Chronic Unpredictable Mild Stress Model Research Articles

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.

Comparison of the chronic unpredictable mild stress and the maternal separation in mice postpartum depression modeling

Postpartum depression (PPD) is a serious mental health concern of new mothers worldwide. In view of the particularity of puerpera, the research on pathogenesis and drug development of PPD are highly dependent on animal models. Although both maternal separation (MS) and chronic unpredictable mild stress (CUMS) modeling approaches have been used in PPD studies, the characteristics of the two rodent models have not been compared to explain which is more advantageous in PPD research. In this study, we applied 21-day MS and CUMS paradigms to induce mouse model of PPD and compared their differences in behavior, physiology and gut microbiota. As a result, the two models exhibited significant increases of immobility time in forced swim test (FST) and tail suspension test (TST), whereas sucrose preference index and pup weight were significantly decreased. Both displayed depression-like behaviors, and CUMS was more obvious, which demonstrated by the lower levels of 5-hydroxytryptamine (5-HT) and higher hypothalamic-pituitary-adrenal (HPA) axis related mRNA expression (corticotropin releasing hormone, corticotropin releasing hormone receptor 1) in CMUS group than that in MS group. The gut microbiota in MS and CUMS groups were significantly different in terms of the relative abundances of Bacteroidetes, Firmicutes, Proteobacteria. In conclusion, MS model and CUMS model have different performance in behavior and physiology. The CUMS model showed more obvious parameter changes, which may be more suitable for PPD induced by various social environmental factors.

Sucrose Preference Test as a Measure of Anhedonic Behavior in a Chronic Unpredictable Mild Stress Model of Depression: Outstanding Issues.

Despite numerous studies on the neurobiology of depression, the etiological and pathophysiological mechanisms of this disorder remain poorly understood. A large number of animal models and tests to evaluate depressive-like behavior have been developed. Chronic unpredictable mild stress (CUMS) is the most common and frequently used model of depression, and the sucrose preference test (SPT) is one of the most common tests for assessing anhedonia. However, not all laboratories can reproduce the main effects of CUMS, especially when this refers to a decrease in sucrose preference. It is also unknown how the state of anhedonia, assessed by the SPT, relates to the state of anhedonia in patients with depression. We analyzed the literature available in the PubMed database using keywords relevant to the topic of this narrative review. We hypothesize that the poor reproducibility of the CUMS model may be due to differences in sucrose consumption, which may be influenced by such factors as differences in sucrose preference concentration threshold, water and food deprivation, and differences in animals’ susceptibility to stress. We also believe that comparisons between animal and human states of anhedonia should be made with caution because there are many inconsistencies between the two, including in assessment methods. We also tried to offer some recommendations that should improve the reproducibility of the CUMS model and provide a framework for future research.

Ketamine alleviating depressive-like behaviors is associated with regulation of nNOS-CAPON-Dexras1 complex in chronic unpredictable mild stress rats.

BackgroundA growing number of studies have demonstrated that ketamine induces rapid and sustained antidepressant action. Neuronal nitric oxide synthase (nNOS) signaling has been explored for the treatment of neuropsychiatric disorders for decades. But the effect of ketamine on nNOS signaling is poorly understood. The aim of the present study was to investigate the effect of ketamine on nNOS signaling in a chronic unpredictable mild stress (CUMS) model of depression.MethodsForty-eight rats were randomly divided into four groups: the control group of healthy rats (group C), the healthy rats treated with ketamine 10 mg/kg for 3 days (group CK), the rats model of stress-induced depression group (group D), and the depressed group treated with ketamine 10 mg/kg for 3 days (group DK). The sucrose preference test and open field test were used to assess behavioral changes. Immunohistochemistry, immunofluorescence, and real-time PCR analysis were carried out to measure the expression of nNOS, CAPON, and Dexras1 in the prefrontal cortex (PFC) of the CUMS rats.ResultsCompared with healthy rats, the total distance traveled, the rearing counts, the sucrose preference percentage (SPP), and CAPON and Dexras1 expression in the PFC significantly decreased, while nNOS expression increased in CUMS rats. After treating with ketamine, the total distance traveled, the rearing counts, the SPP, and CAPON and Dexras1 expression significantly increased, while nNOS expression significantly decreased.ConclusionThe results indicated that ketamine improved the depressive behavior of rats, which may be related to the reduced nNOS expression and enhanced CAPON and Dexras1 expression.

