Unpredictable Mild Stress-induced Depressive-like Behaviors Research Articles

Loganin improves chronic unpredictable mild stress-induced depressive-like behaviors and neurochemical dysfunction.

Cornus officinalis Sieb. et Zucc., is a valuable herb commonly used in Chinese medicine clinics. Loganin is a major iridoid glycoside obtained from the traditional Chinese herb Corni Fructus. Loganin, which has been shown to improve depression-like behavior in mice exposed to acute stress, is probably a potential antidepressant candidate. Loganin was evaluated for its effect on chronic unpredictable mild stress (CUMS) induced depressive-like mice, and its action mechanisms were explored. ICR mice were subjected to the CUMS stimulation method to induce depression. The therapeutic effect of loganin on depressive-like behavior was evaluated by a series of behavioral tests such as sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST) and open-field test (OFT). In addition, the serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using ELISA. The levels of monoamine neurotransmitters were detected by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were measured using western blot analysis. The results showed that CUMS induced depressive-like behaviors in mice, as indicated by behavioral tests. Administration of loganin increased the sucrose preference in SPT, as well as decreased the immobility time in FST and TST. Loganin could also improve food intake, and increased crossing times in the OFT. In mechanism, loganin restored the secretion of monoamine neurotransmitters, ACTH and CORT to normal levels. In addition, loganin elevated the expression of BDNF in the hippocampus. In conclusion, loganin exerts antidepressant-like effects in CUMS model mice through modulating monoamine neurotransmitters, ACTH, CORT and BDNF. Loganin effectively ameliorated depressive-like symptoms in CUMS-exposed mice by increasing 5-hydroxytryptamine (5-HT) and dopamine (DA) levels, alleviating hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and increasing BDNF expression. In conclusion, the findings of the current study extensive evidence for the application of loganin in stress-associated disorders, specifically targeting depression.

Polygonum sibiricum polysaccharides alleviate chronic unpredictable mild stress-induced depressive-like behaviors by regulating the gut microbiota composition and SCFAs levels

Polygonum sibiricum polysaccharides alleviate chronic unpredictable mild stress-induced depressive-like behaviors by regulating the gut microbiota composition and SCFAs levels

Rice Germ Ameliorated Chronic Unpredictable Mild Stress-Induced Depressive-like Behavior by Reducing Neuroinflammation.

Stress-induced neuroinflammation is widely regarded as one of the primary causes of depression. Gamma-aminobutyric acid (GABA)-enriched foods relieve stress and reduce inflammatory reactions. This study aimed to evaluate whether rice germ with 30% GABA (RG) reduced neuroinflammation in mice exposed to chronic unpredictable mild stress (CUMS). CUMS mice were administered 40, 90, and 140 mg/kg of RG. CUMS increased serum and hypothalamic pro-inflammatory cytokine (TNF-α and IL-6) levels, which were decreased by RG. In the hypothalamus, CUMS elevated M1-type microglia markers of CD86 and NF-κB, whereas RG lowered these levels. The expression levels of NLRP3 inflammasome complex (NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1), IL-1β, and IL-18 were increased in the hypothalamus of CUMS mice and decreased by RG. RG attenuated depressive-like behaviors in CUMS mice, as measured by the forced swim test and tail suspension test. In conclusion, RG decreased hypothalamic inflammation-related signals, such as TNF-α, IL-6, M1 polarization, NF-κB, NLRP3 inflammasome complex, caspase-1, IL-1β, and IL-18, to diminish depressive-like behavior.

Nootkatone Improves Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors by Repressing NF-κB/NLRP3-Mediated Neuroinflammation.

