. The epidemiological characteristics of pertussis cases in Jiaxing City from 2004 to 2023 were descriptively analyzed, and the spatio-temporal clustering characteristics from 2022 to 2023 were analyzed using spatio-temporal scanning.
Results:
A total of 478 pertussis cases were reported in Jiaxing City from 2004 to 2023, with an average annual reported incidence of 0.53/105. The reported incidence showed an upward trend from 2004 to 2023 (P<0.05), with the highest in 2022 (3.17/105). Higher incidence of pertussis was reported in June to August (149 cases, 31.17%) and November to December (112 cases, 23.43%). There was no statistically significant difference in the reported incidence between males and females (0.56/105 vs. 0.50/105, P>0.05). The cases aged under one year accounted for the highest proportion, with 199 cases (41.63%). Haining City (0.68/105), Jiashan County (0.64/105) and Tongxiang City (0.60/105) ranked the top three in the reported incidence of pertussis. Spatio-temporal scanning analysis showed that from 2022 to 2023, the primary clustering area of pertussis was centered in Daqiao Town of Nanhu District, covering 27 towns (streets) in Nanhu District, Jiashan County, Xiuzhou District and Pinghu City, and the clustering time was from November to December, 2023.
Conclusions
The reported incidence of pertussis was at a low level in Jiaxing City, but showed an upward trend from 2004 to 2023. The incidence of pertussis was higher among infants under one year of age, peaked in June to August and November to December, and was concentrated in Nanhu District and its surrounding areas.
8.Effect of Bushen Huoxue Granules (补肾活血颗粒) on the Nrf2/NLRP3 Inflammasome Axis in the Brain Substantia Nigra of Parkinson's Disease Model Mice
Qi CHEN ; Peng WANG ; Yingfan CHEN ; Shaodan LI ; Minghui YANG
Journal of Traditional Chinese Medicine 2025;66(4):390-398
ObjectiveTo explore the possible mechanism of action of Bushen Huoxue Granules (补肾活血颗粒, BHG) in the treatment of Parkinson's disease (PD) through the Nrf2/NLRP3 inflammasome axis. MethodsA total of 84 male C57/BL 6 mice were randomly divided into blank group, model group, Madopar group, dimethyl fumarate group, and low-, medium, and high-dose BHG group, with 12 mice in each group. Except for the blank group, all groups were induced into PD models by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a concentration of 30 mg/ml for 7 consecutive days. The blank group received an equal volume of saline. After model establishment, the low-, medium, and high-dose BHG groups were treated with 1.5, 3, and 6 g/(kg·d) of the BHG by gavage, respectively. The Madopar group was given 0.113 g/(kg·d) of Madopar tablets by gavage, and the dimethyl fumarate group was given 50 mg/(kg·d) of dimethyl fumarate solution. The blank group and the model group were given 10 ml/(kg·d) of distilled water by gavage. Gavage was administered once daily for 14 days. Behavioral changes were evaluated using the open field test (total distance, central area distance, and average speed), rotarod test (time on the rod), and climbing pole test (climbing time). Serum levels of interleukin-1β (IL-1β), interleukin-18 (IL-18), and myeloperoxidase (MPO) were measured by ELISA. Immunohistochemistry was used to detect tyrosine hydroxylase (TH) expression in the brain substantia nigra. Immunofluorescence was used to detect α-synuclein (α-syn) expression. Western Blot was used to detect Nrf2, NLRP3, Caspase-1, and α-syn protein levels in the brain substantia nigra. RT-PCR was used to detect mRNA expression levels of Nrf2, NLRP3, and Caspase-1 in the brain substantia nigra. ResultsCompared with the blank group, the model group showed decreased total distance, central area distance, and average speed, reduced time on the rotarod, prolonged climbing time, reduced TH expression, increased α-syn expression, decreased Nrf2 protein and mRNA expression, increased NLRP3 and Caspase-1 protein and mRNA expression, and elevated serum IL-1β, IL-18, and MPO levels (P<0.05). Compared with the model group, all drug interventions significantly improved the above indicators (P<0.05). There was no significant differences in all indicators between the high-dose BHG group and the Madopar group (P>0.05). Compared with the dimethyl fumarate group, the medium and high-dose BHG groups showed increased Nrf2 mRNA expression in the brain substantia nigra (P<0.05). Compared with the high-dose BHG group, the low-dose group showed decreased total distance, central area distance, and average speed, reduced serum IL-18 levels, decreased α-syn, Nrf2, NLRP3, and Caspase-1 protein levels, and lower Nrf2 mRNA expression (P<0.05). ConclusionThe mechanism by which BHG treat PD may involve activating the Nrf2/NLRP3 inflammasome axis in the brain substantia nigra, thereby reducing neuroinflammation and α-syn aggregation. The high-dose group showed the best effects.
