Depression In Mice Research Articles

Electroacupuncture remodels the extracellular matrix and promotes synaptic plasticity in a mouse model of depression

Depression is a chronic and recurrent disease without satisfactory treatment strategies. The therapeutic effect of acupuncture is well known in Traditional Chinese medicine (TCM) due to its unique non-pharmacological nature. Electroacupuncture (EA) for antidepressant therapy has been widely recognized and used in clinic. In this study, the lipopolysaccharide (LPS)-induced depression mice model was used to evaluate the anti-depressant effects of EA treatment. Open Field Test (OFT), Force Swimming Test (FST), and Sucrose Preference Test (SPT) were utilized to detect the ethological alterations in mice. The transcriptology technique was used to evaluate the changes in the hippocampal transcriptome in different groups. We measured protein levels using Western blot and immunohistochemistry. Our data showed that LPS induced ethological alterations in mice and enhanced the gene expression related to gene ontology such as the banded collagen fibril, fibrillar collagen trimer, and collagen fibril organization, pathways such as collagen chain trimerization, collagen biosynthesis and modifying enzymes, and collagen formation. EA could reverse the ECM deposition by inhibiting collagen type Ⅳ trimer, extracellular matrix organization, and collagen formation. EA could enhance the MMP1 and MMP9 expression and promote synaptic plasticity. These data indicated that EA possesses an antidepressant effect, this may achieve by increasing MMPs expression and then remodeling the ECM surrounding the neurons, ultimately repairing neural circuits and promoting synaptic plasticity.

The protective effect of Palmatine on depressive like behavior by modulating microglia polarization in LPS-induced mice.

The purpose of the present study was to evaluate the protective effect of Palmatine on LPS-induced depressive like behavior and explore its potential mechanism. The mice were intragastrically treated with Fluoxetine or Palmatine once daily for 1 week. After the last drug administration, the mice were intraperitoneally challenged with LPS and suffered for Sucrose preference test, Tail suspension test, Forced swimming test and Open field test. The pro-inflammatory biomarkers were measured by ELISA, qPCR, WB and immunofluorescence. As a result, the administration of Palmatine effectively lessened depressive-like behavior. Palmatine could decrease the levels of pro-inflammatory cytokines TNF-α, IL-6, the expressions of CD68, iNOS mRNA, as well as increase the levels of anti-inflammatory cytokines IL-4, IL-10, the expressions of CD206, Arg1 mRNA, Ym1 mRNA both in LPS-induced mice and in LPS-induced BV2 cells. The beneficial effect of Palmatine might be attributed to the suppression of M1 microglia polarization and the promotion of M2 microglia polarization via PDE4B/KLF4 signaling. The similar results were observed in CUMS-induced depressive mice. The transfection with PDE4B SiRNA or KLF4 SiRNA indicated that PDE4B and KLF4 were both involved in the Palmatine-mediated microglia polarization. Molecular docking indicated that Palmatine could interact with PDE4B. In conclusion, this research demonstrated that Palmatine attenuated depressive like behavior by modulating microglia polarization via PDE4B/KLF4 signaling.

Camellia nitidissima Chi extract promotes adult hippocampal neurogenesis and attenuates chronic corticosterone-induced depressive behaviours through regulating Akt/GSK3β/CREB signaling pathway

Hormonal imbalance causes depressive behaviours in chronic mental disorders. The use of natural products to relieve depressive symptoms is getting attention due to its minimal side effects and multiple health benefits. The present study aims to test the hypothesis that Camellia nitidissima Chi leave extract (CNC) could have antidepressant effects and whose underlying mechanisms could be related to promote hippocampal neurogenesis. Firstly, we conducted quality control study and identified 17 active compounds in the CNC extract. Then, we performed a series of behaviour tests to evaluate the antidepressant effects in a chronic corticosterone (CORT)-induced depressive mouse model. CNC extract significantly ameliorated CORT-induced depressive behaviours, whose effects were similar to sertraline. Interestingly, CNC extract decreased the levels of CORT and ACTH in the plasma and increased 5-HT in plasma and hippocampus. CNC extract promoted adult hippocampal neurogenesis in the CORT-treated mice in vivo. The neurogenic effects of CNC were also confirmed in primary cultured hippocampal neurons and hESCs with CORT challenge in vitro. Furthermore, CNC enhanced the phosphorylation of Akt, GSK3β and CREB in the hippocampus of CORT-treated mice in vivo as well as CORT-treated PC12 cells in vitro. Co-treatment of wortmannin abolished the effects of CNC. Taken together, CNC could be an effective functional food to stimulate hippocampal neurogenesis for anti-depressant treatment. The neurogenic mechanisms could be related to regulating hypothalamic–pituitaryadrenal axis and activating Akt/GSK3β/CREB signaling pathway.

SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San.

ObjectiveChaihu Shugan San (CSS) has a long history for treating major depressive disorder (MDD), which has been verified effectively and safely in clinical studies. Deficient angiogenesis plays important roles in MDD. However, the underlying mechanisms of CSS on angiogenesis remain poorly understood.MethodsNetwork pharmacology analysis was applied to explore the potential angiogenic targets and pathways between CSS and MDD. These targets would be validated in chronic unpredictable mild stress (CUMS)-induced depressive-like mice by Western blots, immunofluorescence, and immunohistochemistry. Then, the underlying molecular mechanisms were further investigated in brain microvascular endothelial cells (BMVECs) with CSS-containing serum by Western blots and immunofluorescence.ResultsNetwork pharmacology analysis showed that the antidepressant role of CSS was closely associated with Silent information regulator protein 1 (SIRT1)/Forkhead box O1 (FOXO1) axis-mediated angiogenesis. This prediction was confirmed in the following experiments. CSS induced angiogenesis, increased SIRT1 expression, and decreased FOXO1 expression in the hippocampus of CUMS mice. Five percent CSS-containing serum produced a significant increase in BMVECs proliferation, migration, and tube formation, but these effects were reduced by SIRT1 silencing. CSS serum could also promote FOXO1 translocation to the cytoplasm through SIRT1 signaling, which triggered FOXO1 protein degradation. What is more, CSS upregulated VEGFA and BDNF expressions not only in the hippocampus of depressive mice but also in BMVECs supernatants. Of note, these trophic factors play important roles in promoting neurogenesis.ConclusionThe study showed that CSS could promote angiogenesis and neurogenesis in the hippocampus of CUMS-induced mice. The underlying molecular mechanism involves the SIRT1/FOXO1 axis and subsequent regulation of VEGFA and BDNF. These findings provide novel insight into CSS drug development, and targeting the SIRT1/FOXO1 axis might be a promising strategy to treat MDD.

Intranasal Administration of Brain-Derived Neurotrophic Factor Rescues Depressive-Like Phenotypes in Chronic Unpredictable Mild Stress Mice.

IntroductionMajor depression disorder is the most common diagnosed mental illnesses, and it bring a high social and economic burden. However, the current treatment for depression has limitations with side effects. Hence, there is an urgent need to search more effective treatment for major depressive disorder. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons.MethodsWe administered BDNF into chronic unpredictable mild stress (CUMS)-induced depression mice and assessed the effects of intranasal delivery of BDNF in depression by the tail suspension test, forced swimming test, novelty suppressed feeding test, and open-field test.ResultsWe find that the intranasal administration of BDNF reversed the depressive-like behaviors in CUMS mice as measured Further analyses suggested that BDNF treatment reduced pro-inflammatory cytokine (IL-6, TNF-α, iNOS and IL-1β) expressions in the hippocampus of CUMS mice. In addition, our results showed that BDNF markedly reduced oxidative stress in the hippocampus and blood of CUMS mice. Moreover, our data suggested that BDNF treatment increased neurogenesis in the hippocampus of CUMS mice.DiscussionTaken together, our results for the first time demonstrated that intranasal delivery of BDNF protein exhibited anti-depressant-like effects in mice, and therefore may represent a new therapeutic strategy for major depressive disorder.