To explore the effect of nootkatone (NKT) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and the mechanism underlying NKT improving the depressive-like behaviors. The CUMS-induced depression model was established in mice. Fifty mice were randomized into 5 groups (n=10) in accordance with a random number table: control group, CUMS group, CUMS + NKT (6 mg/kg) group, CUMS + NKT (12 mg/kg) group, and CUMS + ketamine group. From the 22th day, NKT (6 or 12 mg/kg) or ketamine (0.5 mg/kg) was given with intragastric administration every day for 21 days. Behavioral tests including forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT) and open-field test (OFT) were carried out. The mRNA and protein expressions of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α in hippocampus were assessed using quantitative realtime polymerase chain reaction (PCR), Western blot analysis, and enzyme linked immunosorbent assay. The nuclear factor-κB (NF-κB)/NOD-like receptor 3 (NLRP3) inflammasome pathway was analyzed using Western blot and immunofluorescence analysis. NKT treatment improved CUMS-induced depressive-like behaviors in mice (P<0.05 or P<0.01). NKT significantly decreased the mRNA and protein levels of IL-1β, IL-18, IL-6, and TNF-α in hippocampus of CUMS mice (P<0.05 or P<0.01). Furthermore, NKT repressed CUMS-induced activation of NF-κB signaling and NLRP3 inflammasome (P<0.01). More important, Nigericin, a NLRP3 activator, destroyed the effect of NKT on repressing neuroinflammation and improving depressive-like behaviors (P<0.05 or P<0.01). NKT ameliorates the depressive-like symptoms, in part by repressing NF-κB/NLRP3-mediated neuroinflammation.

The environmental enrichment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive decline by inducing autophagy-mediated inflammation inhibition

BackgroundPeople exposed to prolonged chronic unpredictable mild stress (CUMS) are easy to suffer from depression and cognitive impairment. Environmental enrichment (EE) had a beneficial effect on depressive-like and cognition-like behaviors by inhibiting inflammation. However, the specific mechanism involved in the inflammation inhibition that occurs after EE treatment for the depression and cognitive decline induced by CUMS remains unclear. In this study, we evaluated the possible mechanism of the beneficial effects on depression and cognition by EE. MethodsRats were randomly divided into 5 groups as follows: (1) Control + standard environment (SE), (2) CUMS + SE, (3) CUMS + EE, (4) CUMS + EE+ 3-methiladenine (3-MA), (5) CUMS + SE + 3-MA. They were exposed to CUMS procedure for 5 weeks except the control group. After CUMS procedure, rats were housed in the EE or SE for 3 weeks. During EE or SE treatment, rats were injected with normal saline or 3-MA every day. 3-MA as an autophagy inhibitor suppresses autophagy via inhibition of class III PI3K. Behavioral tests were used to investigate depressive-like and cognition-like behaviors after EE treatment. Then, autophagy-related proteins, inflammation-related molecules, transmission electron microscopy (TEM) and immunofluoresence were determined. ResultsWe found that CUMS induced depressive-like behaviors and cognitive impairment, reflected in worse behavioral test, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, prolonged immobility and spatial learning and memory impairment. In addition, CUMS rats exhibited the reduced expression of autophagy related proteins including LC3 and Beclin-1 and the increased inflammation activation including microglia cells, NLRP3 inflammasome and proinflammatory cytokines (IL-1β, IL-6 and TNF-α). After EE treatment, these changes were reversed. However, 3-MA, the inhibitor of autophagy, eliminated the neuroprotective effects of EE on depressive-like behaviors and cognitive decline. ConclusionThis study demonstrates that EE can play neuroprotective effects on depression and cognitive impairment by inducing autophagy-mediated inflammation inhibition, which accounts for the reduction of proinflammatory cytokines, including IL-1β, IL-6 and TNF-α.

