Chronic Unpredictable Mild Stress Group Research Articles

Pathophysiological dynamics of acute myocardial infarction rats under chronic psychological stress at different time points

There is a lack of in-depth research on the impacts and changes in chronic psychological stress (CPS) on the cardiovascular system after acute myocardial infarction (AMI). This study aims to explore the comorbid mechanism and dynamic evolution of AMI exposed to CPS. 120 Wistar rats were randomly divided into Sham Operation group, Sham Operation + Chronic Unpredictable Mild Stress (CUMS) group, AMI group and AMI + CUMS group, with each group further divided into subgroups at days 7, 14, and 28. The AMI model was created by ligating the left anterior descending coronary artery, and CUMS model was used to induce CPS in rats. Behavioral changes were assessed through open field tests and sucrose preference tests. Cardiac function and structure were evaluated via echocardiography. The serum levels of TNFα, IL-6, NO, ET, CK-MB, cTNT, and ANP were measured using assay kits. Pathological changes in cardiac and brain tissues were observed under an optical microscope. Comparative analysis across different models revealed that CUMS significantly reduced behavioral activities in rats, with an interaction between CUMS and AMI affecting total distance (P < 0.05). Both CUMS and AMI significantly reduced cardiac function indicators, with their interaction effects on LVEF, LVFS, and CO (P < 0.05). AMI significantly altered cardiac structural parameters, particularly on day 28 (P < 0.05); while the impact of CUMS on cardiac structure was not significant, except for a notable reduction in LVAW/s on day 7 in AMI + CUMS group (P < 0.05). AMI caused significant changes in the serum biomarkers, while CUMS only significantly increased cTnT on day 7, ANP, TNFα, and IL-6 on day 14, and CK-MB on day 28, with their interaction effects on the three myocardial injury markers and TNFα (P < 0.05). Comparative analysis across different time points demonstrated that behavioral activity, cardiac function, CK-MB, cTnT, ANP, TNFα, and ET levels decreased significantly over time in the AMI model rats, while the left ventricular mass increased significantly (P < 0.05). Pathologically, compared with stress or AMI alone, the AMI + CUMS group exhibited more severe myocardia cellular degeneration and inflammatory infiltration, causing larger infract areas in myocardial tissue, as well as cell number decreases and morphological changes in hippocampal tissue. AMI with CPS exacerbates myocardial injury through sustained inflammation and endothelial dysfunction, leading to heart-brain pathology manifestations characterized by decreased cardiac function and hippocampal tissue damage.

Glutamate chemical exchange saturation transfer (GluCEST) MRI to evaluate the relationship between demyelination and glutamate content in depressed mice

Glutamatergic alteration is one of the potential mechanisms of depression. However, there is no consensus on whether glutamate metabolism changes affect the myelin structure of depression in mouse models. Glutamate chemical exchange saturation transfer (GluCEST) is a novel and powerful molecular imaging technique that can visualize glutamate distribution. In this study, we used the GluCEST imaging technique to look at glutamate levels in mice under chronic unpredictable mild stress (CUMS) and how they relate to demyelination. The CUMS mice were exposed to different stress factors for 6 weeks. Evaluated of depression in CUMS mice by behavioral tests. MRI scans were then performed, including T2-mapping, GluCEST, and diffusion tensor imaging (DTI) sequences. Brain tissues were collected for Luxol Fast Blue staining and immunofluorescence staining to analyze the changes in the myelin sheath. Artificially sketched regions of interest (ROI) (corpus callosum, hippocampus, and thalamus) were used to calculate the GluCEST value, fractional anisotropy (FA), and T2 value. Compared with the control group, the GluCEST value in the ROIs of CUMS mice significantly decreased. Similarly, the FA value in ROIs was lower in the CUMS group than in the CTRL group, but the T2 value did not differ significantly between the two groups. The histological results showed that ROIs in the CUMS group had demyelination compared with the CTRL group, indicating that DTI was more sensitive than T2 mapping in detecting myelin abnormalities. Furthermore, the GluCEST value in the ROIs correlates positively with the FA value. These findings suggest that altered glutamate metabolism may be one of the important factors leading to demyelination in depression, and GluCEST is expected to serve as an imaging biological marker for the diagnosis of demyelination in depression.

