Chronic Unpredictable Mild Stress Exposure Research Articles

Electroacupuncture Ameliorates Depressive-Like State and Synaptic Deficits Induced by Hyper-Cholinergic Tone During Chronic Stress in Rats.

BackgroundMajor depressive disorder (MDD) is the leading cause of disability around the world. It is generally agreed that the central cholinergic system plays an important role in emotional regulation. Acetylcholine (ACh) is now a new target for antidepressants. Therefore, the aim of this study was to evaluate the effect of acupuncture on depressive behaviors, cholinergic tones, and synaptic plasticity in the prefrontal cortex (PFC) in chronic unpredictable mild stress (CUMS).Material/MethodsWe randomly divided 36 male Sprague-Dawley (SD) rats into the Normal group, Stress group, Physostigmine+stress (Phys+stress) group, and Electroacupuncture+physostigmine+stress (EA+Phys+stress) group. Rats underwent CUMS exposure for 42 days. After 28 days of CUMS, rats received physostigmine or EA treatment for 2 weeks. Rats in the Phys+stress and EA+Phys+stress group received an intraperitoneal injection of physostigmine (TOCRIS, UK, 5 mg/kg) daily. Rats in the EA+Phys+stress group also received EA stimulation at GV 20 (Baihui), GV 29 (Yintang), LI 4 (Hegu), and LR 3 (Taichong) daily for 2 weeks.ResultsWe found that EA ameliorated weight loss and the depressive-like behaviors in the sucrose preference test, novelty-suppressed feeding test, and open-field test. There was significantly decreased expression of ACh and increased expression of acetylcholinesterase (AChE) after EA treatment. Consistent with the behavior tests and cholinergic tones, there were increased spine density and expressions of synaptic proteins, including brain-derived neurotrophic factor (BDNF), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), postsynaptic density protein 95 (PSD95), and synapsin I in the PFC.ConclusionsThe results suggest that EA can reverse the depressive-like behaviors and synaptic deficits induced by hyper-cholinergic tone during chronic stress via the modulation of hyper-cholinergic tone.

Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal’s ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.

Prolonged Maternal Separation Induces the Depression-Like Behavior Susceptibility to Chronic Unpredictable Mild Stress Exposure in Mice.

Early life stress is an important determinant for developing depression later in life. It is reported that maternal separation (MS) could trigger stress sensitivity in adulthood when exposed to stress again. However, it could also result in resilience to stress-induced depression. The conclusions are contradictory. To address this issue, C57BL/6N newborn pups were exposed to either daily short MS (MS for 15 min per day; MS15) or prolonged MS (MS for 180 min per day; MS180) from the first day postpartum (PD1) to PD21. Adult mice were then subjected to chronic unpredictable mild stress (CUMS) exposure from PD64 to PD105. The behavior tests such as the forced swimming test (FST), tail suspension test (TST), and open-field test were performed once a week during this time. Besides, the hippocampal neurosteroids, serum stress hormones, and hippocampal monoamine neurotransmitters were measured at PD106. We found that mice in the MS180 group displayed the reduced struggling time and the increased latency to immobility in both FST and TST. However, there was no significant difference in the MS15 group. The levels of hippocampal neurosteroids (progesterone and allopregnanolone) were decreased, and the serum levels of corticosterone, corticotropin-releasing hormone, and adrenocorticotropic hormone were overexpressed in the MS180 group. Besides, the expressions of monoamine neurotransmitters such as 5-hydroxytryptamine and 5-hydroxy indole acetic acid significantly decreased in the MS180 group, but not in the MS15 group. All findings revealed that prolonged MS, rather than short MS, could increase the susceptibility to depression-like behavior when reexposed to stress in adulthood. However, future studies are warranted to identify the underlying neuromolecular mechanism of the MS experience on the susceptibility to adult stress reexposure.

The Antidepressant-Like Effects of Shen Yuan in a Chronic Unpredictable Mild Stress Rat Model.

Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.