Quercetin alleviates chronic unpredictable mild stress-induced depressive-like behaviors by promoting adult hippocampal neurogenesis via FoxG1/CREB/ BDNF signaling pathway

Quercetin, a naturally occurring flavonoid, has been reported to exert antidepressant effects, however, the underlying mechanisms are still uncertain. Recent studies have demonstrated that Forkhead box transcription factor G1 (FoxG1) regulates the process of adult hippocampal neurogenesis (AHN) and exerts neuroprotective effects. In this study, we explored whether quercetin plays an anti-depressant role via regulation of FoxG1 signaling in mice and revealed the potential mechanisms. To explore the antidepressant effects of quercetin, mice were subjected to behavioral tests after a chronic unpredictable mild stress (CUMS) exposure. We found that chronic quercetin treatment (15 mg/kg, 30 mg/kg) obviously restored the weight loss of mice caused by CUMS and alleviated CUMS-induced depression-like behaviors, such as increased sucrose consumption, improved locomotor activity and shorten immobility time. In addition, to clarify the relationship between quercetin and AHN, we detected neurogenesis markers in the dentate gyrus (DG) of the hippocampus. Furthermore, FoxG1-siRNA was employed and then stimulated with quercetin to further investigate the mechanism by which FoxG1 participates in the antidepressant effects of quercetin. Our results indicate that chronic quercetin treatment dramatically increased the number of doublecortin (DCX)-positive and BrdU/NeuN-double positive cells. Besides, the expression levels of FoxG1, p-CREB and Brain-derived neurotrophic factor (BDNF) were also enhanced by quercetin in the DG. Strikingly, quercetin failed to reverse the levels of p-CREB and BDNF after FoxG1-siRNA was performed in SH-SY5Y cells and Neural Progenitor Cells (NPCs). Our results thus far suggest that quercetin might exert antidepressant effects via promotion of AHN by FoxG1/CREB/ BDNF signaling pathway.

ニコチンは血清コルチコステロン量の増加を介した慢性予測不能軽度ストレスによるうつ様行動を緩解する

ニコチンは血清コルチコステロン量の増加を介した慢性予測不能軽度ストレスによるうつ様行動を緩解する

Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation

Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-κB/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also improved the depression-like behavior and cognitive function of the rats. It also inhibited NF-κB activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-α, IL-6 and IL-1β, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression.

Curcumin Attenuates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors via Restoring Changes in Oxidative Stress and the Activation of Nrf2 Signaling Pathway in Rats.

Accumulating evidence has demonstrated that oxidative stress is associated with depression. Our present study aimed at investigating the antidepressant effect and the possible mechanisms of curcumin (CUR) in chronic unpredictable mild stress- (CUMS-) induced depression model in rats. After exposure to CUMS for four weeks, the rats showed depressive-like behavior, and the depressive-like behaviors in CUMS-treated rats were successfully corrected after administration of CUR. In addition, CUR could effectively decrease protein expression of oxidative stress markers (Nox2, 4-HNE, and MDA) and increase the activity of CAT. CUR treatment also reversed CUMS-induced inhibition of Nrf2-ARE signaling pathway, along with increasing the mRNA expression of NQO-1 and HO-1. Furthermore, the supplementation of CUR also increased the ratio of pCREB/CREB and synaptic-related protein (BDNF, PSD-95, and synaptophysin). In addition, CUR could effectively reverse CUMS-induced reduction of spine density and total dendritic length. In conclusion, the study revealed that CUR relieves depressive-like state through the mitigation of oxidative stress and the activation of Nrf2-ARE signaling pathway.

Corticotropin-releasing hormone 1 receptor antagonism attenuates chronic unpredictable mild stress-induced depressive-like behaviors in rats.

Hyperactivity of the hypothalamic-pituitary-adrenal axis and impairment of the central corticotropin-releasing factor system are factors in the pathogenesis of depression. Though several antagonists of the corticotropin-releasing factor 1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between corticotropin-releasing factor 1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of CP154526, a corticotropin-releasing factor 1 receptor blocker, which presented some signs of depression. Our results revealed that CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment notably improved the sucrose consumption, produced anti-depressive-like behavior in open-field test, as well as immobility time in forced swimming test. The levels of interleukin-6, interleukin-1β, tumor necrosis factor-α, and corticotropin-releasing hormone concentration in the serum were inhibited effectively by CP154526 or fluoxetine administration. Real-time quantitative PCR and western blot analysis showed the upregulated levels of brain-derived neurotrophic factor and growth associated protein 43 (GAP43) in the hypothalamus of the rats exposed to chronic unpredictable mild stress (CUMS), while different degrees of downregulation in their expression were detected after CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment, respectively. Thus, our data demonstrated that CP154526 exhibited antidepressant effect in CUMS rats, which might be mediated by decreasing the brain-derived neurotrophic factor and GAP43 expression in the hypothalamus.