9.Mechanism of Weiliuan Mixture in Regulating Ferroptosis and Inhibiting Progression of Gastric Cancer Based on Transcriptome
Jingxiao LI ; Shenlin LIU ; Xi ZOU ; Minghao QI
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(6):125-135
ObjectiveTo observe the inhibitory effect of the Weiliuan mixture (WLAHJ) on the subcutaneous xenograft tumor of MKN-74 gastric cancer cells, and explore the potential anti-gastric cancer mechanism of WLAHJ by using transcriptomic sequencing technology to reveal related genes and pathways. Methods30 Balb/c nude mice were randomly divided into model, low-, medium-, and high-dose(15,30,45 g·kg-1) WLAHJ and 5-FU (0.025 g·kg-1) groups to build a subcutaneous xenograft tumor model with MKN-74 human gastric cancer cells. After modeling,each group was continuously treated with the corresponding drugs for 28 days. During the treatment period, the body weight and tumor size of the mice were observed and recorded every 2 days. At the end of the treatment, the mice were sacrificed, and required samples were collected to calculate the tumor inhibition rate of WLAHJ on the subcutaneous xenograft tumor. High-throughput transcriptomic sequencing (RNA-seq) technology was used to analyze the differentially expressed genes in the subcutaneous tumor tissues of the model group and the medium-dose WLAHJ group, thus exploring the potential mechanism of WLAHJ in gastric cancer intervention. Immunofluorescence experiments were conducted to detect the protein expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein-1 (TFR-1), and acyl-CoA synthetase long-chain family member 4 (ACSL4) in subcutaneous xenograft tumors of each group. Cell counting kit-8(CCK-8) and colony formation assays were used to detect the viability and anti-proliferative ability of human gastric cancer AGS and MKN-74 cells at different concentrations of WLAHJ. Kits were used to detect the levels of Fe2+, reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) activity in cells. Western blot was used to detect the expression levels of GPX4, SLC7A11, TRF-1, ACSL4, spermidine/spermine N1-acetyltransferase 1 (SAT1), arachidonic acid 15-lipoxygenase (ALOX15), and key proteins in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. ResultsThe mechanism of WLAHJ in gastric cancer intervention may be related to ferroptosis and the PI3K/Akt /mTOR signaling pathway. The growth of subcutaneous xenograft tumors in nude mice of the WLAHJ and 5-FU groups(P<0.05,P<0.01), GPX4, and SLC7A11 dropped significantly(P<0.01), while TFR-1, ACSL4, SAT1, and ALOX15(P<0.05,P<0.01)increased significantly compared with those in the model group. The levels of ROS, Fe2+, and MDA increased in the WLAHJ and 5-FU groups and the proliferation of gastric cancer cells, SOD activity, the ratios of phosphorybation (p)-mTOR/mTOR, p-PI3K/PI3K, and p-Akt/Akt protein expressions(P<0.05,P<0.01)decreased compared with those in the blank group. ConclusionThe mechanism of WLAHJ in treating gastric cancer may be related to the regulation of the PI3K/ Akt /mTOR signaling pathway to intervene in ferroptosis.
10.The Neurobiological Mechanisms of Runner’s High
Yun-Teng WANG ; Jia-Qi LIANG ; Wan-Tang SU ; Li ZHAO ; Yan LI
Progress in Biochemistry and Biophysics 2025;52(2):358-373
“Runner’s high” refers to a momentary sense of pleasure that suddenly appears during running or other exercise activities, characterized by anti-anxiety, pain relief, and other symptoms. The neurobiological mechanism of “runner’s high” is unclear. This review summarizes human and animal models for studying “runner’s high”, analyzes the neurotransmitters and neural circuits involved in runner’s high, and elucidates the evidence and shortcomings of researches related to “runner’s high”. This review also provides prospects for future research. Research has found that exercise lasting more than 30 min and with an intensity exceeding 70% of the maximum heart rate can reach a “runner’s high”. Human experiments on “runner’s high” mostly use treadmill exercise intervention, and evaluate it through questionnaire surveys, measurement of plasma AEA, miRNA and other indicators. Animal experiments often use voluntary wheel running intervention, and evaluate it through behavioral experiments such as conditional place preference, light dark box experiments (anxiety), hot plate experiments (pain sensitivity), and measurement of plasma AEA and other indicators. Dopamine, endogenous opioid peptides, endogenous cannabinoids, brain-derived neurotrophic factor, and other substances increase after exercise, which may be related to the “runner’s high”. However, attention should be paid to the functional differences of these substances in the central and peripheral regions, as well as in different brain regions. Moreover, current studies have not identified the targets of the neurotransmitters or neural factors mentioned above, and further in-depth researches are needed. The mesolimbic dopamine system, prefrontal cortex-nucleus accumbens projection, ventral hippocampus-nucleus accumbens projection, red nucleus-ventral tegmental area projection, cerebellar-ventral tegmental area projection, and brain-gut axis may be involved in the regulation of runner’s high, but there is a lack of direct evidence to prove their involvement. There are still many issues that need to be addressed in the research on the neurobiological mechanisms of “runner’s high”. (1) Most studies on “runner’s high” involve one-time exercise, and the characteristics of changes in “runner’s high” during long-term exercise still need to be explored. (2) The using of scales to evaluate subjects lead to the lacking of objective indicators. However, some potential biomarkers (such as endocannabinoids) have inconsistent characteristics of changes after one-time and long-term exercise. (3) The neurotransmitters involved in the formation of the “runner’s high” all increase in the peripheral and/or central nervous system after exercise. Attention should be paid to whether peripheral substances can enter the blood-brain barrier and the binding effects of neurotransmitters to different receptors are completely different in different brain regions. (4) Most of the current evidence show that some brain regions are activated after exercise. Is there a functional circuit mediating “runner’s high” between these brain regions? (5) Although training at a specific exercise intensity can lead to “runner’s high”, most runners have not experienced “runner’s high”. Can more scientific training methods or technological means be used to make it easier for people to experience the “runner’s high” and thus be more willing to engage in exercise? (6) The “runner’s high” and “addiction” behaviors are extremely similar, and there are evidences that exercise can reverse addictive behaviors. However, why is there still a considerable number of people in the sports population and even athletes who smoke or use addictive drugs instead of pursuing the “pleasure” brought by exercise? Solving the problems above is of great significance for enhancing the desire of exercise, improving the clinical application of neurological and psychiatric diseases through exercise, and enhancing the overall physical fitness of the population.


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