The antidepressant effects and serum metabonomics of bifid triple viable capsule in a rat model of chronic unpredictable mild stress.

BackgroundProbiotics have shown potential antidepressant effects. This study evaluated the effect and probable mechanisms of bifid triple viable capsules (BTVCs) on a rat model of chronic unpredictable mild stress (CUMS).Materials and methodsRats were randomly divided into Normal, CUMS model, fluoxetine hydrochloride (FLX), BTVCs, and FLX+BTVCs groups. Depressive-like behaviours, pathological changes in the hippocampus, changes in serum metabolites and potential biomarkers, and metabolic pathways were detected via behavioural tests, haematoxylin-eosin staining, nissl staining, non-targetted metabolomics, and ingenuity pathway analysis (IPA).ResultsThe rats displayed depressive-like behaviours after CUMS exposure, but BTVCs ameliorated the depressive-like behaviours. In addition, the pathological results showed that the hippocampal tissue was damaged in rats after CUMS exposure and that the damage was effectively alleviated by treatment with BTVCs. A total of 20 potential biomarkers were identified. Treatment with BTVCs regulated D-phenylalanine, methoxyeugenol, (±)-myristoylcarnitine, 18:3 (6Z, 9Z, 12Z) /P-18:1 (11Z), propionyl-L-carnitine, and arachidonic acid (AA) concentrations, all compounds that are involved with biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, linoleic acid metabolism and AA metabolism. The IPA demonstrated that endothelin-1 signalling and cyclic adenosine monophosphate response element binding protein (CREB) signalling in neurons may be involved in the development of depression.ConclusionOur findings suggest that BTVCs can alleviate depressive-like behaviours, restore damage to the hippocampus in CUMS rats and regulate serum metabolism, which may be related to endothelin-1 signalling or CREB signalling in neurons.

A unique insight for Xiaoyao San exerts antidepressant effects by modulating hippocampal glucose catabolism using stable isotope-resolved metabolomics

Ethnopharmacological relevanceIn traditional Chinese medicine (TCM) theory, depression is an emotional disease, which is thought to be related to stagnation of liver qi and dysfunction of the spleen in transport. Xiaoyao San (XYS) is considered to have the effects of soothing liver-qi stagnation and invigorating the spleen. The spleen has the function to transport and transform nutrients. The liver has also termed the center of energy metabolism in the body. Therefore, exploring the antidepressant effects of XYS from the perspective of energy metabolism may reveal new findings. Aim of the studyGlucose catabolism is an important part of energy metabolism. In recent years, several researchers have found that XYS can exert antidepressant effects by modulating abnormalities in glucose catabolism-related metabolites. The previous research of our research group found that the hippocampus glucose catabolism was disordered in depression. However, the antidepressant potential of XYS through modulating the disorders of hippocampal glucose catabolism and the specific metabolic pathways and targets of XYS action were still unknown. The aim of this study was to address the above scientific questions. Materials and methodsIn this research, the CUMS (chronic unpredictable mild stress) model was used as the animal model of depression. The antidepressant effect of XYS was evaluated by behavioral indicators. The specific pathways and targets of XYS modulating the disorders of glucose catabolism in the hippocampus of CUMS rats were obtained by stable isotope-resolved metabolomics. Further, the isotope tracing results were also verified by molecular biology and electron transmission electron microscopy. ResultsThe results demonstrated that XYS pretreatment could significantly improve the depressive symptoms induced by CUMS. More importantly, it was found that XYS could modulate the disorders of glucose catabolism in the hippocampus of CUMS rats. Stable isotope-resolved metabolomics and enzyme activity tests showed that Lactate dehydrogenase (LDH), Pyruvate carboxylase (PC), and Pyruvate dehydrogenase (PDH) were targets of XYS for modulating the disorders of glucose catabolism in the hippocampus of CUMS rats. The Succinate dehydrogenase (SDH) and mitochondrial respiratory chain complex V (MRCC-Ⅴ) were targets of XYS to improve abnormal mitochondrial oxidative phosphorylation in the hippocampus of CUMS rats. XYS was also found to have the ability to improve the structural damage of mitochondria and nuclei in the hippocampal caused by CUMS. ConclusionsThis study was to explore the antidepressant effect of XYS from the perspective of glucose catabolism based on a strategy combining stable isotope tracing, molecular biology techniques, and transmission electron microscopy. We not only obtained the specific pathways and targets of XYS to improve the disorders of glucose catabolism in the hippocampus of CUMS rats, but also revealed the specific targets of the pathways of XYS compared with VLF.