SRT2104 attenuates chronic unpredictable mild stress-induced depressive-like behaviors and imbalance between microglial M1 and M2 phenotypes in the mice

Although activated microglia-induced neuroinflammation link to the physiopathology of major depressive disorder, the homeostasis of switchable M1/M2 microglia in treating depression are unclear. Recent accumulating evidences suggest that Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, plays a key role in mood regulation, yet its role in the polarization of microglia acting on depressive behaviors remains unknown. Here, we intended to investigate whether activation of SIRT1 in hippocampus has antidepressant potential in relation to microglial phenotypic switch. Chronic unpredictable mild stress (CUMS) treatment was performed on C57BL/6 mice, followed by injecting with SRT2104, a selective SIRT1 agonists. We found that activation of SIRT1 in hippocampus ameliorate CUMS-induced depressive-like behaviors, as indicated by sucrose preference test, tail suspension test and forced swim test. Moreover, activation of SIRT1 abrogated the increased expression of M1 markers (IL-6, IL-1β and iNOS,) and decreased expression of M2 markers (IL-10, TGF-β and Arignase1) induced by CUMS. Notably, activation of SIRT1 shifted microglia polarization toward the M2 phenotype in CUMS-induced depressive-like behaviors of mice. In addition, SRT2104 treatment ameliorated CUMS-induced SIRT1 decreased expression in the hippocampus coincides with the up-regulation phosphorylation levels of GSK3β and PTEN. Taken together, these findings indicated that activation of SIRT1 ameliorate CUMS-induced depressive-like behaviors via shifting microglial polarization toward the M2 phenotype, thereby providing a novel and beneficial therapeutic approach for depression that may be translatable to depression patients in the future.

Ro41-5253, a selective antagonist of retinoic acid receptor α, ameliorates chronic unpredictable mild stress-induced depressive-like behaviors in rats: Involvement of regulating HPA axis and improving hippocampal neuronal deficits

Accumulating reports have highlighted an association between excess retinoids and depression development. Retinoic acid receptor α (RARα) is implicated in the activation of hypothalamus-pituitary-adrenal (HPA) axis and closely involved in the etiology of depression, suggesting it might be a novel target of antidepressant. This study investigated the antidepressant potential of Ro41-5253 (a selective RARα antagonist) and related mechanisms using a depression rat model imitated by social isolation and chronic unpredicted mild stress (CUMS). Sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were applied to assess the antidepressant-like effect. HPA axis activity, RARα expression in hypothalamic paraventricular nucleus (PVN) and hypothalamus, and protein levels of brain-derived neurotrophic factor (BDNF) and synapse-related proteins (PSD95, SYP, MAP2) in hippocampus were measured, respectively. We found that Ro41-5253 treatment ameliorated the depressive-like behaviors in CUMS rats, as evidenced by increased sucrose preference in SPT, raised numbers of crossing and rearing in OFT, reduced immobility time and prolonged swimming time in FST. The HPA axis hyperactivity was attenuated by Ro41-5253 (1 mg/kg) treatment, indicated by reduced serum corticosterone level, decreased adrenal gland index, reduced corticotrophin-releasing hormone protein level in hypothalamus, and recovered hypothalamic glucocorticoid receptor protein level. In addition, Ro41-5253 (1 mg/kg) treatment downregulated RARα protein expression in hypothalamic PVN and hypothalamus, and increased the protein levels of BDNF, PSD95, SYP and MAP2 in the hippocampus. We concluded that Ro41-5253 had antidepressant-like effects on CUMS rats by downregulating HPA axis hyperactivity and improving the hippocampal neuronal deficits.

