Exo-miR-144-3p as a promising diagnostic biomarker for depressive symptoms in heart failure.

AIMS: The prevalence of depression is higher in heart failure (HF) patients. Early screening of depressive symptoms in HF patients and timely intervention can help to improve patients' quality of life and prognosis. This study aims to explore diagnostic biomarkers by examining the expression profile of serum exosomal miRNAs in HF patients with depressive symptoms. METHODS: Serum exosomal RNA was isolated and extracted from 6 HF patients with depressive symptoms (HF-DS) and 6 HF patients without depressive symptoms (HF-NDS). High-throughput sequencing was performed to obtain miRNA expression profiles and target genes were predicted for the screened differentially expressed miRNAs. Biological functions of the target genes were analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, we collected serum exosomal RNAs from HF-DS (n = 20) and HF-NDS (n = 20). The differentially expressed miRNAs selected from the sequencing results were validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Finally, the diagnostic efficacy of the differentially expressed exosomal miRNAs for HF-DS was evaluated by using receiver operating characteristic (ROC) curves. RESULTS: A total of 19 significantly differentially expressed exosomal miRNAs were screened by high-throughput sequencing, consisting of 12 up-regulated and 7 down-regulated exosomal miRNAs. RT-qPCR validation demonstrated that the expression level of exo-miR-144-3p was significantly down-regulated in the HF-DS group, and the expression levels of exo-miR-625-3p and exo-miR-7856-5p were significantly up-regulated. In addition, the expression level of exo-miR-144-3p was negatively correlated with the severity of depressive symptoms in HF patients, and that the area under the curve (AUC) of exo-miR-144-3p for diagnosing HF-DS was 0.763. CONCLUSIONS: In this study, we examined the serum exosomal miRNA expression profiles of HF patients with depressive symptoms and found that lower level of exo-miR-144-3p was associated with more severe depressive symptoms. Exo-miR-144-3p is a potential biomarker for the diagnosis of HF-DS.

Inferior social hierarchy is vulnerable to anxiety-like behavior in chronic pain mice: Potential role of gut microbiota and metabolites.

Social dominance is a universal phenomenon among grouped animals that profoundly affects survival, health, and reproductive success by determining access to resources, and exerting a powerful influence on subsequent behavior. However, the understanding of pain and anxiety comorbidities in dominant or subordinate animals suffering from chronic pain is not well-defined. Here, we provide evidence that subordinate mice are more susceptible to pain-induced anxiety compared to dominant mice. We propose that the gut microbiota may play a mediating role in this mechanism. Our findings demonstrate that transplantation of fecal microbiota from subordinate mice with chronic inflammatory pain, but not dominant mice, into antibiotics-treated pseudo-germ-free mice significantly amplifies anxiety-like phenotypes, highlighting the critical involvement of gut microbiota in this behavioral response. Using chronic inflammatory pain model, we carried out 16S rRNA sequencing and untargeted metabolomic analyses to explore the relationship between microbiota and metabolites in a stable social hierarchy of mice. Interestingly, anxiety-like behaviors were directly associated with some microbial genera and metabolites, especially bile acid metabolism. Overall, we have demonstrated a close relationship between social status and anxiety susceptibility, highlighting the contributions of gut microbiota and the associated metabolites in the high-anxiety state of subordinate mice with chronic inflammatory pain.

The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine.

CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.

Myelin-associated oligodendrocytic basic protein-dependent myelin repair confers the long-lasting antidepressant effect of ketamine.

Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine's long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine's sustained antidepressant effects remain unknown. In this study, we employed spatial transcriptomics (ST) to examine ketamine's lasting effects in the medial prefrontal cortex (mPFC) and hippocampus of mice subjected to chronic social defeat stress and identified several differentially expressed myelin-related genes. Ketamine's ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine's long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine's facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms.

Ultrasound-controlled nano oxygen carriers enhancing cell viability in 3D GelMA hydrogel for the treatment of myocardial infarction.