Effects of regulating gut microbiota by electroacupuncture in the chronic unpredictable mild stress rat model

ObjectiveThis study aims to investigate the effect of electroacupuncture (EA) treatment on depression, and the potential molecular mechanism of EA in depression-like behaviors rats. MethodsA total of 40 male Sprague Dawley rats were divided into three groups: normal control, chronic unpredictable mild stress (CUMS), and EA (CUMS + EA). The rats in CUMS and EA groups underwent chronic stress for 10 weeks, and EA group rats received EA treatment for 4 weeks starting from week 7. Body weight and behavioral tests, including the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were monitored. Gut microbiota composition was assessed via 16S rDNA sequencing, and lipid metabolism was analyzed by using UPLC-Q-TOF/MS technology. ResultsIn comparison to CUMS group, EA could improve the behavior including bodyweight, immovability time, sucrose preference index, crossing piece index and rearing times index. After 4 weeks of EA treatment, 5-HT in hippocampus, serum and colon of depressive rats were simultaneously increased, indicating a potential alleviation of depression-like behaviors. In future studies revealed that EA could regulate the distribution and functions of gut microbiota, and improve the intestinal barrier function of CUMS rats. The regulation of intestinal microbial homeostasis by EA may further affect lipid metabolism in CUMS rats, and thus play an antidepressant role. ConclusionThis study suggested that EA has potential antidepressant effects by regulating gut microbiota composition and abundance, subsequently affecting lipid metabolism.

Network Pharmacology and Transcriptomics to Explore the Pharmacological Mechanisms of 20(S)-Protopanaxatriol in the Treatment of Depression.

Depression is one of the most common psychological disorders nowadays. Studies have shown that 20(S)-protopanaxatriol (PPT) can effectively improve depressive symptoms in mice. However, its mechanism needs to be further explored. In this study, we used an integrated approach combining network pharmacology and transcriptomics to explore the potential mechanisms of PPT for depression. First, the potential targets and pathways of PPT treatment of depression were screened through network pharmacology. Secondly, the BMKCloud platform was used to obtain brain tissue transcription data of chronic unpredictable mild stress (CUMS) model mice and screen PPT-altered differential expression genes (DEGs). Gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using network pharmacology and transcriptomics. Finally, the above results were verified by molecular docking, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). In this study, we demonstrated that PPT improved depression-like behavior and brain histopathological changes in CUMS mice, downregulated nitric oxide (NO) and interleukin-6 (IL-6) levels, and elevated serum levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) after PPT treatment compared to the CUMS group. Eighty-seven potential targets and 350 DEGs were identified by network pharmacology and transcriptomics. Comprehensive analysis showed that transthyretin (TTR), klotho (KL), FOS, and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway were closely associated with the therapeutic effects of PPT. Molecular docking results showed that PPT had a high affinity for PI3K, AKT, TTR, KL, and FOS targets. Gene and protein level results showed that PPT could increase the expression of PI3K, phosphorylation of PI3K (p-PI3K), AKT, phosphorylation of AKT (p-AKT), TTR, and KL and inhibit the expression level of FOS in the brain tissue of depressed mice. Our data suggest that PPT may achieve the treatment of depression by inhibiting the expression of FOS, enhancing the expression of TTR and KL, and modulating the PI3K-AKT signaling pathway.

Fluoxetin suppresses tau phosphorylation and modulates the interaction between tau and tubulin in the hippocampus of CUMS rats

Depression is considered a crucial psychiatric disease correlated with neuronal-dysfunctions induced by stress-stimuli. This study aimed to investigate effect of Fluoxetine (FL) on chronic unpredictable mild stress (CUMS) and explore the associated mechanisms. CUMS rat model was established by treating with lots of stresses. CUMS rats were administered FL, SB216763 (SB), Wortmannin (WT) alone or in combination. CUMS rats were administered 1 % sugar water to conduct sugar water consumption experiment. Acet-Tub, Tyr-Tub, tau46, p-tau-Ser199/202, p-tau-Ser396, p-tau-Ser231, expression was examined using immunohistochemical assay and western blotassay. Interaction between tau and tubulin was evaluated with immunoprecipitation assay. Double immunohistochemical assay was used to identify interaction between Nestin and Tau. The results indicated that FL treatment only increased sugar consumption of CUMS rats (P < 0.05), but also strengthened effects of SB and WT. FL significantly treatment decreased tau phosphorylation (p-tau) in hippocampal tissues of rats compared to those of rats in CUMS group (P < 0.05). FL treatment markedly decreased Acet-Tub and increased Tyr-Tub expression in hippocampal tissues of rats compared to those of rats in CUMS group (P < 0.05). The effects of FL treatment on p-tau down-regulation and tubulin modulation in hippocampal tissues were independent from PI3K and GSK-3 signaling pathways. FL treatment could also enhance proliferation and total tau of newborn neurons of CUMS rats. FL treatment strengthened interaction between tau and botulin in hippocampal tissues of CUMS rats. In conclusion, Fluoxetin suppressed phosphorylation of tau and modulated the interaction between tau and tubulin in hippocampus of adult CUMS rats.