The enriched environment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive impairment by activating the SIRT1/miR-134 signaling pathway in hippocampus

BackgroundChronic unpredictable mild stress (CUMS) is an important risk factor for depression and cognitive deficits in humans. Enriched environment (EE) showed a beneficial effect on depression and cognition by enhancing brain derived neurotrophic factor (BDNF) expression and synaptic plasticity. However, it is still not clearly understood whether an epigenetic mechanism is involved in the BDNF modulation and synaptic plasticity that occurs after EE treatment for the depressive-like behaviors and cognitive deficits elicited by CUMS. In this study, we investigated the possible mechanism of the neuroprotective effect of EE. MethodsAll rats were exposed to the 5-week CUMS procedure except the control group. After CUMS procedure, some rats were stereotaxically injected with SIRT1 pharmacologic inhibitor EX527 or SIRT1 knocking down lentivirus (sh-SIRT1) in the hippocampus followed by EE treatment for 3 weeks. Other rats were directly subjected to EE treatment without stereotaxic injection. Behavioral tests were used to appraise depression and cognition after EE treatment. Then epigenetic molecules, synaptic proteins, dendritic spine density and branches, and synaptic morphology of the dorsal hippocampus were determined. ResultsWe found that CUMS induced depressive-like behaviors including decreased sucrose preference ratio, prolonged immobility and reduced locomotor and exploratory activity; cognitive deficits including spatial learning and memory impairment; reduced dendritic spine density and number of branches; thinned postsynaptic density; downregulated SIRT1/microRNA-134 pathway, decreased BDNF and synaptic proteins including synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) expression in the hippocampus. However, the CUMS-induced depressive-like behaviors, cognitive deficits, dendritic spine density and branch number reduction, postsynaptic density thinning, SIRT1/microRNA-134 pathway downregulation, BDNF and synaptic proteins reduction, including synaptophysin (SYN) and postsynaptic density protein 95 (PSD95), were reversed by EE treatment. However, depressive-like behaviors and cognitive deficits were observed again in rats subjected to stereotaxic injection with EX527 or sh-SIRT1. Furthermore, this study also found that SIRT1/microRNA-134 regulates the downstream molecules BDNF, and the synaptic proteins SYN and PSD95 in primary cultured hippocampal neurons. ConclusionsThis study provides evidence for the neuroprotective role of EE on depression and cognitive deficits by activating the SIRT1/microRNA-134 pathway, which accounts for the regulation of synaptic proteins, including BDNF, PSD95 and SYN, dendritic remodeling and ultrastructure changes of synapses in the hippocampus.

Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors and Prevents Dendritic Spine Loss in Mice Hippocampi

BackgroundPhosphodiesterase 4 is a promising target for developing novel antidepressants. However, prototype phosphodiesterase 4 inhibitors show severe side effects, including nausea and vomiting. N-Isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel phosphodiesterase 4 inhibitor with little emetic potential. In the present study, we investigated the inhibitory effect of FCPR03 on chronic unpredictable mild stress-induced, depressive-like behaviors in mice and explored the underlying mechanisms.MethodsThe depression model of mice was established by chronic unpredictable mild stress. Forced swim test, tail suspension test, and sucrose preference test were used to assess depressive-like behaviors. Golgi-staining was utilized to analyze dendritic morphology and spine density. The level of cAMP was measured by enzyme-linked immnosorbent assay assay. Western blot was used to evaluate protein levels of phosphorylated cAMP-response element binding protein, protein kinase B, glycogen synthase kinase-3β, and brain derived neurotrophic factor in both hippocampus and prefrontal cortex. Postsynaptic density protein 95 and synapsin 1 were also detected by western blot in the hippocampi.ResultsTreatment with FCPR03 (0.5–1.0 mg/kg, i.p.) increased consumption of sucrose in the sucrose preference test in mice exposed to chronic unpredictable mild stress. FCPR03 shortened the immobility time in forced swim test and tail suspension test without affecting locomotor activity. Furthermore, chronic unpredictable mild stress decreased the dendritic spine density and dendritic length in the hippocampus. This change was accompanied by decreased expression of postsynaptic density protein 95 and synapsin 1. Interestingly, FCPR03 prevented dendritic spine loss and increased synaptic protein levels. Moreover, the levels of cAMP, phosphorylated cAMP-response element binding protein, and brain derived neurotrophic factor were elevated in chronic unpredictable mild stress-challenged mice after treatment with FCPR03. In addition, FCPR03 also enhanced the phosphorylation of both protein kinase B and glycogen synthase kinase-3β in mice exposed to chronic unpredictable mild stress.ConclusionThe present study suggests that FCPR03 could prevent both depressive-like behaviors and spine loss induced by chronic unpredictable mild stress in the mice hippocampi.