Heart failure is a critical and ultimate phase of cardiovascular ailment that leads to a considerable incidence of disability and mortality. Among various factors contributing to heart failure, myocardial infarction is one of the most frequent and significant causes, which is still difficult to manage effectively. An innovative therapeutic strategy, namely a 3D bio-printed cardiac patch, has recently emerged as a promising approach to substitute damaged cardiomyocytes in a localized infarct region. Nevertheless, the efficacy of this treatment primarily relies on the long-term viability of the transplanted cells. In this study, we aimed to construct acoustically sensitive nano oxygen carriers to improve cell survival inside the bio-3D printed patch. In this study, we initially created nanodroplets capable of phase transition triggered by ultrasound and integrated them into GelMA (Gelatin Methacryloyl) hydrogels, which were then employed for 3D bioprinting. After adding nanodroplets and ultrasonic irradiation, numerous pores appeared inside the hydrogel with improved permeability. We further encapsulated hemoglobin into nanodroplets (ND-Hb) to construct oxygen carriers. Results of in vitro experiments showed the highest cell survival within the patch of ND-Hb irradiated by the low-intensity pulsed ultrasound (LIPUS) group. The genomic analysis discovered that the increased survival of seeded cells within the patch might be related to the protection of mitochondrial function owing to the improved hypoxic state. Eventually, in vivo studies revealed that the LIPUS+ND-Hb group had improved cardiac function and increased revascularization after myocardial infarction. To summarize, our study successfully improved the permeability of the hydrogel in a non-invasive and efficient manner, facilitating the exchange of substances in the cardiac patch. Moreover, ultrasound-controlled oxygen release augmented the viability of the transplanted cells and expedited the repair of infarcted tissues.

Desulfovibrio confers resilience to the comorbidity of pain and anxiety in a mouse model of chronic inflammatory pain.

BACKGROUND: Patients with chronic pain frequently suffer from anxiety symptoms. It has been well established that gut microbiota is associated with the pathogenesis of pain and anxiety. However, it is unknown whether the gut microbiota, particularly the specific bacteria, play a role in the comorbidity of chronic pain and anxiety. METHODS: Chronic inflammatory pain was induced in mice by a single injection of complete Freund's adjuvant (CFA). Mice were then separated into anxiety-susceptible and anxiety-resilient phenotypes by hierarchical clustering analysis of behaviors. Fecal samples were collected to perform 16S rRNA gene sequencing. Chronic diazepam intervention served as a therapeutic strategy and its effect on the composition of gut microbiota was also determined. RESULTS: α-Diversity and ß-diversity both showed significant differences among the groups. A total of 12 gut bacteria were both altered after CFA injection and reversed by chronic diazepam treatment. More importantly, the pain hypersensitivity and anxiety-like behaviors were relieved by chronic diazepam treatment. Interestingly, we also found that Desulfovibrio was increased in anxiety-resilient group compared to control and anxiety-susceptible groups. CONCLUSION: Abnormal composition of gut microbiota plays an essential role in chronic pain as well as in anxiety. Besides, the increased level of Desulfovibrio in anxiety-resilient mice indicated its therapeutic effects on the comorbidity of pain and anxiety. Collectively, targeting gut microbiota, especially increasing the Desulfovibrio level, might be effective in the alleviation of chronic pain-anxiety comorbidity.

A Bibliometric Analysis of Research on the Role of BDNF in Depression and Treatment.

Brain-derived neurotrophic factor (BDNF), as the most widely distributed and widely studied neurotrophic factor in the mammalian brain, plays a key role in depression and the mechanisms of action for antidepressants. Currently, there is a large number of studies on the role of BDNF in the pathogenesis and therapeutic mechanism of depression. The quantity and quality of these studies, however, are unknown. To give beginners a quicker introduction to this research topic, we therefore performed a bibliometric analysis. A total of 5300 publications were included. We obtained the publications on this topic from the Web of Science database, and a variety of bibliographic elements were collected, including annual publications, authors, countries/regions, institutions, journals, and keywords. Moreover, we found that oxidative stress and neuroinflammation are the hotspots in the field in very recent years. Collectively, this study provides a comprehensive summary and analysis on the role of BDNF in depression and its treatment and offers meaningful values for beginners on this topic.

Risk factors and prediction model of sleep disturbance in patients with maintenance hemodialysis: A single center study.

