Weeks Of Chronic Unpredictable Mild Stress Research Articles

Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats

PurposeChronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. MethodsIn vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. ResultsDecreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. ConclusionThese findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

Human umbilical cord mesenchymal stem cells reverse depression in rats induced by chronic unpredictable mild stress combined with lipopolysaccharide.

Inflammation and oxidative stress are considered crucial to the pathogenesis of depression. Rat models of depression can be created by combined treatments of chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS). Behaviors associated with depression could be improved by treatment with mesenchymal stem cells (MSCs) owing to immunomodulatory functions of the cells. Therapeutic potentials of the MSCs to reverse pro-inflammatory cytokines, proteins, and metabolites were identified by transcriptomic, proteomic, and metabolomic analysis, respectively. A depression model was established in male SD rats by 2 weeks of CUMS combined with LPS. The models were verified by behavioral tests, namely SPT, OFT, EPM, and qRT-PCR for pro-inflammatory cytokines. Such depressed rats were administered human umbilical cord MSCs (hUC-MSCs) via the tail vein once a week for 2 and 4 weeks. The homing capacity was confirmed by detection of the fluorescent dye on day 7 after the hUC-MSCs were labeled with CM-Dil and administered. The expression of GFAP in astrocytes serves as a biomarker of CNS disorders and IBA1 in microglia serves as a marker of microglia activation were detected by immunohistochemistry at 2 and 4 weeks after final administration of hUC-MSCs. At the same time, transcriptomics of rat hippocampal tissue, proteomic and metabolomic analysis of the serum from the normal, depressed, and treated rats were also compared. Reliable models of rat depression were successfully induced by treatments of CUMS combined with LPS. Rat depression behaviors, pro-inflammatory cytokines, and morphological disorders of the hippocampus associated with depression were reversed in 4 weeks by hUC-MSC treatment. hUC-MSCs could reach the hippocampus CA1 region through the blood circulation on day 7 after administration owing to the disruption of blood brain barrier (BBB) by microglial activation from depression. Differentiations of whole-genome expression, protein, and metabolite profiles between the normal and depression-modeled rats, which were analyzed by transcriptomic, proteomics, and metabolomics, further verified the high association with depression behaviors. Rat depression can be reversed or recovered by treatment with hUC-MSCs.

Potential antidepressant-like effects of N-3 polyunsaturated fatty acids through inhibition of endoplasmic reticulum stress.

The growing evidence has demonstrated the importance of endoplasmic reticulum stress (ERS) in the pathophysiology of depression. ERS genes were considered to be potential novel therapeutic targets for depression. To clarify the mechanisms of the chronic unpredictable mild stress (CUMS)-induced ERS response and the potential contributing pathways in depression, and further investigate the potential link between N-3 polyunsaturated fatty acids (PUFAs) and stress-induced ERS disturbances. This study analyzed the expression of ERS-related genes including GRP78, ATF-4, ATF-6, XBP-1, and CHOP, and sigma-1R with real-time PCR in peripheral blood mononuclear cell (PBMC) RNA samples from participants. All of the rats except for those in the control groups were subjected to 5 consecutive weeks of CUMS to establish the depression model, and the antidepressant effects of N-3 PUFAs were observed by behavior tests. Moreover, the effect of diet and stress on the ERS pathways was also investigated using the western blot. Blood CHOP, ATF-4, and XBP-1 levels were notably elevated in depressed patients relative to healthy individuals. Moreover, increased sigma-1R and decreased ATF-6 implied the protective role of sigma-1R through modulating ERS in patients with depression. Animal studies disclosed the novel findings that supplementary N-3 PUFAs in rats alleviated CUMS-induced disturbance of ERS through the ATF-4/XBP-1/CHOP pathway, implying its potential strategy for depression. CUMS-induced depressive-like behaviors are related to the disturbance of ERS. Furthermore, supplementary N-3 PUFAs might be an effective way to alleviate ERS.

Resveratrol Attenuates Chronic Unpredictable Mild Stress-Induced Alterations in the SIRT1/PGC1α/SIRT3 Pathway and Associated Mitochondrial Dysfunction in Mice.