(+)-Sesamin attenuates chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits via suppression of neuroinflammation

Depression is a mood disorder that is related to neuroinflammation and cognition loss. This study is aimed to determine the potential antidepressant effects of (+)-sesamin, a lignan component of sesame, in a mild stress-induced depression mouse model. CD-1 mice were treated with chronic unpredictable mild stress (CUMS) process and orally administrated with sesamin (50 mg/kg/d) for 6 weeks. Behavioral tests including forced swimming test, tail suspension test, open field test, and elevated plus maze test demonstrated that sesamin treatment inhibited CUMS-induced mice depressant-like behaviors and anxiety, without changing immobility. It was found that sesamin prevented stress-induced decease levels of 5-HT and NE in striatum and serum. Cognitive deficits were assessed using Y-maze and Morris water maze test. Sesamin treatment also prevented stressed-induced memory impairments and neuronal damages. Consistently, sesamin also enhanced synapse ultrastructure and improved expressions of PSD-95 in stressed mice hippocampus with improving neurotrophic factors expression including BDNF and NT3. Moreover, sesamin treatment significantly prevented CUMS-induced neuroinflammation by inhibiting over-activation of microglia and expressions of inflammatory mediators including iNOS, COX-2, TNF-α and IL-1β in stressed mice hippocampus and cortex. These results illustrated that sesamin markedly improved CUMS-induced depression and memory loss via inhibiting neuroinflammation, which indicate that as food component, sesamin might be also a novel potential therapeutic for depression.

Clostridium butyricum Attenuates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behavior in Mice via the Gut-Brain Axis.

Abnormal gut microbiome has been associated with depression. The mechanism of probiotics against depression remains unclear. This study aimed to determine whether Clostridium butyricum (Cb) could attenuate chronic unpredictable mild stress-induced depressive-like behavior and its possible mechanisms. Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) and were treated with Cb. Depressive-like behavior was evaluated by a series of behavioral tests. The levels of cerebral 5-hydroxytryptamine (5-HT), brain derived neurotrophic factor (BDNF), glucagon-like peptide-1 (GLP-1) receptor and intestinal were measured. Cb treatment significantly improved CUMS-induced depressive-like behavior in mice. Meanwhile, Cb treatment exhibited prominent effects, increasing 5-HT and GLP-1 and upregulating BDNF expression. Furthermore, Cb-treated mice showed increased secretion of GLP-1 and upregulated GLP-1R expression. Taken together, our results demonstrate an antidepressive effect of Cb in CUMS mice partially attributed to stimulation of intestinal GLP-1 secretion and activation of cerebral GLP-1R.

Chronic unpredictable mild stress-induced depressive-like behavior and dysregulation of brain levels of biogenic amines in Drosophila melanogaster