Bacillus coagulans and Clostridium butyricum synergistically alleviate depression in a chronic unpredictable mild stress mouse model through altering gut microbiota and prefrontal cortex gene expression

Introduction: The prevalence of major depressive disorder (MDD) has gradually increased and has attracted widespread attention. The aim of this study was to investigate the effect of a probiotic compound consisting of Bacillus coagulans and Clostridium butyricum, on a mouse depression model.Methods: Mice were subjected to chronic unpredictable mild stress (CUMS) and then treated with the probiotics at different concentrations. And mice received behavior test such as forced swimming test and tail suspension test. After that, all mice were sacrificed and the samples were collected for analysis. Moreover, prefrontal cortex (PFC) gene expression and the gut microbiota among different groups were also analyzed.Results: Probiotics improved depressive-like behavior in CUMS mice, as indicated by decreased immobility time (p &amp;lt; 0.05) in the forced swimming test and tail suspension test. probiotics intervention also increased the level of 5-hydroxytryptamine (5-HT) in the prefrontal cortex and decreased the adrenocorticotropic hormone (ACTH) level in serum. In addition, by comparing the PFC gene expression among different groups, we found that the genes upregulated by probiotics were enriched in the PI3K-Akt signaling pathway in the prefrontal cortex. Moreover, we found that downregulated genes in prefrontal cortex of CUMS group such as Sfrp5 and Angpt2, which were correlated with depression, were reversed by the probiotics. Furthermore, the probiotics altered the structure of the gut microbiota, and reversed the reduction of cob(II)yrinate a,c-diamide biosynthesis I pathway in CUMS group. Several species like Bacteroides caecimuris and Parabacteroides distasoni, whose abundance was significantly decreased in the CUMS group but reversed after the probiotics intervention, showed significantly positive correlation with depression associated genes such as Tbxas1 and Cldn2.Discussion: These findings suggested that CUMS-induced depression-like behavior can be alleviated by the probiotics, possibly through alterations in the PFC gene expression and gut microbiota.

Du-moxibustion ameliorates depression-like behavior and neuroinflammation in chronic unpredictable mild stress-induced mice

BackgroundNeuroinflammation is involved in the advancement of depression. Du-moxibustion can treat depression. Here, we explored whether Du-moxibustion could alleviate neuroglia-associated neuro-inflammatory process in chronic unpredictable mild stress (CUMS) mice. MethodsC57BL/6J mice were distributed into five groups. Except for the CON group, other four groups underwent CUMS for four consecutive weeks, and Du-moxibustion was given simultaneously after modeling. Behavioral tests were then carried out. Additionally, Western blot was conducted to measure the relative expression levels of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). Immunofluorescence was employed to evaluate the positive cells of ionized calcium binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP). Furthermore, interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) were analyzed using an ELISA assay. ResultsWe found that CUMS induced depression-like behaviors, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, decreased the time in open arms and prolonged immobility. Furthermore, versus the CON group, the expression of HMGB1, TLR4, MyD88, NF-κB, positive cells of Iba-1, IL-1β and TNF-α were increased but positive cells of GFAP were decreased in CUMS group. However, the detrimental effects were ameliorated by treatment with CUMS+FLU and CUMS+DM. LimitationsA shortage of this study is that only CUMS model of depression were used, while other depression model were not included. ConclusionsDu-moxibustion alleviates depression-like behaviors in CUMS mice mainly by reducing neuroinflammation, which offers novel insights into the potential treatment of depression.