Influence of Polygonum minus Aqueous Extract on Monoamine Oxidase-A Transcriptional Activators KLF-11 and SIRT1 Levels in the Hippocampus of Stress-induced Depressed Mice

Background: Monoamine oxidase-A (MAO-A) enzyme is responsible for the breakdown of monoamines (serotonin and norepinephrine). MAO-A is also a target to treat the depressive disorders. Kruppel-likefactor11(KLF11) and Sirtuin1(SIRT1) are the main transcriptional activators of MAO-A. Polygonum minus (P. minus) aqueous extract showed some neuroprotective properties in previous studies like improved memory and positive mood. The aim of current study was to evaluate the effects of P. minus aqueous effects on KLF11 and SIRT1 levels in hippocampus of stressed mice. Materials and Methods: Balb/c mice (22g-26g) were used in this study and P. minus aqueous extract was administered for 8 weeks with three different doses (P. minus 50mg, P. minus 100 mg and P. minus 200mg) in different groups. Amitriptyline 20 mg was used as positive control antidepressant. Chronic ultra-mild stress protocol was used for 6 weeks to induce the depression among mice groups except control group. Results: The results showed that all doses of P. minus reduce the KLF11 level significantly but only P. minus 200mg showed reduction in SIRT1 level in hippocampus of mice significantly. Conclusion: It is concluded that P. minus aqueous extract treatment showed a significant reverse in an elevated level of KLF11 and SIRT1 in hippocampus of stressed mice after treatment of 8 weeks

Lysosomal dysfunction is associated with NLRP3 inflammasome activation in chronic unpredictable mild stress-induced depressive mice

NLRP3 inflammasome pathway-mediated inflammatory response is closely associated with depression. Increasing attention has been recently paid to the links between autophagy and depression, however, the relationship between autophagy and NLRP3 inflammasome in depressive behavior remain poorly understood. In the present study, the potential roles of autophagy-lysosome pathway in NLRP3 inflammasome regulation were investigated both in vivo (chronic unpredictable mild stress (CUMS)-induced depressive mouse model) and in vitro (LPS-induced cellular model) model. It demonstrated that CUMS induces depressive-like behaviors in mice, accompanied by increased expression of NLRP3 inflammasome and inflammatory responses. Meanwhile, it promoted the autophagosome marker LC3 and autophagic adapter protein p62 accumulation, accompanied by the decrease of lysosomal cathepsins B and D expression in the prefrontal cortex of mice. Notably, a significant colocalization of NLRP3 and LC3 in CUMS mice by immunofluorescence co-staining were observed. For the in vitro study, disrupting the lysosomal function with Baf A1 significantly increased the LPS-induced NLRP3 inflammasome accumulation and pro-inflammatory factors (IL-1β and IL-18) production in BV2 cells. Collectively, our results suggested that the autophagic process is related to NLRP3 inflammasome activation, and dysfunctional lysosome in autophagy-lysosomal pathway may retard NLRP3 inflammasome degradation, facilitating the production of pro-inflammatory factors, thereby contributing to depressive behavior in CUMS mice.

Antidepressant-like Effects of Polygonum minus Aqueous Extract in Chronic Ultra-Mild Stress-Induced Depressive Mice Model.

Depression is the most common behavior disorder that leads to many disabilities. The main aim of this study was to evaluate the effects of a Polygonum minus (P. minus) aqueous extract on chronic ultra-mild stress (CUMS)-induced depressive mice model. Chronic ultra-mild stress can disturb the neurotransmitters levels and plasticity of the hippocampus. Balb/c male mice were used in this study, which consisted of six groups (n = 14). Treatment was given for eight weeks, and chronic ultra-mild stress was applied for six weeks. Commercially available P. minus extract (BioKesum®) was used in this study. The behavior and neurochemical parameters were investigated through behavioral Tests and ELISA assays. P. minus administration significantly (p < 0.05) restored CUMS-induced behavior abnormalities, decreased the immobility time, and increased the sucrose preference and increased the spatial memory. P. minus treatment also showed the decreased level of serum corticosterone and increased the level of hippocampal neurotransmitters (Serotonin and Norepinephrine) significantly (p < 0.05). The brain-derived neurotrophic factor (BDNF) level also increased significantly in both the prefrontal cortex and hippocampus (p < 0.05). P. minus treatment exhibited significant (p < 0.05) reduction of Monoamine Oxidase-A (MAO-A) in the hippocampus. These findings indicate that P. minus aqueous extract exhibits antidepressant effects, including decreased immobility time, increased spatial memory, reduced corticosterone, increased BDNF level, and reduced MAO-A enzyme level with increasing the monoamines (serotonin and norepinephrine) in the hippocampus.