Lithium produces bi-directionally regulation of mood disturbance, acts synergistically with anti-depressive/-manic agents, and did not deteriorate the cognitive impairment in murine model of bipolar disorder

Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca2+ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca2+ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca2+ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.

Effect of Rehmanniae Radix on depression-like behavior and hippocampal monoamine neurotransmitters of chronic unpredictable mild stress model rats

To investigate the effect of Rehmanniae Radix on depression-like behavior and monoamine neurotransmitters of chronic unpredictable mild stress(CUMS) model rats. CUMS combined with isolated feeding was used to induce the depression model of rats. The depression-like behavior of rats was evaluated by sucrose preference test, open field test, and forced swim test. Hematoxylin-Eosin(HE) staining was used to investigate the pathological changes of neurons in the CA1 and CA3 area of hippocampus. Ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS) was used to detect the contents of 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), 3,4-dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA), norepinephrine(NE), and 3-methoxy-4-hydroxyphenyl glycol(MHPG) in rats. Western blot was used to detect the protein expressions of tryptophan hydroxylase 2(TPH2), serotonin transporter(SERT), and monoamine oxidase A(MAO-A) in the hippocampus of rats. Compared with the normal group, depressive-like behavior of rats was obvious in the model group. The arrangements of neurons in the CA1 and CA3 area of hippocampus were loose and disorderly. The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in the hippocampal area were decreased(P<0.01). The protein expression of TPH2 was decreased(P<0.01), but those of SERT and MAO-A were increased(P<0.01). In the Rehmanniae Radix groups with 1.8 g·kg~(-1) and 7.2 g·kg~(-1), the depression-like behavior of CUMS rats and pathological changes of neurons in CA1, CA3 area of hippocampus were improved. The protein expression of TPH2(P<0.05, P<0.01) was increased, and those of SERT and MAO-A were down-regulated(P<0.05, P<0.01). The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in hippocampus were increased(P<0.05, P<0.01). The changes in DA, DOPAC, HVA, DA/(DOPAC +HVA), NE, DHPG, and NE/DHPG were not statistically significant. The results suggested that Rehmanniae Radix improved depression-like behavior of CUMS rats, and the mechanism might be related to the regulation of synthesis, transportation, and metabolism of 5-HT neurotransmitter in the hippocampus.

Honokiol improves depression-like behaviors in rats by HIF-1α- VEGF signaling pathway activation.

