| Depression is a common chronic affective disorder.Cognitive dysfunction is one of the core symptoms of depression and increases the incidence of Alzheimer’s disease.According to the estimation of World Health Organization,depression may become the second most common disabling disease after coronary heart disease by 2020.The high recurrence rate and long-term onset of depression limit its clinical treatment.Many depressive patients still have cognitive impairment after their emotional symptoms have been alleviated,and it has been found to be the longest residual symptom.However,conventional antidepressants do not play a role in restoring cognitive function.At present,continuous research is needed to discover new antidepressants that can improve cognitive impairment.The chronic mild stress(CMS)model can induce the core symptoms of depression and related behavioral dysfunction,and has become a classic model for the study of the effectiveness of antidepressants.Studies have shown that CMS can induce changes in the morphology and function of the hippocampus and prefrontal cortex,cause cognitive impairment,and lead to neurodegenerative lesions in model animals,but the pathological mechanism is still unclear.Numerous studies have found that the intestinal microbiota and metabolites are almost involved in the entire process of development and functional maintenance of the central nervous system.Animal experiments have also confirmed that chronic mild stress can cause intestinal micro-environmental disorders,alterations in intestinal microflora structure and metabolic abnormalities.These studies suggest that changes in the intestinal microbiota and metabolites have potential effects on cognitive dysfunction in depression.Short-chain fatty acids(SCFAs)are metabolites produced by intestinal microorganisms by fermentation of proteins and carbohydrates,mainly including acetic acid,propionic acid and butyric acid.It was reported that depression-like behavior and cognitive impairment occurred in CMS model animals,and their content of SCFAs in serum and intestinal contents decreased significantly.Reducing the level of SCFAs by using broad-spectrum antibiotics resulted in impaired learning and memory ability,and leaded to cognitive dysfunction in experimental animals.This suggests that SCFAs may be an important "bridge" between intestinal microorganisms and central nervous system.In addition,the study found that SCFAs can not only reach the central nervous system through the blood-brain barrier to directly participate in the regulation of energy metabolism in the central nervous cells,but also cause reprogramming of glucose and lipid metabolism by binding to related receptors.These results suggested that intestinal microbial metabolite SCFAs played an important role in regulating the central glucose and lipid metabolism network as substrates for glucose,cholesterol and lipid metabolism.Moreover,the imbalance of central glucose and lipid metabolism played an important role in the occurrence and development of cognitive dysfunction,which may be a common pathological feature of multiple cognitive dysfunctions.Therefore,this paper established a model of CMS-induced depression-like behavior and cognitive impairment in C57BL/6 mice,focusing on the molecular mechanisms and key targets of SCFAs in regulating central glucose and lipid metabolism networks and improving cognitive dysfunction.In this paper,the CMS-induced depression model in C57BL/6 mouse was established according to literature reports,as well as the pseudo-sterile group and the pseudo-sterile group supplemented with SCFAs were established under normal and CMS models respectively.The results of behavioral experiments showed that compared with the normal group,the CMS model group showed a significant decrease in the activity time of the center zone in open field test and the consumption of sucrose water,as well as the immobility time in the forced swimming test was significantly increased.In addition,the escape latency increased and the proportion of target quadrant activity time decreased significantly in morris water maze test.These results indicated that CMS model mice exhibited depression-like behavior and cognitive dysfunction.The pseudo-sterile group did not exhibit depression-like behavior,but their learning and memory ability were impaired.SCFAs could significantly increased the activity time of the center zone in open field test and the consumption of sucrose water,significantly reduced the immobility time in the forced swimming test,as well as reduced the escape latency and significantly increased the proportion of target quadrant activity time in morris water maze test of CMS model mice.These findings suggested that SCFAs can improve depression-like behavior and cognitive dysfunction induced by chronic mild stress.In order to further explore the specific molecular mechanisms of SCFAs in improving cognitive dysfunction,this paper first explored the changes of central neurogenesis and synaptic plasticity in mice.Compared with the normal group,in the CMS model group,the hippocampal nerve regeneration ability was impaired,as well as brain-derived neurotrophic factor(BDNF)and activity-regulated cytoskeleton-associated protein(Arc)mRNA levels were significantly down-regulated and N-methyl-D-aspartate receptor 2B subunit(NR2B)mRNA levels were significantly up-regulated in the prefrontal cortex,resulting in a decrease in synaptic plasticity.SCFAs significantly inhibited the loss of neurons and increased the number of new neurons in the dentate gyrus(DG)region of CMS model mice,but did not alter the expression of BDNF,Arc and NR2B mRNA levels.Compared with the normal group,in the pseudo-sterile group,the hippocampal nerve regeneration ability was impaired,and synaptic plasticity was reduced by up-regulate the N-methyl-D-aspartate receptor 2A subunit(NR2A)and NR2B mRNA levels.SCFAs could significantly inhibited the loss of neurons and increased the number of new neurons in the hippocampal DG region,and down-regulated NR2A and NR2B mRNA levels to improve synaptic plasticity of pseudo-sterile mice.Secondly,this paper used the methods and techniques of wide target and targeted metabolomics to analyze and compare the changes of glucose,lipid and amino acid related metabolites in hippocampus of each groups.Metabolomics results suggested that CMS caused changes in glucose and lipid metabolism in the hippocampus,and SCFAs only significantly regulated the glucose and lipid metabolism in the hippocampus of the pseudo-sterile group,but had no significant effect on CMS model.Therefore,in subsequent experiments,it is still necessary to conduct an in-depth analysis of metabolite changes in mouse hippocampus,to determine the key targets of SCFAs regulating the central glucose and lipid metabolism network,and to confirm the important role of these targets in improving cognitive dysfunction by SCFAs.The work of this study clarified the effect of SCFAs on depression-like behavior and cognitive impairment in CMS mice,and revealed the mechanism by which SCFAs promoted central neurogenesis and synaptic plasticity in CMS mice.This article also preliminarily explored the changes of central glucose and lipid metabolism and the regulation of SCFAs in CMS mice,providing clues for further study on the molecular mechanism of SCFAs in improving cognitive impairment in depression. |
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