Electroacupuncture intervention alleviates depressive-like behaviors and regulates gut microbiome in a mouse model of depression

Electroacupuncture (EA) is a neuroregulatory therapy for depression. Nonetheless, the effects of EA on the gut microbiome in mice models of depression are not well established. Here, using a chronic unpredictable mild stress (CUMS) model in mice, we evaluated the antidepressant effects of EA and changes in gut microbiota with behavioral tests and 16S rRNA gene sequencing. The results found that EA increased the time spent in the center area of the open-field test and the percentage of sucrose preference and reduced the immobility time in the tail suspension test in CUMS-treated mice. Furthermore, the genus Lachnoclostridium, Ruminococcaceae_UCG-002 and Rikenellaceae_RC9_gut_group were enriched in the CUMS group, which was positively correlated with depressive-like behaviors. Whereas phylum Actinobacteria and genus Allobaculum, Bifidobacterium, Dubosiella, Rikenella and Ileibacterium were enriched in the EA and CUMS + EA groups, all of which were negatively correlated with depressive-like behaviors. This study characterizes gut microbiota under EA treatment and provides new insights into the association of anti-depressive-like effects of EA and gut microbiota.

Chronic unpredictable mild stress increases serum aldosterone without affecting corticosterone levels and induces hepatic steatosis and renal injury in young adult male rats.

Stress is often associated with anxiety and depressive symptoms in adolescents. Stress is associated with components of metabolic syndrome and inflammation. The present study hypothesizes that aldosterone, more than corticosterone, promotes chronic stress-hepatic steatosis and fibrosis, as well as renal inflammation and fibrosis in young adult rats. Thirty-two young adult male Wistar rats of 51 days old were divided into four groups (n = 8 per group): Control (C), chronic unpredictable mild stress (CUMS), control plus vehicle (C plus veh), CUMS plus eplerenone, a selective aldosterone blocker (CUMS plus EP). On postnatal day 51, eplerenone was administered orally through a gastric tube two hours before the start of the stress test. The CUMS paradigm was administered once daily at different times, with no repetition of the stressor sequence for four weeks. Renal inflammation and fibrosis were measured, as well as liver glycogen, triacylglycerol, and fibrosis levels. The serum concentrations of corticosterone, aldosterone, sodium, and creatinine were measured in urine and serum. The CUMS group showed a high level of serum aldosterone without affecting the level of corticosterone, increased urinary sodium, tubular atrophy, glomerular sclerosis, the presence of inflammation, and fibrosis, without affecting creatinine, increased glycogen content, triacylglycerol, and moderate fibrosis in the liver, and treatment with eplerenone prevented the inflammation, fibrosis, glycogen, and triacylglycerol. Our results show that chronic stress-induced aldosterone promotes hepatic steatosis and renal injury more than corticosterone. The prevention by eplerenone supports our hypothesis.

Plasma exosomal miR-30a-5p inhibits osteogenic differentiation of bone marrow mesenchymal stem cells from a chronic unpredictable mild stress-induced depression rat model

With rising society stress, depression-induced osteoporosis is increasing. However, the mechanism involved is unclear. In this study, we explored the effect of plasma exosomal miRNAs on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation in a chronic unpredictable mild stress (CUMS)-induced depression rat model. After 12 weeks of CUMS-induced depression, the pathological changes in the bone tissue and markers of osteogenic differentiation were tested by micro-computed tomography, hematoxylin-eosin staining, and quantitative real-time reverse transcription PCR (qRT-PCR). Plasma exosomes from rats were isolated and co-incubated with BMSCs for 14 d to detect the effect on osteogenic markers. Next-generation sequencing identified the miRNAs in the plasma exosomes, and the differential miRNAs were analyzed and verified by qRT-PCR. BMSCs were infected with lentivirus to upregulate miRNA-30a-5p and incubated in a medium that induced osteogenic differentiation for 14 d. The effect of miR-30a-5p on osteogenic differentiation was determined by qPCR and alizarin red staining. CUMS-induced depression rat model was established successfully, and exhibited reduced bone mass and damaged bone microstructure compared to that of the controls. The observed pathological changes suggested the occurrence of osteoporosis in the CUMS group, and the mRNA expression of osteogenic markers was also significantly reduced. Incubation of BMSCs with plasma exosomes from the CUMS group for 14 d resulted in a significant decrease in the expression of osteogenic markers. Twenty-five differentially expressed miRNAs in plasma exosomes were identified and upregulation of miR-30a-5p was observed to significantly inhibit the expression of osteogenic markers in BMSCs. Our findings contributed to a comprehensive understanding of the mechanism of osteoporosis caused by depression, and demonstrated the potential of miR-30a-5p as a novel biomarker or therapeutic target for the treatment of osteoporosis.