The etiopathogenesis of depression may involve repeated exposure to several unpredictable stressors. This study was conducted to investigate changes induced by chronic unpredictable mild stress (CUMS) and to assess behavioral and neurochemical changes that predict depressive-like behavior in Drosophila melanogaster. Male Drosophila melanogaster flies were exposed to CUMS with several stressors (cold, heat, starvation, and sleep deprivation) in an unpredictable and chronic manner for ten days. At the end of treatment, in vivo behavioral tests (open field, aggression, forced swimming, mating, light/dark box, male fertility evaluation, sucrose preference, weight evaluation) and ex vivo analyses (dopamine and serotonin levels) were performed. Using this CUMS model, we obtained results that contribute to the construction of a depressive model in Drosophila, where we reproduce some behavioral phenotypes corresponding to depressive symptoms, such as immobility in the forced swimming test, less exploration in the light/dark test, changes in mating behavior, changes in the aggressiveness test, reduced sucrose preference, and weight-loss, in addition to a significant reduction in the levels of serotonin and dopamine when compared to the control group. Fluoxetine was used in our study as a positive control to demonstrate that CUMS-induced depressive-like behaviors in flies can be reversed by antidepressants. In conclusion, male Drosophila melanogaster exposed to CUMS display a depressive-like phenotype, and, while this poses some limitations as an animal model for depression, it meets some of the criteria required to be a valid model, such as good face and construct validity.

Extract of sesame cake and sesamol alleviate chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits

Depression is a worldwide severe psychiatric disease associated with cognitive impairments. The aims of the present study are to investigate the preventive effects of alcoholic extract of sesame (Sesamum indicum L.) cake (SLE) and sesamol in a chronic unpredictable mild stress (CUMS)-induced mouse model. Oral administration of SLE (600 mg/kg/day) and sesamol (10 mg/kg/day) significantly restored CUMS-induced mice antidepressant-like behaviors, anhedonia, and anxiety. Importantly, supplementation of SLE and sesamol inhibited oxidative stress and improved serotonin levels in depressed mice brain. Moreover, SLE and sesamol treatment significantly prevented CUMS-induced memory loss in Y-maze and water-maze tests, which was consistent with enhanced the size of postsynaptic densities and postsynaptic density protein 95 (PSD-95) expression in mice hippocampus. These results illustrated that SLE and sesamol markedly improved CUMS-induced depression and memory loss, and provided novel insights into the mechanisms of sesamol and sesame crude extract on the regulation CUMS-induced depression and cognitive impairments.

Hydrogen Sulfide Inhibits Chronic Unpredictable Mild Stress-Induced Depressive-Like Behavior by Upregulation of Sirt-1: Involvement in Suppression of Hippocampal Endoplasmic Reticulum Stress.

BackgroundHydrogen sulfide (H2S) is a crucial signaling molecule with a wide range of physiological functions. Previously, we confirmed that stress-induced depression is accompanied with disturbance of H2S generation in hippocampus. The present work attempted to investigate the inhibitory effect of H2S on chronic unpredictable mild stress-induced depressive-like behaviors and the underlying mechanism.MethodsWe established the rat model of chronic unpredictable mild stress to simulate depression. Open field test, forced swim test, and tail suspension test were used to assess depressive-like behaviors. The expression of Sirt-1 and three marked proteins related to endoplasmic reticulum stress (GRP-78, CHOP, and cleaved caspase-12) were detected by western blot.ResultsWe found that chronic unpredictable mild stress-exposed rats exhibit depression-like behavior responses, including significantly increased immobility time in the forced swim test and tail suspension test, and decreased climbing time and swimming time in the forced swim test. In parallel, chronic unpredictable mild stress-exposed rats showed elevated levels of hippocampal endoplasmic reticulum stress and reduced levels of Sirt-1. However, NaHS (a donor of H2S) not only alleviated chronic unpredictable mild stress-induced depressive-like behaviors and hippocampal endoplasmic reticulum stress, but it also increased the expression of hippocampal Sirt-1 in chronic unpredictable mild stress-exposed rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the protective effects of H2S against chronic unpredictable mild stress-induced depression-like behaviors and hippocampal endoplasmic reticulum stress.ConclusionThese results demonstrated that H2S has an antidepressant potential, and the underlying mechanism is involved in the inhibition of hippocampal endoplasmic reticulum stress by upregulation of Sirt-1 in hippocampus. These findings identify H2S as a novel therapeutic target for depression.

A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice

Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [3H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [3H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression.