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BackgroundChronic pain is frequently comorbid with depression in clinical practice. Recently, alterations in gut microbiota and metabolites derived therefrom have been found to potentially contribute to abnormal behaviors and cognitive dysfunction via the “microbiota–gut–brain” axis.MethodsPubMed was searched and we selected relevant studies before October 1, 2019. The search keyword string included “pain OR chronic pain” AND “gut microbiota OR metabolites”; “depression OR depressive disorder” AND “gut microbiota OR metabolites”. We also searched the reference lists of key articles manually.ResultsThis review systematically summarized the recent evidence of gut microbiota and metabolites in chronic pain and depression in animal and human studies. The results showed the pathogenesis and therapeutics of chronic pain and depression might be partially due to gut microbiota dysbiosis. Importantly, bacteria-derived metabolites, including short-chain fatty acids, tryptophan-derived metabolites, and secondary bile acids, offer new insights into the potential linkage between key triggers in gut microbiota and potential mechanisms of depression.ConclusionStudying gut microbiota and its metabolites has contributed to the understanding of comorbidity of chronic pain and depression. Consequently, modulating dietary structures or supplementation of specific bacteria may be an available strategy for treating chronic pain and depression.

Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivationmediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuinl expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND. Keywords: perioperative sleep disturbance, cognitive impairment, postoperative delirium, postoperative cognitive dysfunction, neuroinflammation

Skeletal muscle consumes two thirds of the body’s energy and may play a role in stress-related disorders. Evidence suggests that the peroxisome proliferator-activated receptor γ coactivator α (PGC-1α)–fibronectin type III domain-containing 5 (FNDC5)–brain-derived neurotrophic factor (BDNF) signaling pathway in skeletal muscle plays a key role in conferring the beneficial effects of exercise. In this study, we aimed to determine whether this pathway contributes to the resilience or susceptibility of mice subjected to chronic social defeat stress (CSDS). BDNF–tropomyosin receptor kinase B (TrkB) and proBDNF–p75 NTR signaling in the medial prefrontal cortex and nucleus accumbens of susceptible but not resilient mice were significantly altered compared with the controls. Furthermore, the levels of PGC-1α, FNDC5, and BDNF, as well as the p-TrkB/TrkB ratio in the skeletal muscle of susceptible but not resilient mice, were significantly lower than those of the controls, but the levels of proBDNF and p75 NTR in the skeletal muscle of susceptible mice were significantly higher than those of the controls. Moreover, there were significant positive associations between social interaction test data and the expression of PGC-1α, FNDC5, and BDNF or the p-TrkB/TrkB ratio in skeletal muscle. These results suggest that the downregulation of the PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle contributes to resilience vs. susceptibility to CSDS. Therefore, alterations in this pathway in skeletal muscle may play a crucial role in mediating stress-related disorders.

Emerging evidence suggests that anesthesia and surgery may induce gut dysbiosis. Gut dysbiosis leads to imbalance in circulating contents of microbiota-derived metabolites and disrupts the integrity of the blood-brain barrier (BBB), contributing to postoperative cognitive dysfunction (POCD). The composition of gut microbiota may be influenced by various antibiotics. However, how perioperative use of antibiotics affects POCD needs more explorations. In the present study, we explored the effect of cefazolin, a common antibiotic used in perioperative period, on cognitive function, BBB integrity, gut bacteria and short chain fatty acids (SCFAs), a group of widely studied metabolites in aged mice, using 18-month-old male mice. Significant BBB disruptions and decreased levels of tight junction proteins, zonula occludens-1 (ZO-1) and Occludin (OCLN) were seen in the mice of POCD model. Cefazolin treatment attenuated these changes induced by anesthesia and surgery. Furthermore, cefazolin reversed the changes in several fecal bacteria (β - , γ/δ - , ε -Proteobacteria , and Bacteroidetes) as determined by qPCR tests. Analysis of plasma SCFAs showed that almost all types of SCFAs were reduced in POCD and cefazolin administration reversed the changes in expression of the two most abundant SCFAs (acetic and propionic acids). In conclusion, this study demonstrated that cefazolin improved POCD. Mechanistically, cefazolin suppressed the disruption of BBB, gut microbiota or SCFAs, thereby ameliorating POCD.

Patients with chronic neuropathic pain (CNP) often complain about their terrible memory, especially the speed of information processing. Accumulating evidence suggests a possible link between gut microbiota and pain processing as well as cognitive function via the microbiota-gut-brain axis. This study aimed at exploring the fecal microbiome and plasma metabolite profiles in middle-aged spared nerve injury (SNI) mice model with cognitive dysfunction (CD) induced by CNP. The hierarchical cluster analysis of performance in the Morris water maze test was used to classify SNI mice with CD or without CD [i.e., non-CD (NCD)] phenotype. 16S rRNA sequencing revealed a lower diversity of gut bacteria in SNI mice, and the increase of Actinobacteria, Proteus , and Bifidobacterium might contribute to the cognitive impairment in the CNP condition. The plasma metabolome analysis showed that the endocannabinoid (eCB) system, disturbances of lipids, and amino acid metabolism might be the dominant signatures of CD mice. The fecal microbiota transplantation of the Sham (not CD) group improved allodynia and cognitive performance in pseudo-germ-free mice via normalizing the mRNA expression of eCB receptors, such as cn1r, cn2r , and htr1a , reflecting the effects of gut bacteria on metabolic activity. Collectively, the findings of this study suggest that the modulation of gut microbiota and eCB signaling may serve as therapeutic targets for cognitive deficits in patients with CNP.