Gastrodin ameliorates depressive-like behaviors via modulating gut microbiota in CUMS-induced mice

PurposeDepression is a psychiatric disorder and the treatment of depression is an urgent problem that need to be solved. Gastrodin (GAS) is a Traditional Chinese Medicine from an orchid and is used for neurological diseases, including depressive disorders. MethodsTo assess the effect of GAS on gut microbiota of depressive mice, we established a chronic unpredictable mild stress (CUMS)-induced mouse model, and GAS was administered to one group of the mice. Animal behavior experiments were used to detect depressive-like behaviors, and 16 S rRNA gene analysis was applied to detect the gut microbiota of each group. All raw sequences were deposited in the NCBI Sequence Read Archive under accession number SRP491061. ResultsGAS treatment significantly improved depressive-like behaviors as well as the diversity and abundance of the gut microbiota. The depressive-like behaviors of the CUMS-GAS group were improved in different degrees compared with the CUMS group. The linear discriminant analysis (LDA) of the gut microbiota showed that the makeup of the gut microbiota in mice changed dramatically in the CUMS-GAS group, compared with the CUMS group, Bacteroides (LDA = 3.94, P < 0.05) were enriched in the CUMS-GAS group at the genus level. In comparison to the CUMS group, the CUMS-GAS group had a greater concentration numbers of Lactobacillus, Corynebacterium, Staphylococcus, Bacteroides, Psychrobacter, and Alistipes. ConclusionOur results suggested that GAS improved depressive-like behaviors in mice and impacted the microbial composition of the gut. Our research indicated that dysbiosis of the gut microbiota may be affected by GAS treatment, which improved depressive-like behaviors in the CUMS-induced mouse model of depression.

Quercetin attenuates brain apoptosis in mice with chronic unpredictable mild stress-induced depression

BackgroundDepression is a common psychiatric disorder with limited effective treatments. Research suggests that depression involves apoptosis mechanisms. Quercetin (QUE) has been reported to have anti-apoptotic activities. In this study, we aimed to investigate the effects and mechanisms of QUE in chronic unpredictable mild stress (CUMS)-induced depression. MethodsAfter establishing mouse models of CUMS-induced depression, the mice were randomly assigned into four groups: control, CUMS, CUMS+QUE, and CUMS+Fluoxetine (FLX). The body weight of the mice was measured during the study. Then, depression-associated behaviors were evaluated using the sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST) and tail suspension test (TST). Apoptosis in the hippocampus and prefrontal cortex was determined using flow cytometry. Bcl-2 and Nrf2 protein expressions in the hippocampus and prefrontal cortex were also detected. Furthermore, Western blot was used to measure the protein levels of p-ERK, ERK, p-CREB, CREB, and Nrf2 in brain tissues. ResultsQUE or FLX administration increased the body weight of the CUMS mice. Behavioral tests indicated that CUMS mice developed a state of depression, but QUE or FLX treatment improved their depression-associated behaviors. Meanwhile, QUE or FLX treatment decreased apoptosis in the hippocampus and prefrontal cortex. Furthermore, the decreased Nrf2 protein expression, ERK and CREB phosphorylation in CUMS group were enhanced by QUE or FLX administration. ConclusionQUE could attenuate brain apoptosis in mice with CUMS-induced depression, and the mechanism may be related to the ERK/Nrf2 pathway, indicating that QUE could be a potential treatment for depression.

Chronic stress promotes gastric cancer progression via the adrenoceptor beta 2/PlexinA1 pathway.