Objectives: This study aimed to explore the risk factors and develop a prediction model of sleep disturbance in maintenance hemodialysis (MHD) patients. Methods: In this study, 193 MHD patients were enrolled and sleep quality was assessed by Pittsburgh Sleep Quality Index. Binary logistic regression analysis was used to explore the risk factors for sleep disturbance in MHD patients, including demographic, clinical and laboratory parameters, and that a prediction model was developed on the basis of risk factors by two-way stepwise regression. The final prediction model is displayed by nomogram and verified internally by bootstrap resampling procedure. Results: The prevalence of sleep disturbance and severe sleep disturbance in MHD patients was 63.73 and 26.42%, respectively. Independent risk factors for sleep disturbance in MHD patients included higher 0.1*age (OR = 1.476, 95% CI: 1.103-1.975, P = 0.009), lower albumin (OR = 0.863, 95% CI: 0.771-0.965, P = 0.010), and lower 10*calcium levels (OR = 0.747, 95% CI: 0.615-0.907, P = 0.003). In addition, higher 0.1*age, lower albumin levels, and anxiety were independently associated with severe sleep disturbance in MHD patients. A risk prediction model of sleep disturbance in MHD patients showed that the concordance index after calibration is 0.736, and the calibration curve is approximately distributed along the reference line. Conclusions: Older age, lower albumin and calcium levels are higher risk factors of sleep disturbance in MHD, and the prediction model for the assessment of sleep disturbance in MHD patients has excellent discrimination and calibration.

Nomograms based on lactate dehydrogenase to albumin ratio for predicting survival in colorectal cancer.

Purpose: We aimed to determine if lactate dehydrogenase to albumin ratio (LAR) might play a prognostic role for patients with operable colorectal cancer (CRC). Patients and Methods: 1334 operable CRC patients in Wuhan Union Hospital Between July 2013 and September 2017 were enrolled in this study and were randomly appointed them into training (n=954) and validation (n=380) sets. The relationship between LAR and overall survival (OS) and disease-free survival (DFS) were determined by restricted cubic splines (RCS) with Cox regression models. LAR was then divided into three categories based on the RCS and compared to the well-known TNM stage system. Finally, survival nomograms were developed by compounding the LAR and other clinical factors. Results: Baseline LAR values and the all-cause mortality were U shaped, which slowly decreased until around 4.50 and then started to increase rapidly when the LAR ranged from 4.50-6.68 and then became flat thereafter (P for non-linearity <0.001). LAR was superior to TNM stage for OS as well as DFS and LAR plus TNM stage could add more net benefit than clinical model alone. Moreover, the survival nomograms based on LAR achieved great predictive ability for OS and DFS in operable CRC patients. Conclusions: LAR could be served as a reliable prognostic factor for OS as well as DFS, with more accurate prognostic prediction than current TNM stage for patients with operable CRC.

Gut microbiota is involved in the antidepressant effects of adipose-derived mesenchymal stem cells in chronic social defeat stress mouse model.

RATIONALE: Growing evidence supports the role of microbiota in regulating gut-brain interactions and, thus, contributing to the pathogenesis of depression and the antidepressant actions. Adipose-derived mesenchymal stem cells (ADSCs), as important members of the stem cell family, were demonstrated to alleviate depression behaviors. However, the role of gut microbiota in ADSCs alleviating depression in chronic social defeat stress (CSDS) model is unknown. OBJECTIVES: To examine the effects of ADSCs on depression symptoms and detect the changes in the composition of gut microbiota. RESULTS: We found that ADSCs administration significantly ameliorated CSDS-induced depression behaviors, which was accompanied by alteration in the gut microbiota. The principal co-ordinates analysis (PCoA) results showed that there was a significant difference between the gut microbiota among the groups. Remarkably, receiver operating characteristic (ROC) curves revealed that order Micrococcales, order Rhizobiales and species Bacteroides acidifaciens are potentially important biomarkers for the antidepressant effects of ADSCs in CSDS model. CONCLUSIONS: ADSCs are effective in treating depression behaviors in CSDS model, which might be partly due to the regulation of abnormal composition of gut microbiota. Thus, ADSCs offer a promising therapeutic strategy for treating depression in patients.