Anti-depressant effect of Zhi-zi-chi decoction on CUMS mice and elucidation of its signaling pathway

Ethnopharmacological relevanceZhi-zi-chi decoction (ZZCD) is used for treating depression as an effectively traditional Chinese medicine. Until now, studies on pharmacological research of ZZCD have mostly been centered in pharmacokinetic level. Little was known about its pharmacological mechanism of relieving depression. Aim of the studyThis study was to evaluate the effect of ZZCD on relieving depression via behavioral tests, serum metabolomics and signaling target expression analysis on chronic unpredictable mild stress (CUMS) model mice. Materials and methodsThe CUMS exposure lasted 7 consecutive weeks. The mice were administrated with ZZCD for the last 3 weeks. Behavioral tests were applied and a serum metabolomics method based on UFLC/Q-TOF-MS with multivariate statistical and global metabolic network analysis was performed to identify relevant metabolites and pathways. Finally, the protein expressions in mouse hippocampi were determined by western blot to verify the metabolomics deduction. ResultsBehavioral parameters were visibly changed after modeling, while high and medium dosage groups showed status improvement compared to the model group. Seventy six metabolites were identified as potential biomarkers from the metabolomics profiles in C18 and HILIC systems. In addition, 9 significant pathways related to changed biomarkers were conducted. The pathways were closely connected by some key targets, which were significantly reduced in the model group compared with those in control group, while ZZCD treated groups showed corrections after 3-week administration. The results revealed that the anti-depression efficacy of ZZCD might be associated with PKA-CREB-BDNF-TrkB-PSD-95 pathway influenced by metabolic changes, verifying the pathway annotation speculation. ConclusionThis study demonstrated that ZZCD had a positive treatment effect on CUMS depression model mice. Metabolomics results revealed the holistic and interconnected metabolic changes of ZZCD in CUMS mice. The metabolic pathway annotation suggested that the anti-depression mechanism of ZZCD might be related to signaling pathway in brain. PKA-CREB-BDNF-TrkB-PSD-95 signaling expression was a verification and complement to the metabolomics results.

Susceptibility to Hyperglycemia in Rats With Stress-Induced Depressive-Like Behavior: Involvement of IL-6 Mediated Glucose Homeostasis Signaling.

Depression is a common psychiatric disorder comorbid with diabetes and may lead to high morbidity, disability, and mortality. However, the underlying mechanism behind their association remains unknown. Cytokine-mediated inflammation in brain may play important roles in the pathogenesis of depression and insulin resistance. In the present study, we subjected the rats to chronic unpredictable mild stress (CUMS) for 3 to 8 weeks. The tests to ascertain depression-like behaviors including open field test (OFT) and forced swimming test (FST) were performed, and levels of morning fasting blood glucose, triglyceride (TG), total cholesterol (CHOL), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C), body weight, food intake, histopathological examinations of liver, adipose tissues and hypothalamus, hypothalamic GLUT4 as well as the IL-6-mediated glucose homeostasis signaling pathway were measured. The results showed that CUMS exposure resulted in the depression-like behavior at various time points in rats. Moreover, the rats exhibited increased peripheral glucose levels, impaired hepatocytes and hippocampal neurons, and decreased hypothalamic GLUT4 levels after 6 weeks of CUMS exposure. Meanwhile, activated IL-6 but suppressed IL-6-mediated glucose homeostasis signaling was observed in the hypothalamus. Markers of lipid metabolism including TG, CHOL, HDL-C and LDL-C were dysregulated, and body weight and food intake were decreased in the CUMS-exposed rats. Our results show that depressed rats induced by 6-week CUMS stimulation display susceptibility to hyperglycemia, which is associated with IL-6-mediated inhibition of glucose homeostasis signaling in the hypothalamus.

RasGRF1 participates in the protective effect of tanshinone IIA on depressive like behaviors of a chronic unpredictable mild stress induced mouse model.

Tanshinone IIA (Tan IIA) is reported to have neuroprotective effects to suppress cell apoptosis of cortical neurons induced by Aβ25-35 through inhibiting oxidative stress. Nevertheless, few studies have investigated the effects of Tan IIA on depressive disorder. Here, we aimed to measure the effects of Tan IIA on chronic unpredictable mild stress (CUMS) induced mouse model and its underlying mechanism. For 28days, mice were subjected to CUMS while Tan IIA was administered once daily at doses of 0, 1, 2.5, 5, or 10mg/kg. CUMS exposure increased depressive-like behaviors, as indicated by increased immobility time in the forced swim and tail suspension tests, decreased sucrose preference in the sucrose preference test, and reduced exploratory behavior in the open field test. All of these behaviors were reversed dose-dependently by Tan IIA treatment. Oxidative stress was determined by measuring malondialdehyde, glutathione peroxidase, and superoxide dismutase activity and total antioxidant capacity. Levels of pro-inflammatory factors IL-1β and IL-18, cAMP response element binding protein and brain derived neurotrophic factor were detected by ELISA and western blot assay, respectively. The results showed that CUMS increased oxidative stress and pro-inflammatory factors and decreased levels of cAMP response element binding protein and brain-derived neurotrophic factor. Tan IIA treatment again reversed these effects. Importantly, RasGRF1 expression increased in CUMS-exposed mice but decreased after Tan IIA administration. Using RasGRF1-/- mice to determine the role of RasGRF1 in mice exposed to CUMS, we found that knockdown of RasGRF1 reversed the effects of CUMS on mice, just like Tan IIA. These results indicate that Tan IIA may reverse depressive-like behaviors in CUMS-exposed mice by regulating RasGRF1.