Increasing evidence indicates that the pathogenesis of depression is closely linked to impairments in neuronal synaptic plasticity. Honokiol, a biologically active substance extracted from Magnolia Officinalis, has been proven to exert significant antidepressant effects. However, the specific mechanism of action remains unclear. In this study, PC12 cells and chronic unpredictable mild stress (CUMS) model rats were used to explore the antidepressant effects and potential mechanisms of honokiol in vitro and in rats. In vitro experiment, a cell viability detection kit was used to screen the concentration and time of honokiol administration. PC12 cells were administered with hypoxia-inducible factor-1α (HIF-1α) blocker, 2-methoxyestradiol (2-ME), and vascular endothelial growth factor receptor 2 (VEGFR-2) blocker, SU5416, to detect the expression of HIF-1α, VEGF, synaptic protein 1 (SYN 1), and postsynaptic density protein 95 (PSD 95) by western blotting. In effect, we investigated whether the synaptic plasticity action of honokiol was dependent on the HIF-1α-VEGF pathway. In vivo, behavioral tests were used to evaluate the reproducibility of the CUMS depression model and depression-like behaviors. Molecular biology techniques were used to examine mRNA and protein expression of the HIF-1α-VEGF signaling pathway and synaptic plasticity-related regulators. Additionally, molecular docking techniques were used to study the interaction between honokiol and target proteins, and predict their binding patterns and affinities. Experimental results showed that honokiol significantly reversed CUMS-induced depression-like behaviors. Mechanically, honokiol exerted a significant antidepressant effect by enhancing synaptic plasticity. At the molecular level, honokiol can activate the HIF-1α-VEGF signaling pathway in vitro and in vivo, as well as promote the protein expression levels of SYN 1 and PSD 95. Taken together, the results do not only provide an experimental basis for honokiol in the clinical treatment of depression but also suggest that the HIF-1α-VEGF pathway may be a potential target for the treatment of depression.

Nonerythropoietic Erythropoietin Mimetic Peptide ARA290 Ameliorates Chronic Stress-Induced Depression-Like Behavior and Inflammation in Mice

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder. But the treatment of depression remains challenging. Anti-inflammatory treatments frequently produce antidepressant effects. EPO-derived helix-B peptide ARA290 has been reported to retain the anti-inflammatory and tissue-protective functions of EPO without erythropoiesis-stimulating effects. The effects of ARA290 on MDD remain elusive. This study established chronic unpredictable mild stress and chronic social defeat stress mouse models. Daily administration of ARA290 during chronic stress induction in two mouse models ameliorated depression-like behavior, similar to fluoxetine. With marginal effects on peripheral blood hemoglobin and red cells, ARA290 and fluoxetine reversed chronic stress-induced increased frequencies and/or numbers of CD11b+Ly6Ghi neutrophils and CD11b+Ly6Chi monocytes in the bone marrow and meninges. Furthermore, both drugs reversed chronic stress-induced microglia activation. Thus, ARA290 ameliorated chronic stress-induced depression-like behavior in mice through, at least partially, its anti-inflammatory effects.

Accelerating Effect of Cucurbita pepo L. Fruit Extract on Excisional Wound Healing in Depressed Rats Is Mediated through Its Anti-Inflammatory and Antioxidant Effects.

Background: Chronic stress can hinder wound healing as it suppresses both the cellular and innate immune responses. Objectives: The study aims to assess the effectiveness of the administration of topical and oral Cucurbita pepo L. (CP) ethanolic extract in prompting excisional wound healing in rats exposed to chronic stress, and to explain how it works. Materials and methods: Fifty albino rats assigned to five groups (n = 10) were utilized in this study. The chronic unpredictable mild stress (CUMS) model was used for 4 weeks to induce depressive-like behavior in rats, and a forced swim test and corticosterone were assessed to confirm its occurrence. During the experiment, an excisional wound was induced in the rats and followed. Oxidant/antioxidants status and pro-inflammatory cytokines levels were measured in the serum and wound area. Gene expression of pro-inflammatory cytokines was also assessed using RT-PCR. Wound closure histopathological changes and immunohistochemical expression of CD68, CD3, and CD4 at the wound area was assessed. Results: The administration of CP, both orally and topically, significantly reduced (p < 0.001) the depressive-like behavior and corticosterone and pro-inflammatory cytokines levels, while it significantly up-regulated the antioxidant activity compared to the untreated and topically CP-treated groups. Both topically CP-treated and combined CP-treated groups showed complete re-epithelialization, reduced inflammatory cells infiltration, collagen fibers deposition, and significantly increased CD3, CD4 positive T cells count, with a superior effect in the combined CP-treated groups. Conclusion: Cucurbita pepo L., administrated both topically and orally, can enhance the wound healing process in rats with depressive-like behavior mostly through the antioxidant, anti-inflammatory, and antidepressant activities observed in this study.

Integrated network pharmacology and hepatic metabolomics to reveal the mechanism of Acanthopanax senticosus against major depressive disorder.

Objective: Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASH) is a traditional herbal medicine widely known for its antifatigue and antistress effects, as well as tonifying qi, invigorating spleen and kidney, and tranquilizing the mind. Recent evidence suggests that ASH has a therapeutic effect on major depressive disorder (MDD), but its mechanism is still unclear. The current study aimed to investigate the effect of ASH on MDD and potential therapeutic mechanisms. Materials and Methods: The chemical compound potential target network was predicted based on network pharmacology. Simultaneously, chronic unpredictable mild stress (CUMS) model mice were orally administrated ASH with three dosages (400, 200, and 100 mg/kg) for 6 weeks, and hepatic metabolomics based on gas chromatography–mass spectrometry (GC–MS) was carried out to identify differential metabolites and related metabolic pathways. Next, the integrated analysis of metabolomics and network pharmacology was applied to find the key target. Finally, molecular docking technology was employed to define the combination of the key target and the corresponding compounds. Results: A total of 13 metabolites and four related metabolic pathways were found in metabolomics analysis. From the combined analysis of network pharmacology and metabolomics, six targets (DAO, MAOA, MAOB, GAA, HK1, and PYGM) are the overlapping targets and two metabolic pathways (glycine, serine, and threonine metabolism and starch and sucrose metabolism) are the most related pathways. Finally, DAO, MAOA, MAOB, GAA, HK1, and PYGM were verified bounding well to their corresponding compounds including isofraxidin, eleutheroside B1, eleutheroside C, quercetin, kaempferol, and acacetin. Conclusion: Based on these results, it was implied that the potential mechanism of ASH on MDD was related to the regulation of metabolism of several excitatory amino acids and carbohydrates, as well as the expression of DAO, MAOA, MAOB, GAA, HK1, and PYGM.

Antidepressant-like activity of oroxylin A in mice models of depression: A behavioral and neurobiological characterization.

Depression is a mood disorder which causes a huge economic burden to both families and societies. However, those monoamine-based antidepressants used in clinical practice have been found to have various limitations. Therefore, currently it is very necessary to explore novel antidepressant targets and medications. As a main active component extracted from Scutellariae radix, oroxylin A possesses many pharmacological functions such as anti-cancer, anti-inflammation and neuroprotection. Here, the present study aims to investigate whether oroxylin A possess antidepressant-like actions using the chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) models of depression, forced swim test, tail suspension test, open field test, sucrose preference test, western blotting, immunofluorescence and viral-mediated gene interference. Our results revealed that treatment of oroxylin A fully prevented both the CUMS-induced and CRS-induced depressive-like behaviors in mice. Moreover, the protecting effects of oroxylin A against CUMS and CRS on mice behaviors were accompanied with a significant enhancement on the levels of brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine kinase B (pTrkB), phosphorylated cAMP-response element binding protein (pCREB) and neurogenesis in the hippocampus. Furthermore, genetic knockdown of BDNF and TrkB in the hippocampus remarkably abolished the antidepressant-like efficacy of oroxylin A in both the CUMS and CRS models of depression, proving that the hippocampal BDNF-TrkB system participates in the antidepressant mechanism of oroxylin A. In summary, our findings are the first evidence showing that oroxylin A possesses potential of being an antidepressant candidate.

Sleep deprivation leads to further impairment of hippocampal synaptic plasticity by suppressing melatonin secretion in the pineal gland of chronically unpredictable stress rats

There has been ample research showing that insomnia is a potential trigger of depression as well as a symptom of depression. These two factors contribute to behavioural problems and are closely related to the plasticity of hippocampal synapses. Although depression and insomnia impair hippocampal synaptic plasticity, the mechanism by which this happens remains a mystery. This study aimed to investigate the pathogenesis of insomnia comorbidity in depression and the regulatory effect of venlafaxine combined with melatonin on hippocampal synaptic plasticity in chronic unpredictable mild stress (CUMS) with sleep deprivation (SD) rats. Thus, rats were subjected to 14 days of chronic mild unpredictable stress, gradually acclimated to sleep deprivation on days 12–14. Followed by 21 consecutive days of sleep deprivation, 18 h per day, with daily gavage of venlafaxine (13.5 mg/kg) + melatonin (72 mg/kg) on days 15–36. Venlafaxine + melatonin treatment improves depression-like behaviour, pentobarbital sodium experimental sleep latency, and sleep duration in CUMS +SD rats. In addition to improving depressive-like behaviors, sleep deprivation also upregulates the expression of caspase-specific cysteine protein 3 (Caspase 3) in the pineal glial cells of chronic mild rats, as well as in hippocampal microglia. Expression of ionic calcium-binding adaptor 1 (iba-1), downregulates the secretion of several synaptic plasticity-related proteins, notably cAMP response element binding protein (CREB), glial cell line-derived neurotrophic factor (GDNF), and the synaptic scaffolding protein Spinophiline (Spinophiline). Hematoxylin-eosin staining showed that the structure of the pineal gland and hippocampus was damaged, and Golgi staining showed that the dendrites and spines in the DG area of the hippocampus were destroyed, vaguely aggregated or even disappeared, and the connection network could not be established. Western blot analysis further revealed a positive correlation between low melatonin levels and reduced Spinophiline protein. Interestingly, venlafaxine + melatonin reversed these events by promoting hippocampal synaptic plasticity by regulating melatonin secretion from the pineal gland. Therefore, it exerted an antidepressant effect in sleep deprivation combined with CUMS model rats. Overall, the results of this study suggest that the pathophysiology of depressive insomnia comorbidity is mediated by impaired pineal melatonin secretion and impaired hippocampal synaptic plasticity. In addition, these responses are associated with melatonin secretion from the pineal gland.

Central and cardiac stress resilience consistently linked to integrated immuno-neuroendocrine responses across stress models in male mice.

Stress resilience, and behavioural and cardiovascular impacts of chronic stress, are theorised to involve integrated neuro-endocrine/inflammatory/transmitter/trophin signalling. We tested for this integration, and whether behaviour/emotionality, together with myocardial ischaemic tolerance, are consistently linked to these pathways across diverse conditions in male C57Bl/6 mice. This included Restraint Stress (RS), 1h restraint/day for 14 days; Chronic Unpredictable Mild Stress (CUMS), seven stressors randomised over 21 days; Social Stress (SS), 35 days social isolation with brief social encounters in final 13 days; and Control conditions (CTRL; un-stressed mice). Behaviour was assessed via open field (OFT) and sucrose preference (SPT) tests, and neurobiology from frontal cortex (FC) and hippocampal transcripts. Endocrine factors, and function and ischaemic tolerance in isolated hearts, were also measured. Model characteristics ranged from no behavioural or myocardial changes with homotypic RS, to increased emotionality and cardiac ischaemic injury (with apparently distinct endocrine/neurobiological profiles) in CUMS and SS models. Highly integrated expression of HPA axis, neuro-inflammatory, BDNF, monoamine, GABA, cannabinoid and opioid signalling genes was confirmed across conditions, and consistent/potentially causal correlations identified for (i) locomotor activity (noradrenaline, ghrelin; FC Crhr1, Tnfrsf1b, Il33, Nfkb1, Maoa, Gabra1; hippocampal Il33); (ii) thigmotaxis (adrenaline, leptin); (iii) anxiety-like behaviour (adrenaline, leptin; FC Tnfrsf1a; hippocampal Il33); (iv) depressive-like behaviour (ghrelin; FC/hippocampal s100a8); and (v) cardiac stress-resistance (noradrenaline, leptin; FC Il33, Tnfrsf1b, Htr1a, Gabra1, Gabrg2; hippocampal Il33, Tnfrsf1a, Maoa, Drd2). Data support highly integrated pathway responses to stress, and consistent adipokine, sympatho-adrenergic, inflammatory and monoamine involvement in mood and myocardial disturbances across diverse conditions.

Selection of the Male or Female Sex in Chronic Unpredictable Mild Stress-Induced Animal Models of Depression.

Depression is a serious public health problem and an important factor leading to disease-related disability. Influenced by many factors, such as psychological, hormonal, and genetic factors, the incidence rate of depression in females is approximately two times that in males. However, in preclinical neuroscience research, the selection of the animals' sex for use in depression models has been controversial. At present, in most preclinical studies, the animals generally chosen in depression models have been male rodents rather than female rodents. It remains doubtful whether the data obtained from male animals can be generalized to female animals. The performance of female animals in preclinical studies of depression has been inconclusive. Based on a review of a large number of original studies in the PubMed database, it was found that although male rodents are more commonly used in the study of depression, the use of female animals also shows good modeling of depression and has its advantages. The influence of the animals' sex in the chronic unpredictable mild stress (CUMS) model needs further research.

DFO treatment protects against depression-like behaviors and cognitive impairment in CUMS mice

Depression has several negative effects on emotion as well as learning and memory abilities. Previous studies showed that depression could exacerbate inflammation, which in turn further aggravated depression. Deferoxamine (DFO) is a chelating agent binding iron and aluminium, and is clinically applied to treat acute ion poisoning and hemochromatosis. Researches showed that it could reduce inflammation via increasing the expression of hypoxia-inducible factor-1alpha (HIF-1α). Here, we established a chronic unpredictable mild stress (CUMS) model to investigate whether DFO exerted a neuroprotective function in depression. The results demonstrated that CUMS (4 weeks) effectively induced depression-like behaviors in mice based on sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), open field test (OFT), and elevated plus-maze test (EPT). It also brought cognitive deficits based on Morris water maze (MWM) test and the impairment of synaptic plasticity based on in vivo electrophysiological recordings. Additionally, CUMS exposure significantly decreased the expression of hippocampal synapse related proteins and the spine density of neurons in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines, and promoted the activation of microglia in the hippocampus. The expression of HIF-1α was down-regulated as expected. However, DFO distinctly reversed the CUMS-induced impairments. The mechanism is associated with the DFO inhibition of inflammation by upregulating HIF-1 expression, thereby alleviating a series of pathology changes. Together, these findings suggest that DFO likely plays a protective role in cognitive impairments and synaptic plasticity deficits resulting from depression.

Animal models of stress-based depression

Depression is one of the most common psychiatric disorders. Despite the prevalence and serious effects of depression, pathological studies of depression are still preliminary. The main reason for this is limited access to valid animal models. Using animal models, the underlying molecular changes and causal relationship between environmental or genetic changes and depression can be studied, which provides a better insight into the pathology of depression. The role of stress as a key factor in the etiology of depression is emphasized. Because of the importance of stress in creating depression disorder in this study, animal models of stress-based depression have been investigated. Animal models of stress-based depression are:1- learned helplessness (LH) model 2- Models based on early-life stress 3- chronic mild stress (CMS) model 4- Social defeat stress model. Studies show that exposure to early life stress can continuously alter DNA methylation in the brain of adult mice or rodents. In this regard, we can mention the role of methylation of the Nr3c1 gene in parts of the hippocampus of the brain, indicating that epigenetic changes may play a role in depressive-like behavior. Also, an unpredictable chronic mild stress model in rodents shows that significantly reduced diffusion of astrocyte cell gap and abnormal ultrastructure gap junction in the prefrontal cortex (PFC) and low levels of adenosine triphosphate (ATP) in the mouse brain, are the cause of depressive-like behavior.

Multi-strain Probiotic Formulation Reverses Maternal Separation and Chronic Unpredictable Mild Stress-Generated Anxiety- and Depression-like Phenotypes by Modulating Gut Microbiome-Brain Activity in Rats.

Depression is a debilitating mental disorder that affects >322 million people worldwide. Despite the availability of several antidepressant agents, many patients remain treatment refractory. A growing literature study has indicated the role of gut microbiota in neuropsychiatric disorders. Herein, we examined the psychobiotic-like activity of multi-strain probiotic formulation in maternal separation (MS) and chronic unpredictable mild stress (CUMS) models of anxiety- and depression-like phenotypes in Sprague-Dawley rats. Early- and late-life stress was employed in both male and female rats by exposing them to MS and CUMS. The multi-strain probiotic formulation (Cognisol) containing Bacillus coagulans Unique IS-2, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Bifidobacterium lactis UBBLa-70, Bifidobacterium breve UBBr-01, and Bifidobacterium infantis UBBI-01 at a total strength of 10 billion cfu along with l-glutamine was administered for 6 weeks via drinking water. Neurobehavioral assessment was done using the forced swim test (FST), sucrose preference test (SPT), elevated plus maze (EPM), and open field test (OFT). Animals were sacrificed after behavioral assessment, and blood, brain, and intestine samples were collected to analyze the levels of cytokines, metabolites, and neurotransmitters and histology. Animals exposed to stress showed increased passivity, consumed less sucrose solution, and minimally explored the open arms in the FST, SPT, and EPM, respectively. Administration of multi-strain probiotics along with l-glutamine for 6 weeks ameliorated the behavioral abnormalities. The locomotor activity of animals in the OFT and their body weight remained unchanged across the groups. Cognisol treatment reversed the decreased BDNF and serotonin levels and increased CRP, TNF-α, and dopamine levels in the hippocampus and/or frontal cortex. Administration of Cognisol also restored the plasma levels of l-tryptophan, l-kynurenine, kynurenic-acid, and 3-hydroxyanthranilic acid; the Firmicutes-to-Bacteroides ratio; the levels of acetate, propionate, and butyrate in fecal samples; the villi/crypt ratio; and the goblet cell count, which manifested in the restoration of intestinal functions. We suggest that the multi-strain probiotic and glutamine formulation (Cognisol) ameliorated the MS + UCMS-generated anxiety- and depression-like phenotypes by reshaping the gut microbiome-brain activity in both sexes.

Effects of repeated drug administration on behaviors in normal mice and fluoxetine efficacy in chronic unpredictable mild stress mice

Mental disorders are characterized by high incidence and high recurrence rates, and only part of patients responded to drug medication. In this case, substantial preclinical investigations are needed. Most antipsychotics taken daily orally in clinics are administered through injection, oral gavage, or minipum implant in rodents, which may induce stress and affect the results of behavioral tests. How drug administrations on behaviors and drug efficacy remains an unsolved problem. In this study, we compared the intraperitoneal injection (IP), intragastric administration (IG), and tail vein injection (TVI) on behaviors, as well as the difference between administration-induced stress and chronic unpredictable mild stress (CUMS). Next, we studied the effects of IG on CUMS model and drug efficacy. We found that IP, IG, and TVI, especially IG, induced a behavior-like phenotype of depression and anxiety, which we call the “CUMS-like behaviors”. However, such behaviors were not equal to depression. When treated CUMS mice with saline by gavage, they didn't show any aggravated phenotype compared with CUMS alone. We observed that fluoxetine by intraperitoneal injection was more effective than intragastric administration. Our study confirmed that repeated administrations lead to CUMS-like behaviors. Although these behaviors are not depression, they have adverse effects on drug efficacy.