Mettl3-mediated m6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant-like effects.

N6 -methyladenosine (m6 A) is the most abundant mRNA modification affecting diverse biological processes. However, the functions and precise mechanisms of m6 A signaling in adult hippocampal neurogenesis and neurogenesis-related depression remain largely enigmatic. We found that depletion of Mettl3 or Mettl14 in neural stem cells (NSCs) dramatically reduced m6 A abundance, proliferation, and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, the m6 A modification of Lrp2mRNA by Mettl3 enhanced its stability and translation efficiency relying on the reader protein Ythdc2, which in turn promoted neurogenesis. Importantly, mice lacking Mettl3manifested reduced hippocampalneurogenesis, which could contribute to spatial memory decline, and depression-like behaviors. We found that these defective behaviors were notably reversed by Lrp2 overexpression. Moreover, Mettl3 overexpression in the hippocampus of depressive mice rescues behavioral defects. Our findings uncover the biological role of m6 A modification in Lrp2-mediated neurogenesis via m6 A-binding protein Ythdc2, andproposearationale that targeting Mettl3-Ythdc2-Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy.

Traditional herbal formula Jiao-tai-wan improves chronic restrain stress-induced depression-like behaviors in mice

ObjectivesJiao-tai-wan (JTW) has been often used to treat insomnia and diabetes mellitus. Recent studies found its antidepressant activity, but the related mechanism is not clear. This study is to evaluate the therapeutic effects of JTW on chronic restraint stress (CRS)-induced depression mice and explore the potential mechanisms. MethodsCRS was used to set up a depression model. Mice in different groups were treated with 0.9 % saline, JTW and fluoxetine. After the last day of CRS, the behavioral tests were conducted. The levels of neurotransmitters, inflammatory cytokines and HPA axis index were detected and the protein expressions of NLRP3 inflammasome complex were determined. H&E, NISSL, TUNEL and immunofluorescence staining were used to observe histopathological changes and the activation of microglia and astrocytes. The potential mechanisms were explored via network pharmacology and verified by Western blot. ResultsThe assessment of liver and kidney function showed that JTW was non-toxic. Behavioral tests proved that JTW can effectively ameliorate depression-like symptoms in CRS mice, which may be related to the inhibition of NLRP3 inflammasome activation. JTW can also improve the inflammatory state and HPA axis hyperactivity in mice, and has a protective effect on CRS-induced hippocampal neurons damage. The network pharmacology analysis and the results of Western blot suggested that the antidepressant effects of JTW may be related to the MAPK signaling pathway. ConclusionOur findings indicated that JTW may exert antidepressant effects in CRS-induced mice by inhibiting NLRP3 inflammasome activation and improving inflammatory state, and MAPK signaling pathway may also be involved.

Xiaoyaosan Exerts Antidepressant-Like Effect by Regulating Autophagy Involves the Expression of GLUT4 in the Mice Hypothalamic Neurons

Many studies have proven that autophagy plays a pivotal role in the development of depression and it also affects the expression of GLUT4 in the hypothalamus. Xiaoyaosan has been shown to exert antidepressant effects in a variety of ways, but its underlying mechanism by which Xiaoyaosan regulates autophagy as well as GLUT4 in the hypothalamus remains unclear. Thus, in this study, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and set up autophagy blockade as a control to explore whether Xiaoyaosan exerts antidepressant effect by affecting autophagy. We examined the effects of Xiaoyaosan on behaviors exhibited during the open field test, tail suspension test and sucrose preference test, and the changes in autophagy in hypothalamic neurons as well as changes in GLUT4 and the related indicators of glucose metabolism in CUMS-induced depressive mouse model. We found that CUMS- and 3-MA-induced mice exhibited depressive-like behavioral changes, with decreased LC3 expression and increased p62 expression, suggesting decreased levels of autophagy in the mouse hypothalamus. The expression of GLUT4 was also decreased, and it was closely related to the level of autophagy through Rab8 and Rab10. Nevertheless, after the intervention of Xiaoyaosan, the above changes were effectively reversed. These results show that Xiaoyaosan can regulate the autophagy in hypothalamic neurons and the expression of GLUT4 in depressed mice.