Environmental challenges, specifically chronic stress, have long been associated with neuropsychiatric disorders, including anxiety and depression. Sirtuin-1 (SIRT1) is a NAD+-dependent deacetylase that is widely distributed in the cortex and is involved in stress responses and neuropsychiatric disorders. Nevertheless, how chronic stress modulates the SIRT1 pathway and associated signaling remains unclear. In this study, we first explored the impact of chronic unpredictable mild stress (CUMS) on the SIRT1/PGC1α/SIRT3 pathway, on GABAergic mechanisms, and on mitophagy, autophagy and apoptosis in mice. We also asked whether activation of SIRT1 by resveratrol (RSV) can attenuate CUMS-induced molecular and behavioral alterations. Two-month-old C57/BL6J mice were subjected to three weeks of CUMS and one week of RSV treatment (30mg/kg; i.p.) during the third week of CUMS. CUMS caused downregulation of the SIRT1/PGC1α/SIRT3 pathway leading to impaired mitochondrial morphology and function. CUMS also resulted in a reduction in numbers of parvalbumin-positive interneurons and increased oxidative stress leading to reduced expression of autophagy- and mitophagy-related proteins. Strikingly, activation of SIRT1 by RSV ameliorated expression of SIRT1/PGC1α/SIRT3, and also improved mitochondrial function, GABAergic mechanisms, mitophagy, autophagy and apoptosis. RSV also rescued CUMS-induced anxiety-like and depressive-like behavior in mice. Our results raise the compelling possibility that RSV treatment might be a viable therapeutic method of blocking stress-induced behavioral alterations.

Repetitive Transcranial Magnetic Stimulation Improves Depression-like Behavior in Rats by Promoting Neural Stem Cell Proliferation and Differentiation

Repetitive transcranial magnetic stimulation (rTMS) is a novel non-invasive neuromodulation technique with neuroprotective properties and is used to treat depression. However, the underlying mechanism of action remains unclear. In this study, we examined the possible mechanism mediating the antidepressant effect of rTMS using animal experiments. Specific pathogen-free rats were treated with rTMS after exposure to social isolation combined with chronic unpredictable mild stress (CUMS). After four weeks of CUMS, the rats exhibited a significant decrease in spatial working memory assessed using open-field testing, a general loss of interest assessed with the sucrose preference test, and a significant reduction in spatial recognition memory ability assessed using the Y-maze. These behavioral deficits were accompanied by decreased numbers of astrocytes in the hippocampus, decreased expression of glial fibrillary acidic protein (GFAP), increased numbers of neural stem cells (NSCs), and increased expression of nestin protein. These results indicated that neuron damage occurred in the depression-like rats. After rTMS intervention, the depression-like behavior was alleviated significantly, and the numbers of NSCs and astrocytes, as well as the expression of GFAP and nestin proteins, returned to normal levels. Overall, it is likely that attenuation of NSC proliferation and differentiation into astrocytes produced a neuroprotective effect on hippocampal neurons, which might partly explain the mechanism by which rTMS alleviates depression.

Effect of Epigallocatechin-3-gallate on Stress-Induced Depression in a Mouse Model: Role of Interleukin-1β and Brain-Derived Neurotrophic Factor

Epigallocatechin 3-gallate (EGCG) is a natural polyphenolic antioxidant in green tea leaves with well-known health-promoting properties. However, the influence of EGCG on a chronic animal model of depression remains to be fully investigated, and the details of the molecular and cellular changes are still unclear. Therefore, the present study aimed to investigate the antidepressant effect of EGCG in mice subjected to chronic unpredictable mild stress (CUMS). After eight consecutive weeks of CUMS, the mice were treated with EGCG (200 mg/kg b.w.) by oral gavage for two weeks. A forced swimming test (FST) was used to assess depressive symptoms. EGCG administration significantly alleviated CUMS-induced depression-like behavior in mice. EGCG also effectively decreased serum interleukin-1β (IL-1β) and increased the mRNA expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampal CA3 region of CUMS mice. Furthermore, electron microscopic examination of CA3 neurons in CUMS mice showed morphological features of apoptosis, loss or disruption of the myelin sheath, and degenerating synapses. These neuronal injuries were diminished with the administration of EGCG. The treatment effect of EGCG in CUMS-induced behavioral alterations was comparable with that of clomipramine hydrochloride (Anafranil), a tricyclic antidepressant drug. In conclusion, our study demonstrates that the antidepressive action of EGCG involves downregulation of serum IL-1β, upregulation of BDNF mRNA in the hippocampus, and reduction of CA3 neuronal lesions.