Gut microbiota is involved in the antidepressant-like effect of (S)-norketamine in an inflammation model of depression.

The non-competitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist, (R, S)-ketamine (ketamine), is known to exert rapid and long-lasting antidepressant-like effects. However, the widely use of ketamine is restricted owing to severe psychotomimetic side-effects and abuse liability. Very recently, we demonstrated that a major metabolite of ketamine, norketamine, in particular the (S)-enantiomer, had a potent antidepressant-like effect. We here examined the effects of a low-dose of norketamine enantiomers on depression symptoms and detected the changes in the composition of gut microbiota. In the behavioral tests, (S)-norketamine, but not (R)-norketamine, showed antidepressant-like effects in the lipopolysaccharide (LPS)-induced mice. At the genus level, (S)-norketamine, but not (R)-norketamine, significantly attenuated the increase in the levels of Escherichia-Shigella and Adlercreutzia, as well as the reduction in the levels of Harryflintia. At the species level, both (S)-norketamine and (R)-norketamine significantly attenuated the increase in the levels of bacterium ic1379 and Bacteroides sp. Marseille-P3166. Notably, (S)-norketamine was more potent than (R)-norketamine at reducing the levels of bacterium ic1379 and Bacteroides sp. Marseille-P3166. Furthermore, (S)-norketamine, but not (R)-norketamine, significantly attenuated the increased levels of Bacteroides caecigallinarum. In conclusion, this study suggests that the antidepressant-like effects of (S)-norketamine might be associated with the changes in the composition of gut microbiota. Therapeutic strategies improving the gut microbiota might facilitate the benefits for depression treatment.

Less Social Support for Patients With COVID-19: Comparison With the Experience of Nurses.

Context: Since December 2019, more than 80,000 patients have been diagnosed with coronavirus disease 2019 (COVID-19) in China. Social support status of COVID-19 patients, especially the impact of social support on their psychological status and quality of life, needs to be addressed with increasing concern. Objectives: In this study, we used social support rating scale (SSRS) to investigate the social support in COVID-19 patients and nurses. Methods: The present study included 186 COVID-19 patients at a Wuhan mobile cabin hospital and 234 nurses at a Wuhan COVID-19 control center. Responses to a mobile phone app-based questionnaire about social support, anxiety, depression, and quality of life were recorded and evaluated. Results: COVID-19 patients scored significantly lower than nurses did on the Social Support Rating Scale (SSRS). Among these patients, 33.9% had anxiety symptoms, while 23.7% had depression symptoms. Overall SSRS, subjective social support scores and objective support scores of patients with anxiety were lower than those of patients without anxiety. This result was also found in depression. In addition, all dimensions of social support were positively correlated with quality of life. Interestingly, in all dimensions of social support, subjective support was found to be an independent predictive factor for anxiety, depression, and quality of life, whereas objective support was a predictive factor for quality of life, but not for anxiety and depression via regression analysis. Conclusion: Medical staffs should pay attention to the subjective feelings of patients and make COVID-19 patients feel respected, supported, and understood from the perspective of subjective support, which may greatly benefit patients, alleviate their anxiety and depression, and improve their quality of life.

Gut microbiota transplantation from db/db mice induces diabetes-like phenotypes and alterations in Hippo signaling in pseudo germ-free mice.

Type 2 diabetes mellitus (T2DM) is an age-related metabolic disease that is of increasing concern. Gut microbiota might have a critical role in the pathogenesis of T2DM. Additionally, Hippo signaling has been associated strongly with the progression of T2DM and the aging process. We adopted db/db male mice as a T2DM model, and the gut microbiota of db/db and m/m mice were transplanted successfully into pseudo germ-free mice. Furthermore, Hippo signaling, including mammalian sterile 20-like protein kinases 1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP), and phosphorylation of YAP (p-YAP) in peripheral tissues were significantly altered and highly correlated with blood glucose in db/db mice. Interestingly, the host after gut microbiota transplantation from db/db mice showed decreased MST1 and LATS1 levels, and p-YAP/YAP ratio in the heart, liver, and kidney compared to those from m/m mice. Negative correlations between fasting blood glucose and Hippo signaling levels in selected peripheral tissues also were identified. These findings suggest that alterations in Hippo signaling in selected peripheral tissues may contribute to the development of T2DM, and that therapeutic interventions improving Hippo signaling by gut microbiota transplantation might be beneficial for the treatment of T2DM and other age-related metabolic diseases.