Chronic stress is a common emotional disorder in cancer patients. Chronic stress promotes progression of gastric cancer (GC) and leads to poor outcomes. However, the underlying mechanisms remain not clear. Herein, we explored the possible mechanisms of chronic stress in GC progression. The Cancer Genome Atlas (TCGA) datasets were analyzed for differentially expressed genes. Clinical data of GC were evaluated for their association with PlexinA1 using TCGAand Kaplan-Meier-plotter databases. Chronic stress of GC patients was evaluated using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Chronic unpredictable mild stress (CUMS) was used to induce chronic stress in mice. Gastric xenograft tumor was constructed using the sewing method. Chronic stress-like behaviors were assessed using light/dark box and tail suspension tests. Protein expression was detected using immunohistochemistry and Western blot analysis. Analyses of TCGA and the Kaplan-Meier-plotter databases showed that patients with high levels of PlexinA1 in GC had worse overall survival than those with low levels of PlexinA1. A total of 36 GC patients were enrolled in the study, and about 33% of the patients had chronic stress. Compared with patients without chronic stress, higher expression levels of adrenoceptor beta 2 and PlexinA1 were observed in patients with chronic stress. The tumor size in mice under CUMS was significantly increased compared with the control mice. Adrenoceptor beta 2, PlexinA1, N-cadherin, and alpha-smooth muscle actin, as well as Ki67 were highly expressed in the tumors of CUMS group. However, E-cadherin was lowly expressed in the tumors of CUMS group. Importantly, chemical sympathectomy with 6-hydroxydopamineor treatment with a selective β2 adrenergic receptor antagonist (ICI118,551) could reverse these effects. Our findings suggest that chronic stress plays an important role in GC progression and there is a potential for blocking the epinephrine-β2AR/PlexinA1 pathway in the treatment of GC.

CHRONIC STRESS RESULTS IN INCREASED PAIN PERCEPTION IN OSTEOARTHRITIS IN VIVO

Osteoarthritis (OA) affects the whole joint and leads to chronic pain. The sympathetic nervous system (SNS) seems to be involved in OA pathogenesis, as indicated by in vitro studies as well as by our latest work demonstrating that sympathectomy in mice results in increased subchondral bone volume in the OA knee joint. We assume that chronic stress may lead to opposite effects, such as an increased bone loss in OA due to an elevated sympathetic tone. Therefore, we analyzed experimental OA progression in mice exposed to chronic stress. OA was induced in male C57BL/6J mice by surgical destabilization of the medial meniscus (DMM) and Sham as well as non-operated mice served as controls. Half of these groups were exposed to chronic unpredictable mild stress (CUMS). After 12 weeks, chronic stress efficiency was assessed using behavioral tests. In addition to measuring body weight and length, changes in subchondral bone were analyzed by μCT. Dynamic Weight Bearing system was used to monitor OA-related pain. Histological scoring will be conducted to investigate the severity cartilage degeneration and synovial inflammation. CUMS resulted in increased anxiety and significant decrease in body weight gain in all CUMS groups compared to non-CUMS groups. CUMS also increased serum corticosterone in healthy mice, with even higher levels in CUMS mice after DMM surgery. CUMS had no significant effect on subchondral bone, but subarticular bone mineral density and trabecular thickness were increased. Moreover, CUMS resulted in significant potentiation of DMM-associated pain. Our results suggest that the autonomic imbalance with increased sympathetic nervous activity induced by chronic stress exacerbates the severity of OA pain perception. We expect significantly increased cartilage degeneration as well as more severe synovial inflammation in CUMS DMM mice compared to DMM mice.

Acute hyper-hypoxia accelerates the development of depression in mice via the IL-6/PGC1α/MFN2 signaling pathway.

Neural cell damage is an important cause of exacerbation of depression symptoms caused by hypoxia, but the mechanism behind it is still unclear. The purpose of this study is to elucidate the role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)/mitofusin-2 (MFN2) signaling axis in the development of depression in mice under hypoxia. Male Institute of Cancer Research mice (age, 6 weeks) were assigned to the normal group, chronic unpredictable mild stress group (CUMS group), or CUMS + hyper-hypoxia group (CUMS + H group). Mice in the CUMS and CUMS + H groups were exposed to CUMS for 28 days. Additionally, mice in the CUMS + H group were exposed to acute hyper-hypoxia from Day 21 for 7 days. After a total of 28 days, behavioral experiments were conducted. All mice were anesthetized and sacrificed. Levels of brain tissue interleukin (IL)-6, reactive oxygen species (ROS), adenosine triphosphate (ATP), and serotonin (5-HT) were analyzed. As compared to the CUMS group, mice in the CUMS + H group had increased IL-6 and ROS levels, but lower open-field activity, preference for sucrose, hippocampal neuronal membrane potential, ATP, and 5-HT levels, as well as MFN2 and PGC1α levels. Acute hyper-hypoxia plays an important role in the development of depression via the IL-6/PGC1α/MFN2 signaling pathway.