Quantitative analysis of 20 purine and pyrimidine metabolites by HILIC-MS/MS in the serum and hippocampus of depressed mice

Purine and pyrimidine metabolism are vital metabolic pathways in the development, proliferation or repairment of cells or tissues associated with various diseases. Here, a simple, all-in-one injection hydrophilic interaction liquid chromatography-tandem mass spectrometry method was developed for simultaneous determination of 20 metabolites: adenine, adenosine, deoxyadenosine, adenosine 5′-monophosphate, cyclic adenosine monophosphate, hypoxanthine, xanthine, inosine, deoxyinosine, xanthosine, xanthosine 5′-monophosphate and uric acid, which are products of purine metabolism; uridine, deoxyuridine, uridine 5′-monophosphate and uracil, are products of pyrimidine metabolism; and corticosterone, methionine, acetylcholine and serotonin. To minimize interference of endogenous molecules in sample matrixes, a combination of activated carbon adsorption and a serum substitute matrix (5% bovine serum albumin in phosphate buffered saline) was utilized and jointly applied. The sensitivity, linearity, stability, precision, accuracy and extraction recovery were evaluated, and the method was demonstrated to be accurate, sensitive and reliable. An analytical strategy was successfully applied to quantitatively determine 20 metabolite levels in the serum and hippocampus of mice with chronic social defeat stress-induced depression. The results showed greatly perturbed purine metabolism in the depressed mice, which was primarily characterized by dramatic increases in hypoxanthine, xanthine and inosine in serum and reduced levels of adenine, adenosine and adenosine 5′-monophosphate in the hippocampus. These findings suggest that this novel strategy can facilitate the quantitative analysis of adenine and other purine and pyrimidine metabolites in tissue and serum and exhibits great potential in the exploration of metabolism-related mechanisms of relevant diseases.

Schisandra chinensis (Turcz.) Baill. essential oil exhibits antidepressant-like effects and against brain oxidative stress through Nrf2/HO-1 pathway activation.

The present study aimed to evaluate the antidepressant-like effect of essential oils from Schisandra chinensis (Turcz.) Baill. (SEO) and its possible mechanisms of SEO. The behavioral despair mouse model in vivo and H2O2-induced PC12 cells model in vitro were employed. And the potential effective components were identified by the spectrum-effect relationships analysis. SEO significantly decreased the immobility time in the forced swimming test and tail suspension test, which indicated a promising antidepressant-like effect of SEO in depressed mice. The decreased levels of SOD, GSH, and CAT, and increased levels of MDA were significantly reversed by SEO treatment, which showed good antioxidant activities both in vitro and in vivo. Besides, SEO significantly promoted the nuclear translocation of Nrf2 and the expression of HO-1 in depressed mice and H2O2-induced PC12 cells. The histopathological examination results showed a potential neuronal protective effect of SEO in the hippocampus and cortex. Furthermore, the upregulation of PI3K/AKT/GSK3β signaling was observed after SEO treatment in the H2O2-induced PC12 cells. Additionally, based on the spectrum-effect relationship analysis, 9 peaks were identified as positively correlated with the antioxidant activity of SEO. These results suggested that SEO promoted Nrf2/HO-1 pathway to improve the oxidative stress status and exerted the antidepressant-like effects.

Identifying Antidepressant Effects of Brain-Derived Neurotrophic Factor and IDO1 in the Mouse Model Based on RNA-Seq Data.

Deletion of brain-derived neurotrophic factor (BDNF) and upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) are associated with depression severity in animals. The neurotransmitter hypothesis of depression at the transcriptomic level can be tested using BDNF- and IDO1-knockout mouse models and RNA-seq. In this study, BDNF+/−, IDO1−/−, and chronic ultra-mild stress (CUMS)-induced depression mouse models and controls were developed, and the differentially expressed genes were analyzed. Furthermore, the ceRNA package was used to search the lncRNA2Target database for potential lncRNAs. Finally, a protein–protein interaction (PPI) network was constructed using STRINGdb. By comparing the control and CUMS model groups, it was found that pathway enrichment analysis and ceRNA network analysis revealed that most differentially expressed genes (DEGs) were associated with protection of vulnerable neuronal circuits. In addition, we found the enriched pathways were associated with nervous system development and synapse organization when comparing the control and BDNF+/−model groups. When replicating the neurotransmitter disruption features of clinical patients, such comparisons revealed the considerable differences between CUMS and knockdown BDNF models, and the BDNF+/−model may be superior to the classic CUMS model. The data obtained in the present study implicated the potential DEGs and their enriched pathway in three mouse models related to depression and the regulation of the ceRNA network-mediated gene in the progression of depression. Together, our findings may be crucial for uncovering the mechanisms underlying the neurotransmitter hypothesis of depression in animals.

Pinocembrin ameliorates depressive-like behaviors by regulating P2X7/TRL4 receptors expression in mouse hippocampus.

Mounting evidence indicates that immune dysfunction may contribute to the neurobiology of major depressive disorder (MDD). Toll-like receptor 4 (TLR4) and P2X7 receptor (P2X7R) were recently reckoned pivotally to regulate NOD-like receptor protein 3 (NLRP3) in microglia. Pinocembrin, one of the primary flavonoids from Pinus heartwood and Eucalyptus, has been studied in various animal models of human disease with anti-inflammatory and antioxidant activities. Herein, we investigated the potential antineuroinflammatory effects of pinocembrin on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior. Male C57BL/6J mice were subjected to CUMS for 4 weeks, treatment group was injected with pinocembrin at a dose of 20 mg/kg. After the stress procedure, behavioral tests, including sucrose preference tests (SPTs) and tail suspension tests (TSTs) were performed to evaluate depressive-like phenotype. Subsequently, the expression of cytokines and microglia-related inflammatory biomarkers were assessed. In the study, we found that pinocembrin significantly blocked the declination of SPT percentage and the extension of TST immobility durations in the depression mouse model. Also, we observed that pinocembrin significantly suppressed microglial activation in the hippocampus. Additionally, pinocembrin downregulated hippocampal NLRP3 through P2X7/TLR4 pathway, and also regulated the CUMS-induced imbalance of pro-inflammatory cytokines, including interleukin-1beta, tumor necrosis factor-alpha and interleukin-6. In conclusion, pinocembrin ameliorates CUMS-induced depressive-like behaviors possibly through downregulating P2X7/TLR4 pathway, providing the mechanism of antidepressant treatment.

Associations Between Disordered Microbial Metabolites and Changes of Neurotransmitters in Depressed Mice.

BackgroundsMany pieces of evidence demonstrated that there were close relationships between gut microbiota and depression. However, the specific molecular mechanisms were still unknown. Here, using targeted metabolomics, this study was conducted to explore the relationships between microbial metabolites in feces and neurotransmitters in prefrontal cortex of depressed mice.MethodsChronic unpredictable mild stress (CUMS) model of depression was built in this study. Targeted liquid chromatography–mass spectrometry analysis was used to detect the microbial metabolites in feces and neurotransmitters in prefrontal cortex of mice. Both univariate and multivariate statistical analyses were applied to identify the differential microbial metabolites and neurotransmitters and explore relationships between them.ResultsNinety-eight differential microbial metabolites (mainly belonged to amino acids, fatty acids, and bile acids) and 11 differential neurotransmitters (belonged to tryptophan pathway, GABAergic pathway, and catecholaminergic pathway) were identified. Five affected amino acid–related metabolic pathways were found in depressed mice. The 19 differential microbial metabolites and 10 differential neurotransmitters were found to be significantly correlated with depressive-like behaviors. The two differential neurotransmitters (tyrosine and glutamate) and differential microbial metabolites belonged to amino acids had greater contributions to the overall correlations between microbial metabolites and neurotransmitters. In addition, the significantly decreased L-tyrosine as microbial metabolites and tyrosine as neurotransmitter had the significantly positive correlation (r = 0.681, p = 0.0009).ConclusionsThese results indicated that CUMS-induced disturbances of microbial metabolites (especially amino acids) might affect the levels of neurotransmitters in prefrontal cortex and then caused the onset of depression. Our findings could broaden the understanding of how gut microbiota was involved in the onset of depression.

Multi-Probiotics ameliorate Major depressive disorder and accompanying gastrointestinal syndromes via serotonergic system regulation

IntroductionMajor depressive disorder (MDD) is a leading global psychiatric disease. MDD is highly comorbid with gastrointestinal abnormalities, such as gut motility dysfunction. An effective strategy to manage depression and its accompanying gastrointestinal symptoms is warranted. ObjectivesThree probiotic strains (Bifidobacterium breve CCFM1025, Bifidobacterium longum CCFM687, and Pediococcus acidilactici CCFM6432) had previously been validated in mice to possess antidepressant-like potential. This study investigated the potential psychotropic effects of a combined three-strain probiotic intervention for human MDD patients. The mechanism of action was further investigated in the stress-induced depression mice model. MethodsMDD patients were given a freeze-dried, mixed probiotic formula for four weeks. The patients’ psychometric and gastrointestinal conditions were evaluated using clinical rating scales before and after treatment. Their gut microbiome was also analysed using 16S rRNA gene amplicon sequencing. The mechanisms underlying the beneficial probiotic effects were determined using a chronic stress-induced depressive mouse model. ResultsMulti-probiotics significantly reduced depression scores, and to a greater extent than the placebo (based on the Hamilton Depression Rating, Montgomery-Asberg Depression Rating, and Brief Psychiatric Rating Scales). Multi-probiotics also significantly improved the patients’ gastrointestinal functions (based on self-evaluation using the Gastrointestinal Symptom Rating Scale). Serotonergic system modification was demonstrated as the key mechanism behind the probiotics’ benefits for the brain and the gut. ConclusionOur findings suggest a novel and promising treatment to manage MDD and accompanying gut motility problems, and provide options for treating other gut-brain axis-related disorders.

P-Coumaric Acid Reverses Depression-Like Behavior and Memory Deficit Via Inhibiting AGE-RAGE-Mediated Neuroinflammation.

Depression, a mood disorder, affects one in fifteen adults, has multiple risk factors and is associated with complicated underlying pathological mechanisms. P-coumaric acid (p-CA), a phenolic acid, is widely distributed in vegetables, fruits and mushrooms. P-CA has demonstrated a protective role against oxidative stress and inflammation in various diseases, including cardiovascular disease, diabetes and cancer. In the current study, we investigated the protection of p-CA against depression and memory impairment in a corticosterone (CORT)-induced chronic depressive mouse model. CORT administration resulted in depression-like behaviors and memory impairment. P-CA treatment alleviated CORT-induced depression-related behaviors and memory impairment. Network pharmacology predicted that p-CA had multiple targets and mediated various signaling pathways, of which inflammation-associated targets and signaling pathways are predominant. Western blotting showed CORT-induced activation of the advanced glycation end product (AGE)-receptor of AGE (RAGE) (AGE-RAGE) signaling and increased expression of the proinflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNFα) in the hippocampus, while p-CA treatment inactivated AGE-RAGE signaling and decreased the levels of IL-1β and TNFα, suggesting that protection against depression and memory impairment by p-CA is mediated by the inhibition of inflammation, mainly via the AGE-RAGE signaling pathway. Our data suggest that p-CA treatment will benefit patients with depression.

Exercise more efficiently regulates the maturation of newborn neurons and synaptic plasticity than fluoxetine in a CUS-induced depression mouse model

Depression, a common and important cause of morbidity and mortality worldwide, is commonly treated with antidepressants, electric shock and psychotherapy. Recently, increasing evidence has shown that exercise can effectively alleviate depression. To determine the difference in efficacy between exercise and the classic antidepressant fluoxetine in treating depression, we established four groups: the Control, chronic unpredictable stress (CUS/STD), running (CUS/RUN) and fluoxetine (CUS/FLX) groups. The sucrose preference test (SPT), the forced swimming test (FST), the tail suspension test (TST), immunohistochemistry, immunofluorescence and stereological analyses were used to clarify the difference in therapeutic efficacy and mechanism between exercise and fluoxetine in the treatment of depression. In the seventh week, the sucrose preference of the CUS/RUN group was significantly higher than that of the CUS/STD group, while the sucrose preference of the CUS/FLX group did not differ from that of the CUS/STD group until the eighth week. Exercise reduced the immobility time in the FST and TST, while fluoxetine only reduced immobility time in the TST. Hippocampal structure analysis showed that the CUS/STD group exhibited an increase in immature neurons and a decrease in mature neurons. Exercise reduced the number of immature neurons and increased the number of mature neurons, but no increase in the number of mature neurons was observed after fluoxetine treatment. In addition, both running and fluoxetine reversed the decrease in the number of MAP2+ dendrites in depressed mice. Exercise increased the number of spinophilin-positive (Sp+) dendritic spines in the hippocampal CA1, CA3, and dentate gyrus (DG) regions, whereas fluoxetine only increased the number of SP+ spines in the DG. In summary, exercise promoted newborn neuron maturation in the DG and regulated neuronal plasticity in three hippocampal subregions, which might explain why running exerts earlier and more comprehensive antidepressant effects than fluoxetine.

Immune Phenotypes of Oligodendroglial‐Lineage Cells in MDD and in Response to Chronic Stress‐Induced Microglial Inflammation

BackgroundMajor Depressive Disorder (MDD) is a complex and heterogenous psychiatric disorder affecting more than 300 million people worldwide. Though the mechanisms underlying MDD are not fully understood, a subset of depressive patients can manifest chronic neuroinflammatory responses. In addition, brain‐imaging studies in MDD patients have provided evidence of white matter reductions and such changes are hypothesized to lead to disruption of Oligodendroglial‐Lineage cells (OLN) homeostatic mechanisms, resulting in destabilization of emotional/cognitive circuitry. The present goal of the study is to investigate whether these histopathological alterations are linked with chronic inflammation through single‐nucleus transcriptomics of MDD patients and in a depression mouse model.MethodsBioinformatics: Raw counts were downloaded from GEO (GSE144136), and expression objects created using Seurat. OLN were subsetted, clustered (using UMAP), and annotated based on their expression of early and late OLN markers. Pseudotime trajectory analysis was conducted using Moncle3. In vivo: The Repeated Social Defeat Stress (RSDS) paradigm (10 days) was used to induce depressive‐like behavior in 8–12‐week‐old male CX3CR1‐GFP+ and CSPG4‐EGFP+ mice. Behavioral tasks (BH) were performed to stratify the defeated mice to susceptible (S; depressive‐like) and resilient (R; non‐depressive) to stress groups. The study focuses on the MDD‐affected prefrontal cortex (mPFC) area (Fig).ResultsSeparate clustering of MDD and Control samples yielded four similar clusters labeled based on their gene expression as: OPCs, Committed OPCs, Immature Oligodendrocytes (OLs), and Mature OLs. One MDD‐specific cluster was also obtained and labeled as Immune OLs (ImOL), given its expression of immune genes, such as: ARGHAP24, ADAM28, LPAR6, C3, CD74, and P2RY12. Further analysis of the ImOL cluster revealedexpression of markers associated with later phases of OLN progeny. Finally, a predictive model of pseudotime trajectory revealed alterations in the progression of OLN progeny in MDD samples. We then sought to identify this novel subset of ImOL in the RSDS model of depression. MHCII, C3 and P2RY12 were examined in conjunction with OLN markers (CSPG4, O4, CNP), with significant changes observed in S groups. Interestingly, microglial phagocytosis of myelin elements (CX3CR1‐GFP, MHCII, CNP), was significantly increased in S groups post RSDS, rendering the ImOL populations as potential recruiters of innate immunity.ConclusionsTogether, our computational data in MDD patients and depression mouse model, show that OLN can swiftly respond to chronic stress, and adopt an immune‐like phenotype, potentially contributing to the white matter disturbances observed in MDD.