Chronic Unpredictable Mild Stress Research Articles

S-ketamine alleviates depression-like behavior and hippocampal neuroplasticity in the offspring of mice that experience prenatal stress

Prenatal stress exerts long-term impact on neurodevelopment in the offspring, with consequences such as increasing the offspring’s risk of depression in adolescence and early adulthood. S-ketamine can produce rapid and robust antidepressant effects, but it is not clear yet whether and how S-ketamine alleviates depression in prenatally stressed offspring. The current study incestigated the preliminary anti-depression mechanism of S-ketamine in prenatally stressed offspring, particularly with regard to neuroplasticity. The pregnant females were given chronic unpredictable mild stress on the 7th-20th day of pregnancy and their male offspring were intraperitoneally injected with a single dose of S-ketamine (10 mg/kg) on postnatal day 42. Our findings showed that S-ketamine treatment counteracted the development of depression-like behaviors in prenatally stressed offspring. At the cellular level, S-ketamine markedly enhanced neuroplasticity in the CA1 hippocampus: Golgi-Cox staining showed that S-ketamine alleviated the reduction of neuronal complexity and dendritic spine density; Transmission electron microscopy indicated that S-ketamine reversed synaptic morphology alterations. At the molecular level, by western blot and RT-PCR we detected that S-ketamine significantly upregulated the expression of BDNF and PSD95 and activated AKT and mTOR in the hippocampus. In conclusion, prenatal stress induced by chronic unpredictable mild stress leads to depressive-like behaviors and hippocampal neuroplasticity impairments in male offspring. S-ketamine can produce antidepressant effects by enhancing hippocampal neuroplasticity via the BDNF/AKT/mTOR signaling pathway.

Neuroprotective Roles of Daidzein Through Extracellular Signal-Regulated Kinases Dependent Pathway In Chronic Unpredictable Mild Stress Mouse Model.

Depression is a stress-related neuropsychiatric disorder causing behavioural, biochemical, molecular dysfunctions and cognitive impairments. Previous studies suggested connection between neuropsychiatric diseases like depression with estrogen and estrogen receptors (ER). Daidzein is a phytoestrogen that functions as mammalian estrogen and regulates gene expressions through extracellular signal-regulated kinases (ERKs) dependent pathway by activating ERβ. ERβ modulates stress responses, physiological processes by activating protein kinases and plays a significant role in various neurological diseases like depression. However, significant roles of daidzein in depression involving ERK1/2, pERK1/2, and mTOR still unknown. Herein, we examined neuroprotective role of daidzein in chronic unpredictable mild stress (CUMS) mouse model. CUMS model was prepared, and placed in six groups namely, control, CUMS, CUMS vehicle, CUMS DZ (Daidzein 1mg/kgbw, orally), CUMS PHTPP (ERβ blocker, 0.3mg/kgbw, i..p.) and CUMS Untreated. Supplementation of daidzein to CUMS mice exhibits decrease depressive and anxiety-like behaviour, improved motor coordination and memory. Further, immunofluorescence results showed daidzein improved ERK1/2, pERK1/2 and mTOR expressions in the cortex, hippocampus and medulla of stressed mice. SOD, catalase and acetylcholinesterase levels were also improved. Blocking of ERβ with PHTPP stressed mice showed deficits in behaviour, low expression of ERK1/2, pERK1/2 and mTOR, and no significant changes in SOD, catalase and acetylcholinesterase level. Collectively, this study suggests that daidzein may ameliorate depressive and anxiety-like behaviour through ERK downregulating pathway by activating ERβ through ERK1/2, pERK1/2 and mTOR. Such study may be useful to understand daidzein dependent neuroprotection through ERβ in depression.