Profile of the bile acid FXR-FGF15 pathway in the glucolipid metabolism disorder of diabetic mice suffering from chronic stress.

Imbalances in bile acid (BA) synthesis and metabolism are involved in the onset of diabetes and depression in humans and rodents. However, the role of BAs and the farnesoid X receptor (FXR)/fibroblast growth factor (FGF) 15 signaling pathway in the development of diabetes and depression is still largely unknown. Therefore, we investigated the potential molecular mechanisms of BAs that may be associated with glucolipid metabolism disorders in diabetic mice subjected to chronic stress. The type 2 diabetes mellitus (T2DM) mouse model was induced by feeding mice a high-fat diet and administering an intraperitoneal injection of streptozotocin (STZ). The chronic unpredictable mild stress (CUMS) procedure was performed by introducing a series of mild stressors. Forty mice were randomly divided into the regular chow feeding group and the high-fat diet feeding group. After two weeks of feeding, the mice were randomly divided into four groups: the Control group, CUMS group, T2DM group, and T2DM+CUMS group. The T2DM group and T2DM+CUMS group received an intraperitoneal injection of STZ to induce the T2DM model. The CUMS and T2DM+CUMS groups were exposed to CUMS to induce depressive-like phenotypes. Blood and tissue samples were obtained for pertinent analysis and detection. Compared with the T2DM mice, T2DM+CUMS mice had higher blood glucose and lipid levels, insulin resistance, inflammation of the liver and pancreas, impaired liver function, and increased total bile acids. These changes were accompanied by attenuated FXR signaling. Chronic stress was found to attenuate FXR expression and its downstream target, FGF15, in the ileum when compared with the T2DM group. FXR may play a role in the diabetic disorder of glucolipid metabolism when aggravated by chronic stress. FXR and its downstream target, FGF15, may be therapeutic targets for treating comorbid T2DM and depression.

Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice

In view of the fact that the G-protein-coupled receptors (GPCRs) sit at the top of the signaling pathways triggering a diverse range of signaling cascades towards a cellular event, GPCRs are regarded as central drug targets. mGlu5, a type of classical GPCRs, is highly expressed in the central nervous system (CNS) and responds to the neurotransmitter glutamate. Researches show that mGlu5 is a potential drug target for the treatment of depression. Up to now, multiple mGlu5 negative allosteric modulators (NAMs) have entered clinical trials, but no small molecule mGlu5 NAM has yet to reach market. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel mGlu5 NAMs. Among them, the novel compound 10b is a high-affinity mGluR5 antagonist, with an IC50 value of 11.5 nM. Besides, we evaluated the anti-depressant effect of compound 10b using the chronic unpredictable mild stress (CUMS)-induced depression model. The data showed that the mice in CUMS group were featured by decreased level of serum 5-HT and increased level of serum CORT, and the expression of synaptic proteins were reduced, including GluA1, GluA2, p-PKA, BDNF and TrkB. However, those factors for identifying sensitivity to depression-like behaviors could be improved by compound 10b treatment. The preliminary toxicology evaluations indicated that compound 10b had a good safety profile in vivo. Collectively, the compound 10b represents a promising lead compound for the treatment of depressive disorder.

The rapid antidepressant effect of acupuncture on two animal models of depression by inhibiting M1-Ach receptors regulates synaptic plasticity in the prefrontal cortex