Abnormalities in gut microbiota and serum metabolites in hemodialysis patients with mild cognitive decline: a single-center observational study.

RATIONALE: Although a growing body of evidence indicates that the scores of cognitive function in hemodialysis patients are significantly lower than those of healthy individuals, underlying mechanisms have not been fully elucidated. OBJECTIVES: To investigate the roles of gut microbiota and serum metabolites in hemodialysis patients with mild cognitive decline (MCD). METHODS: A total of 30 healthy individuals and 77 hemodialysis patients were enrolled and were classified into healthy control (HC), normal cognitive function (NCF), and MCD groups by evaluation of Montreal Cognitive Assessment. Fecal samples were analyzed by 16S rRNA and serum samples were analyzed by gas chromatography-mass spectrometry from all subjects. RESULTS: The 16S rRNA study demonstrated that the gut microbiota profiles, including α- and ß-diversity, and a number of 16 gut bacteria were significantly altered in the MCD group compared with those in HC or those with NCF. A metabonomics study showed that a total of 29 serum metabolites were altered in the MCD group. Receiver operating characteristic curves showed that Genus Bilophila and serum putrescine might be sensitive biomarkers to indicate MCD in patients with hemodialysis. CONCLUSIONS: These findings demonstrate gut microbiota and serum metabolites were probably involved in the pathogenesis of hemodialysis-related MCD. Therapeutic strategies targeting abnormalities in gut microbiota and serum metabolites may facilitate the beneficial effects for hemodialysis patients with MCD.

Vicarious traumatization in the general public, members, and non-members of medical teams aiding in COVID-19 control.

Since December 2019, more than 79,000 people have been diagnosed with infection of the Corona Virus Disease 2019 (COVID-19). A large number of medical staff was sent to Wuhan city and Hubei province to aid COVID-19 control. Psychological stress, especially vicarious traumatization caused by the COVID-19 pandemic, should not be ignored. To address this concern, the study employed a total of 214 general public and 526 nurses (i.e., 234 front-line nurses and 292 non-front-line nurses) to evaluate vicarious traumatization scores via a mobile app-based questionnaire. Front-line nurses are engaged in the process of providing care for patients with COVID-19. The results showed that the vicarious traumatization scores for front-line nurses including scores for physiological and psychological responses, were significantly lower than those of non-front-line nurses (P < 0.001). Interestingly, the vicarious traumatization scores of the general public were significantly higher than those of the front-line nurses (P < 0.001); however, no statistical difference was observed compared to the scores of non-front-line nurses (P > 0.05). Therefore, increased attention should be paid to the psychological problems of the medical staff, especially non-front-line nurses, and general public under the situation of the spread and control of COVID-19. Early strategies that aim to prevent and treat vicarious traumatization in medical staff and general public are extremely necessary.

Contribution of skeletal muscular glycine to rapid antidepressant effects of ketamine in an inflammation-induced mouse model of depression.

RATIONALE: Basic 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. OBJECTIVES: The present study evaluated the effects of systemically administered ketamine treatment in a lipopolysaccharide (LPS)-induced mouse model of depression. METHODS: Non-targeted metabolomics, western blotting, and behavioral tests (locomotion, tail suspension, and forced swimming tests) were performed. RESULT: Ketamine 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. CONCLUSIONS: Our 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.

Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota.