To investigate the role of gut microbiota and metabolites in POCD in elderly orthopedic patients, and screen the preoperative diagnostic indicators of gut microbiota in elderly POCD. 40 elderly patients undergoing orthopedic surgery were enrolled and divided into Control group and POCD group following neuropsychological assessments. Gut microbiota was determined by 16S rRNA MiSeq sequencing, and metabolomics of GC-MS and LC-MS was used to screen the differential metabolites. We then analyzed the pathways enriched by metabolites. There was no difference in alpha or beta diversity between Control group and POCD group. There were significant differences in 39 ASV and 20 genera bacterium in the relative abundance. Significant diagnostic efficiency analyzed by the ROC curves were found in 6 genera bacterium. Differential metabolites in the two groups including acetic acid, arachidic acid, pyrophosphate etc. were screened out and enriched to certain metabolic pathways which impacted the cognition function profoundly. Gut microbiota disorders exist preoperatively in the elderly POCD patients, by which there could be a chance to predict the susceptible population. [http://www.chictr.org.cn/edit.aspx?pid=133843&htm=4], identifier [ChiCTR2100051162].

RationaleBasic and clinical studies have reported rapid and long-lasting antidepressant effects of ketamine. Although previous studies have proposed several mechanisms underlying the antidepressant effects of ketamine, these mechanisms have not been completely elucidated.ObjectivesThe present study evaluated the effects of systemically administered ketamine treatment in a lipopolysaccharide (LPS)-induced mouse model of depression.MethodsNon-targeted metabolomics, western blotting, and behavioral tests (locomotion, tail suspension, and forced swimming tests) were performed.ResultKetamine significantly attenuated the abnormally increased immobility time in a lipopolysaccharide (LPS)-induced mouse model of depression. Aminomalonic acid, glutaraldehyde, glycine, histidine, N-methyl-l-glutamic acid, and ribose levels in skeletal muscle were altered following ketamine administration. Furthermore, ketamine significantly decreased the LPS-induced increase in glycine receptor A1 (GlyA1) levels. However, the glycine receptor antagonist strychnine did not elicit any pharmacological effects on ketamine-induced alterations in behaviors or muscular GlyA1 levels. Exogenous glycine and l-serine significantly improved depression-like symptoms in LPS-induced mice.ConclusionsOur findings suggest that skeletal muscular glycine contributes to the antidepressant effects of ketamine in inflammation. Effective strategies for improving skeletal muscular glycine levels may be a novel approach to depression treatment.

To address the challenges of low diagnostic accuracy of constrained primary frequency regulating (PFR) capacity for coal-fired units due to complex and strongly coupled restricting factors, an intelligent diagnosis method based on an improved snake optimizer-based multi-label random forest classification algorithm is proposed. By analyzing the factors restricting PFR capability, a set of characterization parameters and constraint factors for unit regulating capacity is established. The snake optimizer is enhanced by introducing dynamic update mechanisms and novel search strategies to improve its convergence speed and accuracy. The improved algorithm is then applied to optimize the hyperparameters of the multi-label random forest algorithm, enabling online diagnosis of PFR capacity limitations. Simulation results demonstrate that the proposed algorithm exhibits superior convergence performance, with lower medians of false alarm rate and missing alarm rate across all labels, coupled with reduced result dispersion compared to alternative algorithms. Tests on real operational data show an average false alarm rate of 0.029% and an average missing alarm rate of 0.053 for all labels. The results indicate that the proposed method is feasible and effective, enabling accurate online diagnosis of constrained PFR capacity of coal-fired units.

Patients are more likely to suffer from central nervous system (CNS) complications after anesthesia and surgery. However, postoperative depression (POD) has not yet received sufficient attentions, and its pathogenesis and therapeutic strategies remain poorly understood. We here aimed to investigate whether brain derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling plays an important role in POD. BDNF-TrkB signaling was altered in brain and peripheral tissues, including medial prefrontal cortex (mPFC), hippocampus, liver, and muscle, among control, POD susceptible, and resilient groups. Additionally, we demonstrated that 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, could exert its pharmacologic property to alleviate POD-like symptoms. More importantly, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, also has significant antidepressant effects in POD model, associating with the improving effects on levels of BDNF-TrkB signaling in brain and peripheral tissues. Interestingly, the beneficial effects of ketamine on POD-like symptoms are fully attenuated by a TrkB antagonist. These findings suggest that abnormal expressions of BDNF-TrkB signaling in brain and peripheral tissues are implicated in the pathogenesis of POD, and that therapeutic agents targeting BDNF-TrkB, particularly ketamine, could favor the beneficial effects for POD.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer’s diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.