Chronic clomipramine treatment increases hippocampal volume in rats exposed to chronic unpredictable mild stress

It is well known that neuroinflammation is closely related to the pathophysiology of depression. Due to individual differences in clinical research, the reduction of hippocampal volume in patients with depression is still controversial. In this experiment, we studied a typical kind of tricyclic antidepressant, clomipramine. We designed a series of experiments to find its role in depressive-like behavior, hippocampal neuroinflammation as well as hippocampal volume changes induced by chronic unpredictable mild stress (CMS). Rats exhibited defective behavior and hippocampal neuroinflammation after 12 weeks of CMS, which included elevated expression of cleaved interleukin-1β (IL-1β) and NLRP3 inflammasome together with the activation of microglia. Rats exposed to CMS showed weakened behavioral defects, reduced expression of IL-18, IL-6, and IL-1β along with reversed activation of microglia after clomipramine treatment. This indicates that the antidepressant effect of clomipramine may be related to the reduced expression of NLRP3 inflammasome and cleaved IL-1β. Moreover, we found an increased hippocampal volume in rats exposed to CMS after clomipramine treatment while CMS failed to affect hippocampal volume. All these results indicate that the NLRP3 inflammasome of microglia in the hippocampus is related to the antidepressant effects of clomipramine and CMS-induced depressive-like behavior in rats.

The Impact of Chronic Unpredictable Mild Stress-Induced Depression on Spatial, Recognition and Reference Memory Tasks in Mice: Behavioral and Histological Study.

Depression-induced cognitive impairment has recently been given more attention in research. However, the relationship between depression and different types of memory is still not clear. Chronic unpredictable mild stress (CUMS) is a commonly used animal model of depression in which animals are exposed to chronic unpredictable environmental and psychological stressors, which mimics daily human life stressors. This study investigated the impact of different durations of CUMS on various types of memory (short- and long-term spatial memory and recognition memory) and investigated CUMS’ impact on the ultrastructural level by histological assessment of the hippocampus and prefrontal cortex. Twenty male C57BL/J6 mice (6 weeks old, 21.8 ± 2 g) were randomly divided into two groups (n = 10): control and CUMS (8 weeks). A series of behavioral tasks were conducted twice at weeks 5–6 (early CUMS) and weeks 7–8 (late CUMS). A tail-suspension test (TST), forced swimming test (FST), elevated zero maze (EZM), elevated plus maze (EPM), open field test (OFT), and sucrose-preference test (SPT) were used to assess anxiety and depressive symptoms. The cognitive function was assessed by the novel object recognition test (NORT; for recognition memory), Y-maze (for short-term spatial memory), and Morris water maze (MWM: for long-term spatial memory) with a probe test (for reference memory). Our data showed that 8 weeks of CUMS increased the anxiety level, reported by a significant increase in anxiety index in both EPM and EZM and a significant decrease in central preference in OFT, and depression was reported by a significant increase in immobility in the TST and FST and sucrose preference in the SPT. Investigating the impact of CUMS on various types of memory, we found that reference memory is the first memory to be affected in early CUMS. In late CUMS, all types of memory were impaired, and this was consistent with the abnormal histological features of the memory-related areas in the brain (hippocampus and prefrontal cortex).

Effect Of Aerobic Exercise On The Learning And Memorizing Abilities And Hippocampal Psd-95 In Depressive Rats

PURPOSE: 4 weeks of CUMS (Chronic Unpredictable Mild Stress) was to build depressive rats and investigate the effect of an aerobic exercise intervention on hippocampal PSD-95 (postsynaptic density-95) expression and spatial learning and memorizing ability. METHODS: 30 male SD rats randomly divided into 3 groups: the Control group (C), the Model group (M), and the Exercise group (E). M and E were subjected to CUMS stimulation and/or aerobic exercise for 4 weeks respectively. E received swimming training for 4 weeks (60 min/day, 6 days/week). OFT was used to test CUMS related anxiety-like behavior in order to detect the success of model. MWM was performed to evaluate their spatial learning and memorizing ability. The expression of PSD-95 was tested by RT-PCR and WB. The experimental data was reported as mean ± SE. A statistical significant level was defined when P < 0.05. RESULTS: 1) OFT: CUMS can decrease the central zone duration and exercise alleviates anxiety-like behavior (C:16.02 ± 7.96; M:8.3 ± 1.25; E:22.61 ± 10.7, P < 0.05); 2)MWM detection: during 6 days of the navigation experiment, M showed more difficulty to find the platform compared with C and E(P < 0.05), while there was no significant difference between C and E (P > 0.05); During the space exploring experiment, M spent much time to find the platform compared with C and E (C:3.14 ± 0.38; M:1.57 ± 0.79; E:2.57 ± 0.53, P < 0.05); 3) mRNA and protein detection: compared with C, the mRNA(C:1.29 ± 0.39; M:0.56 ± 0.19; E:1.21 ± 0.11) and protein level of PSD-95 (C:0.99 ± 0.05; M:0.77 ± 0.05; E:1.19 ± 0.09) significantly decreased in group M, while increased in group E(P < 0.05). CONCLUSIONS: 4 weeks of aerobic exercise intervention effectively reverses the depression symptoms and improves their spatial learning and memorizing ability in rats pretreated by CUMS stimulation. In addition, aerobic exercise can rescue and significantly up-regulate the expression of PSD-95 in hippocampus which suppressed by CUMS stimulation. In summary, this study demonstrated the improvement of CUMS-associated learning and memorizing ability by exercise via enhanced expression of PSD-95 in hippocampus.

Baicalin ameliorates chronic unpredictable mild stress-induced depression through the BDNF/ERK/CREB signaling pathway

Brain-derived neurotrophic factor (BDNF) can activate the extracellular regulated protein kinase (ERK)/cAMP response element binding protein (CREB) cascade revealing an important role in antidepressant effects. Here, we studied the neuroprotective effect of baicalin (BA) in mice with chronic unpredictable mild stress (CUMS)-induced via a BDNF/ERK/CREB signaling pathway. Depression was induced via six weeks of CUMS in male ICR mice, and drug therapy was given simultaneously for the last three weeks. Cognitive dysfunctions were then evaluated via sucrose preference test (SPT), open field test (OFT), Morris water maze test (MWM), tail suspension test (TST), and novelty suppressed feeding test (NSF). Western blot and real-time PCR were then used to detect the relative expression of ERK, CREB, p-ERK, and p-CREB. Integrated optical density (IOD) tests of p-ERK and p-CREB were then evaluated via immunofluorescence. The behavior results showed that the cognitive dysfunctions increased in the CUMS group versus the control (CON) group (p < 0.01). There were decreases in fluoxetine (FLU) and BA groups (p < 0.05, p < 0.01). The protein ratios of p-ERK/ERK, p-CREB/CREB and ERK mRNA, and CREB mRNA expression decreased in the CUMS group (p < 0.01) and markedly increased in the FLU and BA groups (p < 0.05, p < 0.01). The IOD value of the p-ERK and p-CREB in the CUMS group was decreased versus the CON group (p < 0.01), and these changes were improved via BA and FLU treatment (p < 0.05, p < 0.01). This study indicated that BA can improve cognitive functions and has antidepressant effects in mice, which may be associated with activation of the BDNF/ERK/CREB signaling pathway in the hippocampus.

Asparagus cochinchinensis extract ameliorates menopausal depression in ovariectomized rats under chronic unpredictable mild stress

BackgroundDepression is a serious and common psychiatric disorder generally affecting more women than men. A woman’s risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model.MethodsTo model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6 weeks, which promotes the development of depression-like symptoms. During the final 4 weeks of CUMS, rats were treated with either AC extract (1000 or 2000 mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10 mg/kg, IP).ResultsWe report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels.ConclusionThese results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.

C-low threshold mechanoafferent targeted dynamic touch modulates stress resilience in rats exposed to chronic mild stress.

Affiliative tactile interactions buffer social mammals against neurobiological and behavioral effects of stress. The aim of this study was to investigate the cutaneous mechanisms underlying such beneficial consequences of touch by determining whether daily stroking, specifically targeted to activate a velocity/force tuned class of low-threshold c-fiber mechanoreceptor (CLTM), confers resilience against established markers of chronic unpredictable mild stress (CMS). Adult male Sprague Dawley rats were exposed to 2weeks of CMS. Throughout the CMS protocol, some rats were stroked daily, either at CLTM optimal velocity (5cm/s) or outside the CLTM optimal range (30cm/s). A third CMS exposed group did not receive any tactile stimulation. The effect of CMS on serum corticosterone levels, anxiety- and depressive-like behaviors in these three groups was assessed in comparison to a control group of non-CMS exposed rats. While stroking did not mitigate the effects of CMS on body weight gain, CLTM optimal velocity stroking did significantly reduce CMS-induced elevations in corticosterone following an acute forced-swim. Rats receiving CLTM optimal stroking also showed significantly fewer anxiety-like behaviors (elevated plus-maze) than the other CMS exposed rats. In terms of depressive-like behavior, whereas the same velocity-specific resilience was observed in a forced-swim test and social interaction test both groups of stroked rats spent significantly less time interacting than control rats, though they also spent significantly less time in the corner than non-stroked CMS rats. Together, these findings support the theory CLTMs play a functional role in regulating the physiological condition of the body.

Urine metabolomic responses to aerobic and resistance training in rats under chronic unpredictable mild stress.

BackgroundIt is known that bioenergetics of aerobic and resistance exercise are not the same but both can effectively improve depression. However, it is not clear whether and how different types of exercise can influence depression through the same metabolic regulatory system. Metabolomics provides a way to study the correlation between metabolites and changes in exercise and/or diseases through the quantitative analysis of all metabolites in the organism. The objective of this study was to investigate the effects of aerobic and resistance training on urinary metabolites by metabolomics analysis in a rodent model of depression.MethodsMale Sprague-Dawley rats were given chronic unpredictable mild stress (CUMS) for eight weeks. The validity of the modeling was assessed by behavioral indices. After four weeks of CUMS, the rats that developed depression were randomly divided into a depression control group, an aerobic training group and a resistance training group. There was also a normal control group. From week 5, the rats in the exercise groups were trained for 30 min per day, five days per week, for four weeks. The urine samples were collected pre and post the training program, and analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy.ResultsBoth types of training improved depression-like behavior in CUMS rats. Compared with normal control, 21 potential biomarkers were identified in the urine of CUMS rats, mainly involved in energy, amino acids and intestinal microbial metabolic pathways. Common responses to the training were found in the two exercise groups that the levels of glutamine, acetone and creatine were significantly recalled (all P<0.05) Aerobic training also resulted in changes in pyruvate and trigonelline, while resistance training modified α-Oxoglutarate, citric acid, and trimethylamine oxide (all P<0.05).ConclusionsAerobic and resistance training resulted in common effects on the metabolic pathways of alanine-aspartate-glutamate, TCA cycle, and butyric acid. Aerobic training also had effects on glycolysis or gluconeogenesis and pyruvate metabolism, while resistance training had additional effect on intestinal microbial metabolism.

Effect Of Aerobic Exercise On The Learning And Memorizing Abilities And Hippocampal Vegf In Depressive Rats

PURPOSE: Depression model building in rats based on 4 weeks of CUMS (Chronic Unpredictable Mild Stress) and the investigation of the effect of aerobic exercise intervention on hippocampal VEGF expression and spatial learning and memorizing ability in depressive model rats. METHODS: 30 male SD rats randomly divided into 3 groups: the Control group (C), the Model group (M), and the Exercise group (E). M and E were subjected to CUMS stimulation and/or aerobic exercise for 4 weeks respectively. E received swimming training for 4 weeks (60 min/day, 6 days/week). SPT was used to test rat’s sucrose preference and detect the success of model. MWZ was performed to evaluate their spatial learning and memorizing ability. The expression of VEGF was tested by RT-PCR and WB. The experimental data was reported as mean±SE. The threshold of significance level was set at P<0.05. RESULTS: 1) SPT: there was no difference in the total water consumption in each group (P >0.05). But depressive rats (M: 36.67±10.61; E:36.00±16.43) showed significant difference compared with C in consumption of sugar water (C:53.83±10.93, P<0.05); 2)MWM detection: during 6 days of navigation experiment, M showed more difficulty to find the platform compared with C and E(P<0.05), while there was no significant difference between C and E (P>0.05); During the space exploring experiment, M spent much time to find the platform compared with C and E (C:3.14±0.38; M:1.57±0.79; E:2.57±0.53, P<0.05); 3) mRNA and protein detection: compared with C, the mRNA(C:1.24±0.22;M:0.57±0.25;E:1.14±0.07) and protein level of VEGF (C:0.90±0.06;M:0.52±0.11;E:0.81±0.05) significantly decreased in group M, while increased in group E(P<0.05). CONCLUSIONS: 4 weeks of aerobic exercise intervention effectively reverses the depression symptoms and improves their spatial learning and memorizing ability in rats pretreated by CUMS stimulation. In addition, aerobic exercise can rescue and significantly up-regulate the expression of VEGF in hippocampus which suppressed by CUMS stimulation. The correlation between the VEGF expression level and depressive behaviors in rats suggests that the enhanced expression of VEGF in hippocampus might be one of the neurobiological mechanisms mediating the effects of aerobic exercise on depression and spatial learning and memorizing ability.

Antidepressant-Like Effects of Chaihu Shugan Powder () on Rats Exposed to Chronic Unpredictable Mild Stress through Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis.

To investigate the antidepressant-like effects of Chaihu Shugan Powder (CSP, ) and to explore its underlying mechanisms. Thirty-two Sprague-Dawley rats were randomly divided into control (CON), chronic unpredictable mild stress (CUMS), fluoxetine (FLU), and CSP groups, 8 rats in each group. All of the rats except for those in the control group were subjected to 3 consecutive weeks of CUMS to establish the depression model. The open field test (OFT), forced swimming test (FST), and sucrose preference test were used to assess the anti-anxiety and antidepressant effects of CSP. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling was used to determine the apoptosis rate in the hippocampal tissues. The mRNA and protein levels of glucose-regulated protein (GRP) 78, spliced X-box-binding protein (XBP)-1, CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and c-Jun N-terminal kinase (JNK) in the hippocampus of rats were evaluated by real-time PCR and Western blot analysis, respectively. Administration of CSP alleviated anxiety and depression-like behavior in CUMS rats, as revealed by enhanced time and distance in the center of the OFT (P<0.05), an increased preference for sucrose, and longer swimming time and shorter immobility time during the FST (all P<0.05). In addition, CSP treatment significantly reduced the rate of apoptosis in rat hippocampal neurons (P<0.05). The mRNA and protein expression levels of GRP78, spliced XBP-1, and CHOP were down-regulated along with the expression of caspase-12 and cleaved caspase-12 proteins (all P<0.05), whereas total and phosphorylated JNK1 protein levels did not differ significantly between control and CSP-treated rats. CSP can improve depression-like behavior in rats exposed to CUMS, possibly by suppressing CHOP and caspase-12 mediated apoptosis in the rat hippocampus.

Valproic acid administration exerts protective effects against stress-related anhedonia in rats

Anhedonia or inability to experience pleasure is the sign of various neuropsychiatric conditions. Current treatment options do not provide adequate control of anhedonia. The present study was conducted to evaluate the protective effects of valproic acid (VPA) as a nonspecific histone deacetylase (HDAC) inhibitor to reverse the effects of stress on induction of anhedonia and explore possible mechanisms.To induce anhedonia, a rat model of chronic unpredictable mild stress (CUMS) was established. Animals were assigned into no stress, stress (6 weeks of CUMS) and two treatment groups. VPA treatment was carried out for 4 continuous weeks (200 mg/kg/day). Behavioral assessments were performed using sucrose consumption (SCT) and new object recognition (NOR) tests. The expression of genes was evaluated using qRT-PCR. The cell density was determined using Nissl staining.Rats with CUMS showed depressive-like behaviors and impaired memory performance compared with the non-stressed group (p < 0.01). Moreover, they had significantly higher levels of HDAC3 and MC4R expression in the nucleus accumbens (NAc) compared to the non-stressed group (p < 0.01). The NAc cell density was significantly higher in the non-stressed rats (p < 0.05). Corticosterone plasma level was increased in the CUMS compared to the non-stressed group (p < 0.05). In the CUMS + VPA subgroup, the corticosterone (CORT) plasma level was lower compared with the CUMS + Saline and/or the CUMS groups (p < 0.05).These findings suggest that VPA can improve anhedonia and stress. Although the protective effect of VPA might link to decreasing HDAC3 and MC4R genes expression in NAc.

Ameliorative effect of anthocyanin on depression mice by increasing monoamine neurotransmitter and up-regulating BDNF expression

• Total anthocyanin content of purple cauliflower is higher than the usual vegetable. • The PAPC was first found to ameliorate the depression in mice. • PAPC ameliorated depression by increase neurotransmitters and BDNF expression. Anthocyanin is a plant-specific secondary metabolite with various bioactivities. Purple cauliflower is an emerging vegetable which rich in anthocyanins by breed improvement in recent years. In this study, effects and relevant mechanisms of purified anthocyanin from purple cauliflower (PAPC) on chronic unpredictable mild stress (CUMS)-induced mice model of depression were investigated. After three weeks of CUMS induced, the mice were intragastric administration with PAPC for six weeks. The results showed that PAPC treatment significantly improved depression-like behaviors in mice following CUMS, increased monoamine neurotransmitter content and inhibited monoamine oxidases (MAO) in the brain. It also increased the expression of tyrosine receptor kinase B, brain-derive neurotrophic factor (BDNF), phosphorylation levels of extracellular-regulated kinase 1/2 (ERK1/2) and cAMP-responsive binding element (CREB) in hippocampus. And PAPC treatment increased numbers of nestin- and doublecortin-positive cells, as well as spine density and total dendritic length in hippocampus. We proposed that PAPC ameliorated depression by inhibiting MAO activity, thus increasing monoamine neurotransmitter content and mediating the ERK/CREB/BDNF signaling pathway to up-regulate expression of BDNF, which also promotes neurogenesis and dendrite development in hippocampus.

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.

Helicid Ameliorates Learning and Cognitive Ability and Activities cAMP/PKA/CREB Signaling in Chronic Unpredictable Mild Stress Rats.

Helicid (4-formylphenyl-O-β-D-allopyranoside), an active component found in seeds from the Chinese herb Helicia nilagirica, has been reported to exert sedative, analgesic, hypnotic and antidepressant effects. The present study was designed to evaluate the antidepressant, learning and cognitive improvement effects of helicid in a chronic unpredictable mild stress (CUMS) model of depression in rats and to explore cAMP/protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway. Sprague-Dawley rats were randomly assigned to six groups (n = 10): control; CUMS; CUMS + fluoxetine (5 mg/kg) and CUMS + helicid at 8, 16 and 32 mg/kg. All rats were subjected to 12 weeks of CUMS protocols and drug administration during the last 6 weeks of CUMS. Our results showed that helicid, at a dose of 32 mg/kg, significantly reversed decreases in body weight and sucrose consumption, increased the distance and number of crossings in the open-field test (OFT), reduced immobility times in the forced swimming test (FST) and improved spatial memory in the Morris water maze (MWM); all of these effects had been induced by CUMS paradigm. Immunohistochemistry showed that administration of helicid could promoted the proliferation of neurons in the hippocampal CA1 and dentate gyrus (DG) regions. CUMS rats treated with helicid had dramatically decreased protein levels of serotonin transporters (SERTs). In addition, CUMS resulted in a significant reduction in the expression of cAMP, PKA C-α and p-CREB, each of which were partially attenuated by helicid administration. These results indicated that helicid could improve depressive behaviors, learning and cognitive deficits and increase hippocampal neurogenesis, which may be mediated by the regulation of SERTs, activation of the cAMP/PKA/CREB signaling pathway and upregulation of p-CREB levels in hippocampal.

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.