It is well known that the incidence of postoperative cognitive dysfunction (POCD) is high in elderly patients. The pathogenesis and therapeutic mechanisms of POCD, however, have not yet been completely elucidated. The effects of gut microbiota, particularly in terms of regulating brain function, have gradually attracted increasing attention. In this study, we investigated the potential role of gut microbiota in POCD in aged male mice and attempted to determine whether alterations in gut microbiota would be helpful in the diagnosis of POCD. POCD and non-POCD mice were classified by hierarchical cluster analysis of behavioral results. Additionally, α- and ß-diversity of gut microbiota showed a differential profile between the groups. In total, 24 gut bacteria were significantly altered in POCD mice compared with those in non-POCD mice, in which 13 gut bacteria were significantly correlated with escape latency in the Morris water maze test (MWMT). Remarkably, receiver operating characteristic curves revealed that the Dehalobacteriaceae family and Dehalobacterium genus are potentially important bacteria for the diagnosis of POCD. These findings indicate that alterations in the composition of gut microbiota are probably involved in the pathogenesis of POCD in aged mice. Novel therapeutic strategies regulating specific gut bacteria may be helpful for the prevention and treatment of POCD.

Key role of gut microbiota in anhedonia-like phenotype in rodents with neuropathic pain.

Patients with chronic neuropathic pain frequently suffer from symptoms of anhedonia, which is a core symptom of depression. Accumulating studies suggest that gut microbiota may play a role in depression via gut-microbiota-brain axis. However, it is unknown whether gut microbiota plays a role in neuropathic pain-associated anhedonia. Here, we used a rat model of spared nerve injury (SNI). Hierarchical cluster analysis of sucrose preference test (SPT) results was used to classify the SNI rats with or without anhedonia-like phenotype. The 16S ribosomal RNA sequencing analysis showed abnormal composition of gut microbiota in the anhedonia susceptible compared to sham-operated rats and resilient rats. Furthermore, antibiotics-treated mice showed pain as well as depression-like and anhedonia-like phenotypes, suggesting a role of gut microbiota in these abnormal behaviors. Transplantation of fecal microbiota from anhedonia susceptible rats into antibiotics-treated pseudo-germ-free mice significantly exaggerated pain and depression-like phenotypes, including anhedonia. In contrast, transplantation of fecal microbiota from resilient rats into antibiotics-treated pseudo-germ-free mice significantly improved pain and depression-like phenotypes, including anhedonia. In conclusion, this study suggests that abnormal composition of gut microbiota may contribute to anhedonia susceptibility post SNI surgery, and that gut microbiota also plays a role in the pain as well as depression-like phenotypes. Interestingly, fecal microbiota transplantation from SNI rats with or without anhedonia can alter pain, depression-like and anhedonia-like phenotypes in the pseudo-germ-free mice. Therefore, it is likely that gut microbiota plays a key role in the pain as well as depression-like phenotypes including anhedonia in rodents with neuropathic pain.

Ketamine Alleviates Postoperative Depression-Like Symptoms in Susceptible Mice: The Role of BDNF-TrkB Signaling.

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.

Role of Actinobacteria and Coriobacteriia in the antidepressant effects of ketamine in an inflammation model of depression.

Ketamine, an N-methyl-d-aspartic acid receptor (NMDAR) antagonist, elicits rapid-acting and sustained antidepressant effects in treatment-resistant depressed patients. Accumulating evidence suggests that gut microbiota via the gut-brain axis play a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. Here we investigated the role of gut microbiota in the antidepressant effects of ketamine in lipopolysaccharide (LPS)-induced inflammation model of depression. Ketamine (10 mg/kg) significantly attenuated the increased immobility time in forced swimming test (FST), which was associated with the improvements in α-diversity, consisting of Shannon, Simpson and Chao 1 indices. In addition to α-diversity, ß-diversity, such as principal coordinates analysis (PCoA), and linear discriminant analysis (LDA) coupled with effect size measurements (LEfSe), showed a differential profile after ketamine treatment. Furthermore, a total of 30 bacteria were significantly altered in the LPS + saline treated mice and LPS + ketamine treated mice. Interestingly, two bacteria, including the phylum Actinobacteria and the class Coriobacteriia were significantly correlated with the immobility time of FST. Importantly, the receiver operating characteristic (ROC) curves demonstrated that the phylum Actinobacteria and the class Coriobacteriia were potential biomarker for the antidepressant effects of ketamine in an inflammation model. These findings suggest that antidepressant effects of ketamine might be related to the regulation of abnormal composition of gut microbiota, and that the phylum Actinobacteria and the class Coriobacteriia might be potential biomarkers for ketamine's antidepressant efficacy.