BackgroundIt is unclear whether acupuncture has a rapid antidepressant effect and what is the main mechanism. MethodsIn this study, forced swimming stress test (FST) in mice were divided into five groups: control group, acupuncture group, scopolamine group, arecoline group, and acupuncture + arecoline group. Chronic unpredictable mild stress (CUMS) model rats were divided into six groups: naïve (non-CUMS) group, CUMS group, acupuncture group, scopolamine group, arecoline group, and acupuncture + arecoline group. Twenty-four hours after the end of treatment, FST was conducted in mice and rats. The expression of M1-AchR, AMPA receptors (GluR1 and GluR2), BDNF, mTOR, p-mTOR, synapsin I, and PSD95 in the prefrontal cortex was determined by western blot. The spine density of neurons in the prefrontal cortex was detected by golgi staining. ResultsThe results showed that acupuncture reduced the immobility time of FST in two depression models. Acupuncture inhibited the expression of M1-AchR and promoted the expression of GluR1, GluR2, BDNF, p-mTOR, synapsin I, PSD95, and increased the density of neuron dendritic spine in the prefrontal cortex. ConclusionsThe rapid antidepressant effect of acupuncture may be activating the “glutamate tide” - AMPA receptor activation - BDNF release - mTORC1 pathway activation through inhibiting the expression of M1-AchR in the prefrontal cortex, thereby increasing the expression of synaptic proteins and regulating synaptic plasticity.

Aerobic Exercise Improves Depressive-like Behavior in CUMS-Induced Rats via the SIRT3/ROS/NLRP3 Signaling Pathway.

This study aimed to investigate the effect of exercise on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in rats and to explore the role of the SIRT3/ROS/NLRP3 signaling pathway in this process. Twenty-nine male 8-week-old Sprague Dawley rats were divided into a control group (CON) (nine rats) and a model group (twenty rats). Thirteen chronic stress stimuli were randomly applied once or twice per day for 35 days to induce depression in the model group rats. After the model was established, the model group rats were randomly divided into the CUMS group (CUMS) and the aerobic exercise + CUMS group (EX + CUMS). The EX + CUMS group received 8 weeks of aerobic exercise intervention for 6 days per week. Behavioral assessments were performed using the sucrose preference test and forced swimming test. The expression of SIRT3, NLRP3, IL-1β, and IL-18 in the hippocampus was detected using RT-PCR. The ROS level in the hippocampus was detected using immunofluorescence. The protein levels of SIRT3 and NLRP3 in the hippocampus were detected using western blotting. The protein levels of IL-1β and IL-18 in the hippocampus were measured using ELISA. After 5 weeks of chronic stress stimuli, the hippocampal function of rats in the CUMS model group was impaired, and their sucrose preference was reduced, while their forced swimming time was prolonged. The expression of SIRT3 decreased, ROS increased, and the expression of NLRP3 and the levels of IL-1β and IL-18 increased. Aerobic exercise increased the sucrose preference of rats, shortened their immobility time, increased the expression of SIRT3, and reduced the levels of ROS, NLRP3, IL-1β, and IL-18. Exercise can improve the depressive behavior of CUMS model rats, and its mechanism may be related to the upregulation of SIRT3 in the hippocampus, which plays an anti-inflammatory role.

The beneficial effects of vortioxetine on BDNF, CREB, S100B, β amyloid, and glutamate NR2b receptors in chronic unpredictable mild stress model of depression.

Depression, one of the most significant mental disorders, is still poorly understood in terms of its pathogenetic mechanisms despite its well-recognized association with stress. The current study's goal was to ascertain how the novel antidepressant drug vortioxetine (VOR) affected the BDNF (brain-derived neurotrophic factor), S100, amyloid β (Aβ), CREB (cAMP response element-binding protein), and NR2B, as well as its impact on depression-like behaviors, and tissue damage in an experimental rodent model of depression caused by chronic unpredictable stress. We employed twenty-eight Wistar albino male rats, and we randomly divided them into four groups, each consisting of 7 rats: control, CUMS (chronic unpredictable mild stress), CUMS+vortioxetine (CUMS+VOR), and CUMS+fluoxetine (CUMS+FLU). Sucrose preference and forced swimming tests (SPT and FST, respectively), PCR, ELISA, and histopathological and immunohistochemical evaluation were made on brains. The behaviors of reduced immobility in the FST and increased sucrose preference were observed in the CUMS group and they improved in the groups treated with VOR and FLU. Compared with the control group, the group exposed to CUMS showed increased Aβ and decreased BDNF, CREB, and S-100 expressions, as well as neuronal degeneration (p<0.001). VOR and FLU treatment ameliorate the findings. This study demonstrated significant ameliorative effects of VOR in an experimental model of chronic unpredictable depression to reduce brain tissue damage and depression-like behaviors in rats. Effects of CUMS on the brain and possible effects of VOR.