Long-term maternal separation potentiates depressive-like behaviours and neuroinflammation in adult male C57/BL6J mice

Early life experience is closely related to depression caused by stress in adulthood. Early life experience, including maternal separation (MS), has been shown to evoke stress sensitivity to depression upon re-exposure to stress in adults. However, MS has also been shown to lead to resilience to stress-induced depression, which is contradictory and rarely studied. To investigate the effects of MS on depression in adults and the related mechanism, male C57/BL6J mouse pups were exposed to different MS procedures from postnatal day (PD)1 to PD21. Body weight (BW) measurements and behavioural tests (the forced swimming test (FST) and open field test (OFT)) were performed on PD41 to explore depressive and anxiety-like behaviours. Then, as adults, the mice were exposed to chronic unpredictable mild stress (CUMS) for 28 days, and then behavioural tasks were recorded. After CUMS exposure, the mice in the MS180 group (which were separated from their mothers for 3 h on PD1-PD21) showed significantly decreased time spent in the centre of the open field and reduced velocity in the OFT, a reduced latency to immobility in the FST, and decreased BW. However, the mice in the MS15 group (which were separated from their mothers for 15 min on PD1-PD21) performed similarly to NSNC mice (which were not separated from their mothers) in the behavioural tests. We further found that the expression of Iba1, a marker of neuroinflammation, was increased in the MS180 group but not in the MS15 group. In addition, our study showed decreased mRNA and protein expression of CRMP2, an important neuroprotective factor, in the MS180 group, but CRMP2 expression was unchanged in the MS15 group. This study confirmed the generation of different behavioural responses to stress exposure in adulthood due to different degrees of MS. Neuroinflammation and neuroprotection are involved, which requires further research.

Neuroprotective Effects of Fluoxetine Against Chronic Stress-Induced Neural Inflammation and Apoptosis: Involvement of the p38 Activity

Depression is considered a widespread neuropsychiatric disease associated with neuronal injury within specific brain regions. Fluoxetine, a selective serotonin reuptake inhibitor, has been widely used in depressed patients. Recently, fluoxetine has demonstrated neuroprotective effects apart from the effect on serotonin. However, the underlying mechanism involved in this neuroprotection remains unclear, in particular, whether fluoxetine exerts antidepressant effects via protecting against neuronal injury. Here, we found that treatment with fluoxetine (10 mg/kg, i.p.) for 2 weeks ameliorated depression-like behaviors in a chronic unpredictable mild stress (CUMS)-induced rat model of depression and was accompanied with an alleviation of glia activation and inhibition of interleukin-1β (IL-1β), interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α) expression in the hippocampal dentate gyrus (DG) region. Meanwhile, CUMS rats treated with fluoxetine showed reductions in neuronal apoptosis and a downregulation of the apoptotic protein Bax, cleaved caspase 3, and caspase 9 levels. These effects appear to involve a downregulation of p38 mitogen-activated protein kinase (MAPK) signaling within the DG hippocampus as the specific inhibitor of p38 MAPK, SB203580, significantly suppressed apoptosis, as well as ameliorated depressive behaviors resulting from CUMS exposure. Moreover, fluoxetine could rescue neuronal deterioration and depression-like phenotypes caused by overexpression of p38 in DG. This finding extends our knowledge on the antidepressant-like effects of fluoxetine, which appear to at least partially profit from neuroprotection against inflammation and neuronal apoptosis via downregulation of the p38 MAPK pathway. The neuroprotective mechanisms of fluoxetine may provide some novel therapeutic avenues for stress-related neurological diseases.

GRP Receptor Regulates Depression Behavior via Interaction With 5-HT2a Receptor.

ObjectiveAccumulating evidences indicate that gastrin-releasing peptide receptor (GRPR) may contribute to the pathophysiology of depression. However, the mechanism of the involvement of GRPR in the progression of depression remains unclear. Here, we showed the extent to which stress and antidepressant treatment impact GRPR expression, and explored the interactions between 5-HT2a receptor (5-HT2aR) and GRPR at the cellular level.MethodsThe rat depression models were created with chronic unpredictable mild stress (CUMS). Then, these rats were treated with fluoxetine for 4 weeks after CUMS. We measured body weight and performed behavioral tests to determine the effects of stress and fluoxetine on depressive-like behaviors. Real-time PCR and western blotting were used to measure the mRNA and protein expression levels of GRPR in the hypothalamus. Then, Flag-tagged protein (pcmv-Flag-5HT2aR) and Myc-tagged protein (pcmv-Myc-GRPR) expression vectors were constructed, identified, and transfected into human embryo kidney 293 (HEK293) cells. The interaction between 5-HT2aR and GRPR was detected by coimmunoprecipitation and double-label immunofluorescence.ResultsThe rats subjected to 4 weeks of CUMS showed depressive-like behaviors, including decreased body weight, sucrose preference, and distance traveled, rearing frequency and velocity in the open field test and increased immobility time in the forced swimming test. Fluoxetine treatment reversed CUMS-induced depressive-like behavior. The mRNA and protein expression of GRPR in the hypothalamus was significantly increased after 4 weeks CUMS exposure, and treatment with fluoxetine reversed these changes. Coimmunoprecipitation showed that 5-HT2aR and GRPR combine with each other in vitro. Immunofluorescence revealed that the 5-HT2aR and GRPR were colocalization in both the cell membrane and cytoplasm.ConclusionOur study enhances the understanding of the involvement of GRPR in depression. This study also provides in vitro experimental evidence of the interaction between 5-HT2aR and GRPR, which may play an important role in the pathogenesis of depression.

Resveratrol and quercetin attenuate depressive-like behavior and restore impaired contractility of vas deferens in chronic stress-exposed rats: involvement of oxidative stress and inflammation.

Chronic stress is associated with male sexual problems including ejaculatory dysfunctions. The aim of this study was to determine whether resveratrol (RS) or quercetin (QE) has protective effects on vas deferens (VD) contractility in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were separated into six groups: control, control + RS and control + QE, stress, stress + RS, and stress + QE. Stress groups were subjected to UCMS procedure for 5weeks. Animals in treatment groups were injected intraperitoneally with RS (20mg/kg) or QE (30mg/kg) for 5weeks during UCMS period. UCMS caused depressive-like behaviors and enhanced systemic levels of corticosterone. The nerve-evoked contractile responses of VD significantly impaired and, noradrenaline- and ATP-induced contractile responses of VD significantly increased in stressed rats. UCMS exposure also markedly enhanced oxidative stress and inflammation in VD tissues. Treatment with RS or QE significantly ameliorated all the aforementioned parameters. The current study demonstrated that RS or QE protected against chronic stress-induced VD dysfunction by their antioxidant and anti-inflammatory effects on VD, suggesting that oxidative stress and inflammation may be synergistic parts in the development of VD dysfunction associated with chronic stress-induced depression.

CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling

Depression is a complicated etiological pattern, and its pathology and effective treatments are highly limited.C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, playing crucial roles in metabolic regulatory properties. However, the effects of CTRP3 on depression are largely unknown. In the present study, we found that CTRP3 expression levels were markedly reduced in hippocampus of mice with depression induced by chronic unpredictable mild stress (CUMS). In mouse model with depression, CTRP3-deficient mice aggravated depression-associated behaviors, as evidenced by the reduced locomotor activity and sucrose consumption, while the elevated immobility time in the tail suspension test (TST) and forced swimming test (FST). Moreover, CUMS-induced neuron death and increased expression of cleaved Caspase-3 were significantly accelerated by CTRP3 knockout. Furthermore, CTRP3 deletion intensified pro-inflammatory response in CUMS-exposed mice, which was associated with the activation of nuclear factor-κB(NF-κB) signaling. The activity of mitogen-activated protein kinases (MAPKs), including p38 and JNK, was further promoted in hippocampus of CTRP3-knockout mice with CUMS exposure. In contrast,CTRP3 over-expression showed anti-apoptotic and anti-inflammatory effects in lipopolysaccharide (LPS)-treated microglial cells. Importantly, the in vitro experiments demonstrated that CTRP3 knockdown-exacerbated apoptosis and inflammatory responsewere remarkably abrogated by the blockage of p38 and JNK signaling pathways in microglia stimulated by LPS. Next, in CUMS-exposed mice with CTRP3 deficiency, suppressing p38 and JNK markedly alleviated depressive-like behavior,hippocampal neuron death, apoptosis and inflammation. Therefore, CTRP3 may be an innovative therapeutic target for treating patients with depression through regulating p38 and JNK signaling.

