Rat Model Of Stress-induced Depression Research Articles

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.

Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model.

To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on 1H-NMR metabolomics techniques, and to explore the potential mechanisms of exercise for the treatment of depression. Rats were randomly divided into blank control group (C), CUMS control group (D), pre-exercise with CUMS group (P), CUMS with aerobic exercise group, CUMS with resistance exercise group (R), and CUMS with aerobic + resistance exercise group (E). The corresponding protocol intervention was applied to each group of rats. Body weight, sucrose preference and open field tests were performed weekly during the experiment to evaluate the extent of depression in rats. Plasma samples from each group of rats were collected at the end of the experiment, and then the plasma was analyzed by 1H-NMR metabolomics combined with multivariate statistical analysis methods to identify differential metabolites and perform metabolic pathway analysis. (1) Compared with the group D, the body weight, sucrose preference rate, and the number of crossings and standings in the different types of exercise groups were significantly improved (p < 0.05 or p < 0.01). (2) Compared to group C, a total of 15 differential metabolites associated with depression were screened in the plasma of rats in group D, involving 6 metabolic pathways. Group P can regulate the levels of 6 metabolites: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group A can regulate the levels of 6 metabolites: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose and acetoacetic acid. Group R can regulate the levels of 6 metabolites: choline, lactate, inositol, glucose, phosphocreatine and acetoacetic acid. Group E can regulate the levels of 5 metabolites: choline, citric acid, glucose, acetone and acetoacetic acid. The different types of exercise groups can improve the depressive symptoms in CUMS rats, and there are common metabolites and metabolic pathways for their mechanism of effects. This study provides a powerful analytical tool to study the mechanism of the antidepressant effect of exercise, and provides an important method and basis for the early diagnosis, prevention and treatment of depression.

Administration of serotonin and norepinephrine reuptake inhibitors tends to have less ocular surface damage in a chronic stress-induced rat model of depression than selective serotonin reuptake inhibitors

Depressed patients who medicate with selective serotonin reuptake inhibitors (SSRIs) often report ocular dryness. Epidemiological studies have found that serotonin and norepinephrine reuptake inhibitors (SNRIs) are not risk factors for dry eye in depressed patients. However, the effect of SNRIs on the ocular surface is unknown. A depression rat model was induced by chronic unpredictable mild stress (CUMS), and SNRIs or SSRIs were administered to the rats for 3 or 6 weeks. The levels of norepinephrine (NE) and serotonin in tear fluid were tested by ELISA. The corneal fluorescence and lissamine green staining were used to evaluate ocular surface damage. NE and/or serotonin were administered to human corneal epithelial cells in vitro. RNA sequencing (RNA-seq) analysis was performed to investigate the mRNA expression profiles. Tear NE levels were higher in the SNRIs group, and ocular surface inflammation and apoptosis were significantly reduced compared to the SSRIs group. RNA-Seq indicated that NE significantly activate MAPK signaling pathway. NE can inhibit serotonin-induced activation of the NF-κB signaling pathway through α-1 adrenergic receptors and promotes the proliferation of corneal epithelial cells through activation of the MAPK signaling pathway. SNRIs administration have less ocular surface damage than SSRIs. NE protects human corneal epithelial cells from damage, and reduce inflammation on the ocular surface via activating the MAPK signaling pathway. SNRIs might be used as an appropriate treatment for depression-related DED.

Integrated 16S rRNA sequencing and metabolomics analysis to investigate the antidepressant role of Yang-Xin-Jie-Yu decoction on microbe-gut-metabolite in chronic unpredictable mild stress-induced depression rat model.

Objectives: Our goals were to evaluate the antidepressant efficacy of Yang-Xin-Jie-Yu Decoction (YXJYD) in Chronic Unpredictable Mild Stress (CUMS)-induced depression rat model and to investigate the underlying mechanisms. Design: We used CUMS-induced depression rat model to evaluate whether oral administration of YXJYD with different doses (2.1 g/kg, 1.05 g/kg and 0.525 g/kg, respectively) improve the depressive-like symptoms, and then performed UHPLC-Q-TOF-MS to explore the active ingredients of YXJYD. Subsequently, rat’s cecal contents, serum, and urine were collected from the control group, CUMS model group, and YXJYD high-dose (2.1 g/kg) treatment group. The 16S rRNA sequencing was performed on the cecal contents, based on Illumina MiSeq platform, and ANOVA analysis were used to analyze the composition variety and screen differential expression of gut bacteria in the three groups. 1H Nuclear Magnetic Resonance (NMR) analysis was used for analyzing the metabolites obtained from cecal contents, serum, and urine, and KEGG enrichment analysis was used to identify pathways of differential metabolites. An integrated 16S rRNA sequencing and metabolomic data were conducted to characterize the underlying mechanisms of YXJYD Results: The gut microbial communities, and serum, cecal content, urine metabolic compositions were significantly significantly altered in CUMS-induced depressive rats, while YXJYD effectively ameliorated the CUMS-associated gut microbiota dysbiosis, especially of Monoglobus, and alleviated the disturbance of serum, cecal content, urine metabolome and reversed the changes of key depressive and gut microbiota-related metabolites, such as succinic acid, taurine, hippuric acid, melatonin. With an integrated study of the gut microbiota and metabolomes, we identified the pathway of tricarboxylic acid cycle (TCA cycle) and propanoate metabolism as the regulated target of YXJYD on host-microbiome interaction. Conclusion: Our findings further confirmed the imbalance of metabolism and intestinal microbial is closely related to CUMS-induced depression. YXJYD regulates gut microbiome to affect body metabolomes and then produce antidepressant-like effect in CUMS-induced depressive rats while its molecular mechanism possibly be increased Monoglobus abundance in gut microbiota and regulated the TCA cycle pathway and propanoate metabolism in host.

Reduced Synaptic Plasticity Contributes to Resistance Against Constant-Stimulus Electroconvulsive Treatment in a Rat Model of Stress-Induced Depression.

PurposeDepression is a common mood disorder in humans worldwide. Electroconvulsive therapy (ECT) remains the most effective treatment for patients with drug-resistant or severe depression; however, during ECT, electrical resistance can occur, antagonizing ECT efficacy. We aimed to investigate how depressed patients develop resistance to electric shocks during ECT.MethodsRats exposed to chronic unpredictable stress exert similar impairments in hippocampal synaptic plasticity as those in depressed humans, including hippocampal neuronal atrophy and reduced synaptic function and synapse-related proteins. Therefore, a rat model was used to model depressive-like behaviors in the current study. Depression-like behavior was stimulated in Sprague Dawley (SD) rats that were then randomized into six groups: control group (C); a rat model of stress-induced depression group (D); and four groups in which a rat model of stress-induced depression received one, three, five, or seven electroconvulsive shocks (ECS; DE1, DE3, DE5, and DE7). The sucrose preference test (SPT) and Morris water maze (MWM) were utilized to evaluate anhedonia and spatial learning and memory in rats, respectively. Synaptic plasticity was recorded electrophysiologically in terms of field excitatory postsynaptic potential (fEPSP) and long-term potentiation (LTP).ResultsThe rat model of stress-induced depression triggered a decrease in the sucrose preference percentage (SPP) and the baseline fEPSP slope relative to those observed for the C group, and these changes were significantly rescued by ECT in a shock number-dependent manner within five shocks. However, the rat model of stress-induced depression displayed an increase in the escape latency and a decrease in space exploration time, in addition to decreased LTP relative to those in the C group, which was further augmented by ECT in a shock number-dependent manner within five shocks.ConclusionChanges in synaptic plasticity might be responsible for the development of resistance against constant-stimulus ECT in a rat model of stress-induced depression.

Antidepressant-like effects of helicid on a chronic unpredictable mild stress-induced depression rat model: Inhibiting the IKK/IκBα/NF-κB pathway through NCALD to reduce inflammation

We previously reported that helicid, an active plant monomer of Helicid nilgirica Bedd, had good antidepressant pharmacological activities. However, the potential mechanism of action remains unknown. Current investigation showed the antidepressant-like effects of helicid and its effects on the neurocalcin delta (NCALD) gene, and its mechanism of action through a depression model in rats exposed to chronic unpredictable mild stress (CUMS). We evaluated depression symptoms using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). By silencing NCALD and using rescue experiments, the IL-6, iNOS, IL-1β, COX-2, and TNF-α levels in the hippocampus or peripheral blood were determined using western blotting and ELISAs. The expression of IKKβ, p-IкBα, p-IKKβ, NF-кB p65, and IкBα were tested using western blots of the cytoplasmic or nuclear samples. Helicid and silencing NCALD relieved the CUMS-irritated depressive-like actions of rats, which were shown by increased consumption of sucrose, numbers of rearings, total running distance, zone crossings, and reduced immobility times. Helicid or silencing NCALD reversed the CUMS-induced high levels of IL-1β, COX-2, IL-6, TNF-α, and iNOS in the hippocampus or peripheral blood. Helicid or silencing NCALD also reduced the expressions of p-IκBα and p-IKKβ in the cytoplasm and the expression of nuclear NF-κB p 65 in hippocampus, and simultaneously elevated cytoplasmic expressions of IκBα, IKKβ, and NF-κB p65 in the hippocampus. Notably, after NCALD overexpression, the biochemical indices of rat helicid administration were reversed. In conclusion, the antidepressant action of helicid was mediated through NCALD in rats of CUMS by repressing hippocampal neuro-inflammation and abating the activation of the IKK/IκBα/NF-κB pathway.

Free Wanderer Powder regulates AMPA receptor homeostasis in chronic restraint stress-induced rat model of depression with liver-depression and spleen-deficiency syndrome.

Free Wanderer Powder (FWP) is a classic formula for depression with digestive dysfunctions, i.e., liver-depression and spleen-deficiency syndrome (LDSDS) in Chinese Medicine. But its protective mechanism has not been fully clarified. Here a chronic restraint stress (CRS) induced rat model showed depression with LDSDS in food intake, metabolism, and behaviour tests. Then 75 rats were randomly divided, and received CRS and different treatment with behaviour tests. Expressions of c-Fos and AMPA-type glutamate receptor subunits GluR1-3 in hippocampus CA1, CA3, DG and amygdala BLA were detected by immunohistochemistry, western blot and RT-PCR, respectively. In CRS rats, FWP alleviated depressive behaviour and c-Fos expression. FWP suppressed the increasement of GluR1 in CA1 and DG, p-GluR1 in CA1, and p-GluR2 and GluR3 in BLA. FWP also blocked the decrease of GluR1 and Glur2/3 in CA3, p-GluR1 in CA3, and p-GluR2 in CA1 and CA3. Furthermore, constituents of FWP and their potential targets were explored using UHPLC-MS and systematic bioinformatics analysis. There were 23 constituents identified in FWP, 9 of which regulated glutamatergic synapse. Together, these results suggest that FWP contains effective constituents and alleviates depression with LDSDS by regulating AMPA-type glutamate receptor homeostasis in amygdala and hippocampus.

Antidepressant effect of EGCG through the inhibition of hippocampal neuroinflammation in chronic unpredictable mild stress-induced depression rat model

Abstract In our study, a chronic unpredictable mild stress-induced depression rat model was constructed then the antidepressant effects and mechanisms of Epigallocatechin-3-O-gallate (EGCG) have been evaluaed accordingly. In the study, there were three subgroups of stochastically-selected male Wistar rats, namely, Control, CUMS-induced (chronic unpredictable mild stress) and CUMS with EGCG administration. The outcomes of sucrose preference and open-field tests presented the antidepressant-like effects of EGCG. With EGCG treatment, the levels of IL-6 and NO had significantly declined. Through EGCG administration, the suppressed expression of caspase-3 and caspase-9 mRNA in hippocampus was exhibited in the experiment. The implication of experimental outcomes can be served as preclinical evidences for therapeutic applications in the treatment of depression potentially, because of the antidepressant-like role of EGCG played against inflammation to protect neurons in hippocampus.

Differential serum exosome microRNA profile in a stress-induced depression rat model

BACKGROUNDIncreasing evidence has shown the important role of exosomes in the maintenance of brain function and pathogenesis of brain disease, but little is known about their association with depression. The aim of this project was to explore the miRNA profile of exosomes in the serum of rats with depression induced by chronic unpredictable mild stress (CUMS). METHODSA rat model of depression was replicated via CUMS. Behavioral performance was observed, and serum exosomes were isolated and identified. The protein expression levels of brain-derived neurotrophic factor (BDNF), TrkB, and synaptotagmin 1 in the hippocampus, prefrontal cortex (PFC), and serum exosomes were measured. GO and KEGG enrichment analysis of differential genes was carried out using the R package clusterProfiler. RESULTSThe CUMS rats showed depression-like behaviors, together with decreased expression levels of BDNF, TrkB, and synaptotagmin 1 in the hippocampus, PFC, and serum exosomes. GO and KEGG enrichment analysis indicated that the differential expression of miRNAs might play an important role in the pathogenesis of stress-induced depression through the MAPK pathway, Wnt pathway, and mTOR pathway. LIMITATIONSThe protein expression levels of BDNF, TrkB, and synaptotagmin 1 were measured only in the hippocampus and PFC. The function of the differentially expressed miRNAs was not verified in the animal model, which should be investigated in detail in future studies. CONCLUSIONSThe miRNA profile was altered in rats with stress-induced depression, which might be considered a potential biomarker for the early diagnosis of depression.

Serum metabolomics reveals the intervention mechanism and compatible regularity of Chaihu Shu Gan San on chronic unpredictable mild stress-induced depression rat model.

To provide a comprehensive study of the intervention mechanism and compatible regularity of Chaihu Shu Gan San (CSGS) in a chronic unpredictable mild stress (CUMS)-induced depression model. Ethological study and ELISA assay were applied to measure the phenotypes of depression after CUMS stimulate and assess the antidepressant activity of fluoxetine, CSGS and its compatibilities. The serum metabolic profile changes were revealed by untargeted Q/TOF MS-based metabolomics followed by multivariate statistical analysis. CSGS exhibits an significant intervention effect on CUMS-induced depression. After the multivariate statistical analysis, 17 potential serum biomarkers were identified and 16 of them could be regulated by CSGS. The intervention of CSGS on CUMS-induced depression involved five key pathways. Moreover, each functional unit (monarch, minister, assistant and guide medicine) in CSGS regulates different metabolites and metabolic pathways to achieve different effects on antidepressant; however, their intervention efficacies are inferior to the holistic formula, which may be due to the synergism of bioactive ingredients in the seven herbs of CSGS. CSGS produced an obvious antidepressant activity. The comprehensive and holistic metabolomics approach could be a powerful tool to study the intervention mechanism and the compatibility rule of traditional Chinese medicine.

EPA is More Effective than DHA to Improve Depression-Like Behavior, Glia Cell Dysfunction and Hippcampal Apoptosis Signaling in a Chronic Stress-Induced Rat Model of Depression.

Clinical evidence indicated that eicosapentaenoic acid (EPA) was more effective than docosahexaenoic acid (DHA) in depression treatment. However, possible mechanisms remain unclear. Here, a chronic unpredictable mild stress (CUMS)-induced model of depression was used to compare EPA and DHA anti-depressant effects. After EPA or DHA feeding, depression-like behavior, brain n-3/n-6 PUFAs profile, serum corticosterone and cholesterol concentration, hippocampal neurotransmitters, microglial and astrocyte related function, as well as neuronal apoptosis and survival signaling pathways were studied. EPA was more effective than DHA to ameliorate CUMS-induced body weight loss, and depression-like behaviors, such as increasing sucrose preference, shortening immobility time and increasing locomotor activity. CUMS-induced corticosterone elevation was reversed by bother fatty acids, while increased cholesterol was only reduced by EPA supplement. Lower hippocampal noradrenaline and 5-hydroxytryptamine concentrations in CUMS rats were also reversed by both EPA and DHA supplement. However, even though CUMS-induced microglial activation and associated increased IL-1β were inhibited by both EPA and DHA supplement, increased IL-6 and TNF-α levels were only reduced by EPA. Compared to DHA, EPA could improve CUMS-induced suppressive astrocyte biomarkers and associated BDNF-TrkB signaling. Moreover, EPA was more effective than DHA to attenuate CUMS-induced higher hippocampal NGF, GDNF, NF-κB, p38, p75, and bax expressions, but reversed bcl-2 reduction. This study for the first time revealed the mechanisms by which EPA was more powerful than DHA in anti-inflammation, normalizing astrocyte and neurotrophin function and regulating NF-κB, p38 and apoptosis signaling. These findings reveal the different mechanisms of EPA and DHA in clinical depression treatment.

Antidepressant-like effects of penta-acetyl geniposide in chronic unpredictable mild stress-induced depression rat model: Involvement of inhibiting neuroinflammation in prefrontal cortex and regulating hypothalamic-pituitaryadrenal axis

We previously reported that penta-acetyl geniposide ((Ac)5GP, an acetylated derivative of geniposide) exhibited better pharmacological functions than geniposide, a major active component of Gardenia jasminoides Ellis. This study demonstrated the antidepressant-like effects of (Ac)5GP and its involved mechanisms using a rat depression model caused by chronic unpredictable mild stress (CUMS). Behavioral tests including sucrose preference, open field and forced swimming were applied to evaluate depression symptoms. IL-1β, IL-6 and TNF-α mRNA and protein levels in prefrontal cortex (PFC) were respectively measured by quantitative PCR and ELISA. The protein levels of IκBα, p-IκBα, NF-κB p65, NLRP3, pro- and mature-IL-1β in PFC were determined by western blot. The activity of hypothalamic–pituitaryadrenal (HPA) axis was also measured. (Ac)5GP treatment alleviated the CUMS-induced depressive-like behaviors in rats, as indicated by increased sucrose intake, increased total crossing and rearing numbers, improved central activity and reduced immobility time. (Ac)5GP reversed the CUMS-induced elevations of IL-1β, IL-6 and TNF-α mRNA and protein levels in PFC. (Ac)5GP reduced degradation and phosphorylation of IκBα and protein level of nuclear NF-κB p65 in PFC. (Ac)5GP also decreased the mRNA and protein levels of NLRP3 and reduced the ratio of mature-IL-1β protein over total IL-1β protein (pro-IL-1β + mature-IL-1β) in PFC. Moreover, (Ac)5GP reduced serum levels of adrenocorticotropic hormone/corticosterone and mRNA level of hypothalamic corticotrophin-releasing hormone. In conclusion, (Ac)5GP treatment improved the depressive-like behaviors in CUMS rats perhaps by suppressing neuroinflammation in PFC and inhibiting activations of NF-κB and NLRP3 and also attenuating HPA axis hyperactivity.

BDNF-Related Imbalance of Copine 6 and Synaptic Plasticity Markers Couples With Depression-Like Behavior and Immune Activation in CUMS Rats.

Chronic stress is a contributing risk factor in the pathogenesis of depression. Although the mechanisms are multifaceted, the relationship can be ascribed partly to stress-related alterations in immune activation and brain plasticity. Considering the increasing evidence regarding the role of Copine 6 in the regulation of synaptic plasticity, the aim of the present study is to investigate Copine 6 expression in the hippocampus and the prefrontal cortex (PFC) in a stress-induced depression rat model. The behavior of the rats was evaluated via the open field test, saccharin preference test, elevated plus maze test, tail suspension test, Morris water maze, and forced swimming test. The plasma concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured, and the protein expressions of brain-derived neurotrophic factor (BDNF), Copine 6, and synaptic plasticity markers in the hippocampus and the PFC were also detected. The results showed that chronic unpredictable mild stress (CUMS) induces depression-like behavior in rats, accompanied by increased plasma concentrations of CRP and IL-6. Moreover, the protein expressions of BDNF, Copine 6, and synapsin I were decreased in both the hippocampus and the PFC of CUMS rats, and the protein expression of synaptotagmin I was decreased in the hippocampus. Furthermore, Pearson’s test revealed a potential relationship between the depression-like behavior, the plasma CRP concentration, and the protein expressions of BDNF, Copine 6, synapsin I, or synaptotagmin I in the hippocampus or the PFC. Together with our previous results, the current findings suggest that apart from immune activation, the BDNF-related imbalance of Copine 6 expression in the brain might play a crucial role in stress-associated depression-like behaviors and synaptic plasticity changes.

Changes in PPARδ expression in a rat model of stress-induced depression.

Depression is a common mental disorder that has been linked to a decrease in the expression of serotonin and/or the serotonin transporter in the brain. Antidepressants that target the monoaminergic system are widely used in the clinical setting. Peroxisome proliferator-activated receptor δ (PPAR δ) overexpression or activation is thought to improve depression-like behaviours in rodents. The present study was designed to characterize the changes in PPARδ expression in the hippocampus in rats with stress-induced depression. We used an unpredictable chronic mild stress (CMS) model in rats to study the role of PPARδ in the hippocampus. Behaviour was evaluated via a forced swim test (FST), a tail suspension test (TST), and a sucrose preference test (SPT). Then, the changes in PPARδ expression and other signals were determined using Western blots. We found that PPARδ expression in the hippocampus was markedly reduced in rats with depression. Moreover, the expression of the serotonin transporter was also significantly decreased. Treatment with a PPARδ agonist enhanced the expression of PPARδ and the serotonin transporter in the hippocampus of rats with stress-induced depression. Additionally, treatment with a PPARδ agonist increased the expression of the serotonin transporter in cultured hippocampal (H19-7) cells, and this action was ablated in the absence of PPARδ, which was attenuated with shRNA. Taken together, we found that PPARδ plays an important role in the regulation of serotonin transporter expression and that chronic stress may lower PPARδ expression in the brain via apoptosis and may attenuate serotonin transporter expression, thus inducing depression in rats.

Metabonomic identification of the effects of the Zhimu-Baihe saponins on a chronic unpredictable mild stress-induced rat model of depression

The herbal pair Zhimu-Baihe (Zhimu: Anemarrhena asphodeloides; Baihe: Lilium brownii var. viridulum) is a traditional Chinese medicament used for the treatment of depression. However, the relevant mechanisms of action has not been clarified. This study investigated the anti-depressant activity of the total saponins from Zhimu and Baihe and the mechanisms underlying using a chronic unpredictable mild stress (CUMS)-induced rat model of depression. High performance liquid chromatography with electrochemical detection (HPLC-ECD) was applied to determine the levels of three monoamine neurotransmitters, 5-hydroxytryptamine (5-HT), noradrenaline (NE) and dopamine (DA), in the rat hippocampus. Optimized pretreatment of samples and mass spectrometry conditions were used to analyse the metabonomic profile of the hippocampus. The 5-HT and NE levels in the CUMS group were reduced compared with the control group, whereas all groups had similar DA levels. The metabonomic profile of the hippocampus revealed 32 differential metabolites between the CUMS and control group, among which 18 metabolites were significantly recovered in the Anemarrhena saponins and Lilium saponins (AL) combination intervention group. These results suggested an anti-depressant effect of AL. Moreover, 24 metabolites in AL group were better recovered compared with the Anemarrhena saponins (AS) or Lilium saponins (LS) intervention groups, suggesting a synergetic effect of AS and LS in the treatment of depression. The anti-depressant effect might be related to the regulation of several metabolic pathways, including monoamine neurotransmitter synthesis (especially 5-HT and NE), and amino acid, fatty acid, and phospholipid metabolism in rats.

Chronic unpredictable mild stress impairs erythrocyte immune function and changes T-lymphocyte subsets in a rat model of stress-induced depression

Stress has been shown to suppress immune function and increase susceptibility to inflammatory and psychiatric diseases. This study sought to investigate the changes in erythrocyte immune functions and T-lymphocyte subsets and to explore the mechanism implicated in the process of stress-induced depression by employing a rat depression model induced by chronic unpredictable mild stress (CUMS). The body weights and behavioral changes of the rats were recorded, and plasma corticosterone levels were determined by radioimmunoassay. Erythrocyte immune function and T-lymphocytes subsets were respectively measured by the method of yeast rosette and flow cytometry at different time intervals, and their relationship was analyzed. Results indicated that a reduction was observed in the following: the rats’ crossing and rearing movement times, the volume of sucrose intake and the preference for sucrose in the depression model group. Plasma corticosterone levels were elevated; the rate of E-C3bR decreased, and E-IC was increased. Some alterations in the percentage of T-lymphocytes and IL-2 appeared in the depression model group and some relationships existed between these parameters. Collectively, these findings disclose that long-time stress could induce changes in rat behavior and activities through an effect on erythrocyte immune functions and T-lymphocyte subsets.

Magnolol treatment reversed the glial pathology in an unpredictable chronic mild stress-induced rat model of depression

Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open-field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P<0.05).Moreover, treatment with magnolol effectively increased GFAP mRNA and protein levels in UCMS rats. These results confirmed the antidepressant-like effect of magnolol, which maybe primarily mediated by reversing the glial atrophy in the UCMS rat brain.

Study on the mechanism of interleukin-6 in the colonic motility changes of depression rat model

[Abstract] Objective To study the changes of colonic motility in chronic stress-induced depression rat model, the association between interleukin 6 （IL-6） and depression and its effects on contraction of colonic smooth muscle in vitro. Methods There were 30 healthy adult Wistar rats, of which chronic stress-induced depression model was created in 15 rats and the other 15 rats were in control group. The ratio of sugar consumption to body weight and the percentage of sugar preference were tested in these two rats groups through sugar preference experiments. The behavioral changes of two rats groups were detected by open field test. Colonic motility was evaluated with simulated fecal discharge experiment, and the serum IL-6 level was measured with enzyme linked immunosorbent assay （ELISA）. IL-6 in colon tissue at mRNA level was determined by RT-PCR. The contraction ability of rat colonic smooth muscle was observed. The colonic smooth muscle of control group was treated with different concentration of IL-6, the effects of IL6 on normal colonic smooth muscle and its response to acetylcholine （Ach） were evaluated. Results In model group, the ratio of sugar consumption to body weight was 0. 12±0. 03, the percentage of sugar preference was 16. 17%-±2.61%, total walking distance was （741.54±341.10） cm and total times of upright was 15.69＋ 8.00, which were all significantly lower than those of control group （0.18±0.02, 25.54±2.32%, 1336.20 cm±698.80 cm and 24.87±7.90, respectively） （P= 0. 041, 0. 044, 0. 002 and 0. 001）. It took （109. 78±48.00） min for defecating in model group, which was significantly longer than that of control group （28.00±11.10） min （P=0. 002）. The IL6 levels were high both in the serum and colon tissue of model group rats. The response of colonic smooth muscle to Aeh was weaker in model group than that of control group （P=0. 035）. In model group, there were no significant difference in the response of colonic smooth muscle to IL-6 at 200, 500 and 1000 pg/ml （P =0. 935,0. 825, 0. 766）. After Ach added, there was significant difference in the response to Aeh between IL-6 at 500, 1000 pg/ml （R=1.14804-0. 1000 and 1. 1361±0. 1500） and control group only added with Ach （R= 1. 6100±0. 4500） （P= 0. 000 and 0. 004）. Conclusion IL-6 level increase in chronic stress-induced depression rat model and causes smooth muscle contraction disorder through reducing the sensitivity of intestinal smooth muscle to Ach. Key words: Stress; Depressive disorder; Disease models, animal; Colon; Kinetics; Interleukin-6

Clomipramine treatment reversed the glial pathology in a chronic unpredictable stress-induced rat model of depression

Growing evidence indicates that glia pathology contributes to the pathophysiology and possibly the etiology of depression. The study investigates changes in behaviors and glial fibrillary associated protein (GFAP) in the rat hippocampus after chronic unpredictable stress (CUS), a rat model of depression. Furthermore, we studied the effects of clomipramine, one of tricyclic antidepressants (TCAs), known to modulate serotonin and norepinephrine uptake, on CUS-induced depressive-like behaviors and GFAP levels. Rats exposed to CUS showed behavioral deficits in physical state, open field test and forced swimming test and exhibited a significant decrease in GFAP expression in the hippocampus. Interestingly, the behavioral and GFAP expression changes induced by CUS were reversed by chronic treatment with the antidepressant clomipramine. The beneficial effects of clomipramine treatment on CUS-induced depressive-like behavior and GFAP expression provide further validation of our hypothesis that glial dysfunction contributes to the pathophysiology of depression and that glial elements may represent viable targets for new antidepressant drug development.

Increased expression of corticotropin-releasing factor receptor mRNA in the locus coeruleus of stress-induced rat model of depression

Hypersecretion of corticotropin-releasing factor (CRF) has been hypothesized to occur in depression. To investigate CRF receptor (CRFR) response to the increased production of CRF in chronically stressed rats, we measured by in situ hybridization the expression of CRFR mRNA in the locus coeruleus (LC) concomitant with measuring plasma adrenocorticotropin (ACTH). The expression of both CRFR mRNA in the LC and the plasma level of ACTH increased significantly in “depression-model rats” which exhibit reduced activity following exposure to 14 days forced walking stress (FWS), but not in “spontaneous recovery rats” whose activity was restored after the long-term stress. These results suggest that the LC neurons continue to be stimulated by CRF, and that the hypothalamic-pituitary-adrenal (HPA) axis is hyperfunctioning in the depression-model rats.