Chronic Unpredictable Mild Stress in Rats Induces Colonic Inflammation.

Chronic psychological stress is associated with an increased risk for relapse of inflammatory bowel diseases (IBD) and impedes the treatment of this condition. However, the impact of stress on the risk of IBD onset remains unclear. The goal of the present study was to examine whether chronic unpredictable mild stress (CUMS) could initiate or aggravate the onset of colon inflammation in rats which, in turn, would be capable of triggering bowel disease. We found that CUMS exposure increased infiltration of CD-45 positive cells and MPO activity, as well as augmented the expression of the inflammatory cytokines, IFN-γ and IL-6 within the colon of these rats. In addition, CUMS treatment changed the composition and diversity of gut microbiota and enhanced intestinal epithelial permeability, indicating the presence of a defect in the intestinal barrier. This CUMS-induced disruption of mucosal barrier integrity was associated with a reduction in expression of the tight junction protein, occludin 1, and an inhibition in mucosal layer functioning via reductions in goblet cells. Results from bacterial cultures revealed an increased presence of bacterial invasion after CUMS treatment as compared with that observed in controls. Thus, our data indicate that CUMS treatment induces alterations of the fecal microbiome and intestinal barrier defects, which facilitates bacterial invasion into colonic mucosa and further exacerbates inflammatory reactions within the colon. Accordingly, chronic stress may predispose patients to gastrointestinal infection and increase the risk of inflammation-related gut diseases.

Cang-ai volatile oil improves depressive-like behaviors and regulates DA and 5-HT metabolism in the brains of CUMS-induced rats

Ethnopharmacological relevanceCang-ai volatile oil (CAVO) is a traditional Chinese medicine (TCM) inhalational preparation for the treatment of some depressive and emotive disorders. Aim of the studyThis research aimed to evaluate the efficiency and possible mechanism of intranasal CAVO administration on depression in chronic unpredictable mild stress (CUMS)-induced rats compared to lavender volatile oil (LVO) treatment after CUMS exposure and bilateral olfactory bulb impairment (OBI) in rats. Materials and methodsForty depressive-like model rats induced by CUMS were evaluated by the forced swim test (FST), open field test (OFT), and sucrose preference test (SPT). The model rats were divided into five groups: CUMS (n = 8), CAVOh + CUMS (n = 8), CAVOl + CUMS (n = 8), LVO + CUMS (n = 8), and OBI + CAVO + CUMS (n = 8). The CUMS-induced rats were treated for a period of 4 weeks. The other healthy rats were regarded as the control (CTR, n = 8) subjects. The levels of serotonin (5-HT) and dopamine (DA) and their respective metabolites homovanillic acid (HVA) and 5-hydroxyindol acetic acid (5-HIAA) were measured in brain tissue homogenates of CUMS-induced rats using enzyme-linked immunosorbent assay (ELISA). ResultsCAVO ameliorated depressive-like behaviors (p < 0.05). The levels of DA in the CUMS group were lower than those in the CTR and CAVOh groups (**p < 0.01 and *p < 0.05). The levels of HVA were lower in the CUMS group than in the CTR, LVO, OBI + CAVOh and CAVOh groups (**p < 0.01 and *p < 0.05) and lower in the OBI + CAVOh group than in the CAVOh group (**p < 0.01). The levels of 5-HT in the CUMS group were lower than those in the CTR and CAVOh groups (**p < 0.01). The levels of 5-HIAA were lower in the CUMS and OBI + CAVOh groups than in the CTR, LVO and CAVOh groups (**p < 0.01). ConclusionsCAVO can improve depressive-like behaviors concomitant with the regulation of DA and 5-HT metabolism in the brains of CUMS-induced rats.

The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice

Ghrelin is an orexigenic hormone that also plays an important role in mood disorders. Our previous studies demonstrated that ghrelin administration could protect against depression-like behaviors of chronic unpredictable mild stress (CUMS) in rodents. However, the mechanism related to the effect of ghrelin on CUMS mice has yet to be revealed. This article shows that ghrelin (5 nmol/kg/day for 2 weeks, i.p.) decreased depression-like behaviors induced by CUMS and increased hippocampal integrity (neurogenesis and spine density) measured via Ki67, 5-bromo-2-deoxyuridine (BrdU), doublecortin (DCX) labeling and Golgi-cox staining, which were decreased under CUMS. The behavioral phenotypes of Growth hormone secretagogue receptor (Ghsr)-null and wild type (WT) mice were evaluated under no stress condition and after CUMS exposure to determine the effect of Ghsr knockout on the behavioral phenotypes and stress susceptibility of mice. Ghsr-null mice exhibited depression-like behaviors under no stress condition. CUMS induced similar depression- and anxiety-like behavioral manifestations in both Ghsr-null and WT mice. A similar pattern of behavioral changes was observed after hippocampal GHSR knockdown. Additionally, both Ghsr knockout as well as CUMS exhibited deleterious effects on neurogenesis and spine density in the dentate gyrus (DG). Besides, CCK8 assay and 5-Ethynyl-2′-deoxyuridine (EdU) incorporation assay showed that ghrelin has a proliferative effect on primary cultured hippocampal neural stem cells (NSCs) and this proliferation was blocked by D-Lys3-GHRP-6 (DLS, the antagonist of GHSR, 100 μM) pretreatment. Ghrelin-induced proliferation is associated with the inhibition of G1 arrest, and this inhibition was blocked by LY294002 (specific inhibitor of PI3K, 20 μM). Furthermore, the in vivo data displayed that LY294002 (50 nmol, i.c.v.) can significantly block the antidepressant-like action of exogenous ghrelin treatment. All these results suggest that ghrelin/GHSR signaling maintains the integrity of hippocampus and has an inherent neuroprotective effect whether facing stress or not.

Resveratrol and dimethyl fumarate ameliorate testicular dysfunction caused by chronic unpredictable mild stress-induced depression in rats

Chronic stress is a major factor contributing to male infertility. Increasing evidence has demonstrated that resveratrol or dimethyl fumarate (DMF) has antioxidant and anti-inflammatory functions. Our study aimed to evaluate the protective effects of resveratrol or DMF against testicular dysfunction associated with chronic unpredictable mild stress (CUMS)-induced depression in rats. Rats were subjected to 8 weeks of CUMS to induce depressive−like symptoms. CUMS-induced depressive-like behaviours in rats were evidenced by increased serum corticosterone levels and decreased serum and hippocampal serotonin levels as well as decreased hippocampal BDNF levels. CUMS significantly reduced sucrose preference and increased immobility time in stressed rats. Furthermore, CUMS exposure resulted in a significant decrease in serum testosterone levels and testicular expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage (CYP450scc) enzyme and C-kit. CUMS significantly decreased and increased testicular expression of β-catenin and GSK-3β, respectively. CUMS also resulted in a significant increase in testicular expression of NF-κB, TNF-α, IL-Iβ, and Bax and decreased Bcl-2 expression levels. CUMS increased testicular MDA levels and significantly decreased testicular GSH and serum total antioxidant capacity levels. The histopathological results provided evidence for the biochemical and molecular analyses. All of these effects were significantly ameliorated by the administration of resveratrol or DMF. In conclusion, our study reveals that resveratrol or DMF exert profound testicular protective effects in CUMS rats that are mediated in part by suppressing oxidative stress, inflammation, and apoptosis leading to the upregulation of serum testosterone levels, and testicular StAR, CYP450scc, c-kit and β-catenin levels.

N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat.

Depression is a heterogeneous disorder and associated with inflammatory responses. The influences of N-acetylcysteine (NAC) on neuroinflammation associated depression-like behavior have not been investigated yet, and associated biochemical changes are currently unclear. Therefore, we assessed the effects of NAC on neuroinflammation associated depression-like behavior induced through chronic unpredictable mild stress (CUMS) in rats. The antidepressant-like effect of NAC was depicted using the sucrose preference test and the forced swimming test (FST) while CUMS-induced alteration in the locomotor index was measured using the open field test (OFT) and actophotometer. Our results revealed that CUMS exposure markedly aggravated depression-like behavior, the levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and reduced the serotonin levels. One-week consecutive NAC (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o., a selective serotonin reuptake inhibitor) treatment significantly increased sucrose preference index, reduced immobility time in the FST, and the increased the number of squares crossed, number of rearing in the OFT and locomotion in the actophotometer in the CUMS-exposed rats. Moreover, the levels of pro-inflammatory cytokines in the hippocampus as well as pre-frontal cortex were suppressed, and remarkably restored the serotonin levels by NAC (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) administration. However, NAC (25 mg/kg, p.o.) exerted insignificant protection against CUMS-induced depressive-like behavior and associated neuro-inflammation. This study demonstrates that NAC exhibited the antidepressant-like effect in the CUMS-exposed rats, which might be mediated by anti-inflammatory potential and restoring serotonergic responses in the stressed rats.

Neuroprotective Effects of Ginsenoside-Rg1 Against Depression-Like Behaviors via Suppressing Glial Activation, Synaptic Deficits, and Neuronal Apoptosis in Rats.

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.

Curcumin Protects Against Chronic Stress-induced Dysregulation of Neuroplasticity and Depression-like Behaviors via Suppressing IL-1β Pathway in Rats

Accumulating evidence has accrued demonstrating that inflammatory processes in the central nervous system (CNS) are associated with various neurological disorders including depression. However, whether inflammation-mediated neuronal damage is involved in depression-like behaviors induced by chronic stress and, in particular, whether suppression of inflammation could then serve as a potential strategy in depression therapy remains largely unknown. The present study aimed to investigate the neuronal mechanisms and signaling pathways through which inflammation results in neuronal deterioration in a rat model of depression and thus identify agents with potential roles as antidepressant treatments. Our results showed that chronic unpredictable mild stress (CUMS) exposure induced microglia activation and overexpression of the cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α) within the medial prefrontal cortex (mPFC), effects which were paralleled with neuronal structural changes. In contrast, chronic administration of either IL-1β or nuclear factor κB (NF-κB) antagonists significantly ameliorated this dysregulation of neuronal structure and biochemical parameters such as SSH1 and phospho-cofilin within the mPFC, as well as the display of depression-like behaviors induced by CUMS exposure. More importantly, pretreatment with curcumin (40 mg/kg, i.p., 5 weeks), produced antidepressant-like actions and repressed the inflammatory responses and neuronal structural abnormalities. These findings reveal some of the molecular neuroinflammation pathways associated with depression and suggest new avenues of investigation for the development of potential antidepressant therapies in the treatment of inflammation-related neuronal deterioration in this disorder.

Resveratrol and dimethyl fumarate ameliorate depression-like behaviour in a rat model of chronic unpredictable mild stress

Chronic stress occurs in everyday life and induces depression. Emerging evidence shows that oxidative stress, inflammation and apoptosis are main contributing pathophysiologic mechanisms of depression. Resveratrol and dimethyl fumarate (DMF) are natural antioxidants that have diverse biological activities. Our study aimed to determine whether resveratrol and DMF affected these systems in rats exposed to chronic unpredictable mild stress (CUMS)-induced depression-like behaviours. Rats were submitted to 8 weeks of CUMS to induce depressive-like behaviour. The depressive-like behaviour of rats induced by CUMS was revealed by an elevated serum corticosterone level and decreased serum and hippocampal serotonin levels. Our results showed that CUMS significantly-induced behavioural abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CUMS exposure significantly decreased BDNF and β-catenin expression levels as well as increased GSK-3β expression level in hippocampus. Furthermore, CUMS exposure resulted in a significant increase in expression levels of NF-κB, TNF-α and IL-Iβ accompanied by decreased Bcl-2 expression level. CUMS increased hippocampal MDA level and significantly decreased hippocampal GSH and serum total antioxidant capacity levels compared to the control group. Histopathological examinations provided evidence for the biochemical and molecular analysis. All of these effects were significantly ameliorated by administration of resveratrol and DMF. In conclusion, our study revealed that resveratrol and DMF exerted promising antidepressant-like effects in CUMS rats that are mediated in part by suppressing the neuroinflammation, oxidative stress, apoptosis and up-regulating hippocampal BDNF and β-catenin levels. Serum serotonin analysis may be a reliable indicator for monitoring depression.