Study on the Mechanism of Dictyophora duplicata Polysaccharide in Reducing Depression-like Behavior in Mice

Background/Objectives: Depression is a prevalent worldwide mental health disorder that inflicts significant harm to individuals and society. Dictyophora duplicata is an edible fungus that contains a variety of nutrients, including polysaccharides. This study aims to investigate the monosaccharide composition and molecular weight of the Dictyophora duplicata polysaccharide (DDP-B1), followed by an exploration of its antidepressant effects in chronic unpredictable mild stress (CUMS) mice. Methods: Dictyophora duplicata was purified using a DEAE-52 column and an S-400 column to obtain DDP-B1. The monosaccharide composition and molecular weight of DDP-B1 were investigated via high-performance gel permeation chromatograph. Six-week-old C57BL/6 male mice were utilized for the CUMS modeling to evaluate the antidepressant efficacy of DDP-B1. Fluoxetine served as the positive control group. The depressive-like behaviors and brain pathology of mice were evaluated. Immunofluorescence (IF) staining, metabolomics analysis, and western blot were employed to further investigate the underlying mechanisms. Results: DDP-B1 significantly alleviated the depression-like behavior of CUMS mice and increased the expression of SYN and PSD-95 in the mice’s brains, which was further validated by western blot. Metabolomics analysis indicated a reduction in serum glutamate in CUMS mice following DDP-B1 treatment. Moreover, DDP-B1 treatment led to an increase in levels of GABAAR, BDNF, p-TrkB and p-p70S6K. Conclusions: DDP-B1 regulated abnormalities in the glutamatergic system, subsequently activated the BDNF-TrkB-mTOR pathway and mitigated the pathological manifestations of CUMS mice. This study validated the potential of DDP-B1 as an antidepressant medication and established a theoretical foundation for the development of fungi with similar properties.

The role of astrocytes in depression, its prevention, and treatment by targeting astroglial gliotransmitter release

The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression.

Jianghua Kucha black tea containing theacrine attenuates depression-like behavior in CUMS mice by regulating gut microbiota-brain neurochemicals and cytokines

Theacrine and theaflavins are known for their potential to mitigate depression and cognitive impairment. Jianghua Kucha black tea (JH) contains both compounds, yet its antidepressant properties are seldom documented. This study evaluated the effects of JH on depression in chronic unpredictable mild stress (CUMS) mice and explored the underlying mechanisms through integrative analyses of gut microbiota and fecal metabolomics. JH was found to significantly alleviate CUMS-induced depression-like behavior by improving body weight, food intake, 1% sucrose preference, immobility time, and numbers of crossings and standings compared to Zhuyeqi black tea (ZYQ), which contains theaflavins. JH notably altered the gut microbiota composition, enriching genera such as Turicibacter, Faecalibaculum, Akkermansia, and Desulfovibrio, while inhibiting genera norank_f__Muribaculaceae and Lactobacillus. Additionally, JH modified the fecal metabolite profile, characterized by increased levels of several secondary bile acids (BAs) and decreased levels of several purine intermediate metabolites. Furthermore, JH upregulated levels of monoamine neurotransmitters (5-HT and DA) and brain-derived neurotrophic factor (BDNF), while downregulating pro-inflammatory cytokines IL-6 and TNF-α in brain tissue. These findings suggested that JH could mitigate CUMS-induced depression-like behavior, potentially by modulating gut microbiota composition and function, as well as brain neurochemicals and cytokines.

Electroacupuncture combined with NSCs-Exo alters the response of hippocampal neurons in a chronic unpredictable mild stress paradigm in ovx rats

Electroacupuncture combined with NSCs-Exo alters the response of hippocampal neurons in a chronic unpredictable mild stress paradigm in ovx rats

Moringa oleifera Lam. seed lectin (WSMoL) reduces chronic stress-induced anxiety and depression in mice by lessening inflammation and balancing brain chemicals

Phyto-based treatments for anxiety and depression are gaining attention. The efficacy of the water-soluble Moringa oleifera seed lectin (WSMoL) in reducing acute anxiolytic and depressive-like behaviors in mice has been previously demonstrated. In the present study, it was evaluated the effects of WSMoL on reducing anxiety and depressive-like symptoms in a mouse model of unpredictable chronic mild stress (UCMS). The animals were divided into groups and exposed to a four-week UCMS regimen. Following this, the mice received daily intraperitoneal injections of vehicle (non-stressed and UCMS control groups), WSMoL (2 or 4 mg/kg), or fluoxetine (10 mg/kg) for 21 days. Neurobehavioral tests included the open field test and elevated plus maze test to assess anxiety-like behavior, and the tail suspension test and sucrose preference test to evaluate depression-like behavior. Biochemical analyses measured serum corticosterone and cytokines as well brain levels of cytokines and monoamines. All tests indicated that WSMoL significantly (p < 0.05) reversed the anxiety and depression-like behaviors induced by UCMS. The stress protocol increased serum corticosterone levels and WSMoL treatment was not able to normalize corticosterone secretion. WSMoL treatment reduced serum and brain levels of IL-2, IL-6, and TNF-α, indicating reduced neuroinflammation, and increased brain levels of dopamine, serotonin, and noradrenaline. In summary, WSMoL mitigated UCMS-induced anxiety and depression-like behaviors by reducing neuroinflammation and modulating brain monoamine levels.

Impact of Adult Hippocampal Neurogenesis on Neuronal Output Patterns from the Subiculum to the Lateral Hippocampus During Anxiety

Adult hippocampal neurogenesis (AHN) has an effect on mood regulations. Promoting AHN could recover stressed-induced symptoms such as depression and anxiety. In this study, we used voluntary physical exercise, fosTRAP2, functional magnetic resonance imaging (FMRI) and positron emission tomography (PET) technology to evaluate the effect of AHN on mice during unpredictable chronic mild stress (UCMS). Additionally, we inject fluoxetine to increase AHN.

20 (S)-Protopanaxadiol Alleviates DRP1-Mediated Mitochondrial Dysfunction in a Depressive Model In Vitro and In Vivo via the SIRT1/PGC-1α Signaling Pathway

Depression is a complex and common mental illness affecting physical and psychological health. Panax ginseng C. A. Mey is a traditional Chinese medicine with abundant pharmacological activity and applications in regulating mood disorders. 20 (S)-Protopanaxadiol is the major intestinal metabolite of ginsenoside and one of the active components in ginseng. In this study, we aimed to investigate the therapeutic effects of 20 (S)-Protopanaxadiol on neuronal damage and depression, which may involve mitochondrial dynamics. However, the mechanism underlying the antidepressant effects of 20 (S)-Protopanaxadiol is unelucidated. In the present study, we investigated the potential mechanisms underlying the antidepressant activity of 20 (S)-Protopanaxadiol by employing a corticosterone-induced HT22 cellular model and a chronic unpredicted mild stress (CUMS)-induced animal model in combination with a network pharmacology approach. In vitro, the results showed that 20 (S)-Protopanaxadiol ameliorated the corticosterone (CORT)-induced decrease in HT22 cell viability, decrease in 5-hydroxytryptamine (5-HT) levels, and increase in nitric oxide (NO) and malondialdehyde (MDA) levels. Furthermore, 20 (S)-Protopanaxadiol exerted improvement effects on the CORT-induced increase in HT22 cell mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and apoptosis. In vivo, the results showed that 20 (S)-Protopanaxadiol ameliorated depressive symptoms and hippocampal neuronal damage in CUMS mice, and sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-1-Alpha (PGC-1α) activity were activated in the hippocampus of mice, thereby alleviating mitochondrial dysfunction and promoting the clearance of damaged mitochondria. In both in vivo and in vitro models, after inhibiting SIRT1 expression, the protective effect of 20 (S)-Protopanaxadiol on mitochondria was significantly weakened, and dynamin-related protein 1 (DRP1)-mediated mitochondrial division was significantly reduced. These findings suggest that 20 (S)-Protopanaxadiol may exert neuroprotective and antidepressant effects by attenuating DRP1-mediated mitochondrial dysfunction and apoptosis by modulating the SIRT1/PGC-1α signaling pathway.

Vitamin C improved anxiety and depression like behavior induced by chronic unpredictable mild stress in adolescent rats by influencing on oxidative stress balance, neurotransmitter systems, and inflammatory response

ABSTRACT Objectives: Stress is an adaptive response to different events in daily life that could strain physically, emotionally, or psychologically. Adolescence is an important developmental period due to physical, psychological, and social maturation. The aim of our study is to state whether chronic unpredictable mild stress (CUMS) during adolescence in male rats can cause anxiety and depression in adulthood and whether vitamin C (Vit C) can prevent this problem or not. Methods: For this purpose, we performed behavioral tests, including open field test, elevated plus maze, and forced swimming test. In addition, we investigated the metabolism of serotonin, the level of inflammation, oxidative stress and brain-derived neurotrophic factor (BDNF) in the brain cortex tissue of animals. Results: Results indicated that CUMS exacerbates mood-related behaviors by affecting the brain oxidative stress balance, inflammatory response, and serotonin metabolism. Moreover, we found that CUMS-Vit C co-treatment could significantly reverse CUMS-induced complications by restoration of the mentioned biochemical parameters. Discussion: Taken together, we would like to suggest the use of Vit C supplementation as a safe, inexpensive, and effective strategy for the management of CUMS.

Effect of acupuncture on AMPK/ULK1 signaling pathway of hippocampus in chronic stress-induced depression rats

To observe the effect of manual acupuncture stimulation on changes of behavior and hippocampal signaling pathways of AMP-activated kinase (AMPK)/UNC-51-like kinase 1 (ULK1) in rats with chronic unpredictable mild stress (CUMS)-induced depression, so as to explore its molecular mechanism underlying improvement of depression. Thirty-two male SD rats were randomly divided into normal control, model, acupuncture and medication (fluoxetine) groups, with 8 rats in each group. The depression model was established by using CUMS (fasting, water depredation, restraint, swimming in cold water, crowding, stroboscope stimulation, and tail clipping, each of which was used once a week) for 6 weeks. Manual acupuncture stimulation was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 10 min, once daily, 6 times a week for 6 weeks before every-day modeling. Rats of the medication group received gavage of fluoxetine (10 mg/kg) once a day for 6 weeks before every-day modeling. The percentage of sucrose preference, and the percentages of open arm times and open arm time in the elevated plus maze experiments were detected. The expression levels of AMPK, phosphorylated (p)-AMPK, ULK1, p-ULK1, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the hippocampus tissue were detected by Western blot, and the expression of autophagy effecting protein (Beclin-1) and the selective autophagy receptors (p62) mRNA in the hippocampal tissue was detected using real-time fluorescence quantitative PCR, respectively. Compared with the normal group, the percentage of sucrose preference, percentage of times of entering the open arm and percentage of open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1 /ULK1 ratio of proteins, and Beclin-1 mRNA were significantly decreased (P<0.01, P<0.05), and the expression levels of p-mTOR /mTOR ratio and p62 mRNA were significantly increased (P<0.01, P<0.05) in the model group. In comparison with the model group, the percentage of sucrose preference, percentage of open arm times and open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1/ULK1 ratio of proteins, and Beclin-1 mRNA were significantly increased in both acupuncture and medication groups (P<0.01, P<0.05), while the expression levels of p-mTOR /mTOR ratio of proteins, and p62 mRNA were markedly decreased only in the medication group (P<0.05). Acupuncture treatment can alleviate depression-like behavior in CUMS rats, which may be related to its functions in up-regulating AMPK/ULK1 signaling pathway to induce cellular autophagy in the hippocampus.

Effects of Krill Oil and Coconut Oil on Behavioral Changes and Inflammatory Markers in Rats with Chronic Unpredictable Mild Stress Induced Depression Model.

This study was conducted to determine the effects of two different types of fat (krill oil [KO] and coconut oil [CO]) on obesity, behavioral tests, and some inflammatory markers when consumed with a high-fat or control diet in rats with depression. The study was conducted mainly in two phases: the induction of depression (37 days) and the dietary intervention (60 days). After the induction of depression by chronic unpredictable mild stress, dietary intervention started. Sixty male Sprague-Dawley rats were divided into 6 groups with 10 rats in each group: (1) standard diet (SD), (2) SD + 5% KO, (3) SD + 5% medium-chain triglyceride (MCT)* (*CO to contain 5% MCT), (4) high-fat diet (HFD), (5) HFD + 5% KO, and (6) HFD + 5% MCT*. The open field test (OFT), forced swimming test (FST), and sucrose preference test were performed at baseline, end of the depression induction, and dietary intervention to observe behavioral changes in rats. After the final behavioral test, animals were sacrificed, and blood samples were collected for biochemical analyses C-reactive protein (milligram per liter), cortisol (microgram per deciliter), and insulin (micro-international units per milliliter) to assess inflammatory changes in the blood. All data were analyzed under two headings: baseline, end of depression induction, end of dietary intervention, and dietary intervention groups. Body weight gain was highest in the SD+KO and lowest in the SD+MCT group (P < .05). When behavioral tests were evaluated according to dietary intervention, it was found that the SD+MCT group spent the most time in the center, the least time in the periphery, and the lowest immobilization time (P < .05). In FST, the SD+KO with the highest weight gain was the most immobile group (P < .05). The study indicates that the weight-reducing effects of MCTs resulted in positive behavioral responses, particularly in OFT and FST. Through these properties, MCTs can be used medicinally in the prevention and treatment of behavioral changes due to depression.

Hypoxanthine Produces Rapid Antidepressant Effects by Suppressing Inflammation in Serum and Hippocampus.

The occurrence and development of depression are closely related to disorders of the brain and peripheral substances. Abnormal metabolites in the blood affect the signal regulation function of the nerve center, which is one of the key factors for depression episodes. This study was focused on metabolites in serum and the mechanism of its antidepressant in the hippocampus. In the present study, serum metabolites in patients with depression were screened by metabolomic techniques. Various depressive mouse models and behavioral tests were used to assess its antidepressant effects. The expressions of inflammatory signaling were detected by using Western blot, ELISA, and immunofluorescence. We found that the metabolite hypoxanthine in the serum of patients with depression was significantly reduced, and the same result was also found in two mouse models of depression such as chronic unpredictable mild stress (CUMS) and social defeat stress (SD). By administering different doses of hypoxanthine (5, 10, 15 mg/kg), we found that only 15 mg/kg was able to significantly reduce the latency and increase food consumption in the novelty suppressed-feeding test (NSF), which was also able to reverse the depressive phenotypes of mice in the CUMS model after a single administration at 2 h later. Hypoxanthine obviously reduced the expressions of inflammation in serum and downregulated the expressions of MAPK and NLRP3-related pathways in the hippocampus in CUMS mice. Moreover, hypoxanthine also suppressed the activations of glial cells including GFAP and IBA-1 in hippocampal CA1, CA3, and dentate gyrus (DG). To sum up, hypoxanthine exerted antidepressant effect relying on the inhibition of peripheral and hippocampal inflammations by regulating MAPK, NLRP3-related pathways, and glial cells. This was the first time that we have found a disordered metabolite in patients with depression and further systematically demonstrated its efficacy and potential mechanism of antidepressants, providing new ideas for antidepressant drug development.

GABAB modulate NF-κB/NLRP3 pathways in electroacupuncture prevention of depression in CUMS rats

BackgroundOur previous research has demonstrated that electroacupuncture (EA) has the potential to mitigate depression-like symptoms resulting from chronic stress. However, further investigation is required to fully understand the underlying mechanisms. The regulatory role of γ-aminobutyric acid type B (GABAB) in synaptic plasticity and the involvement of NF-κB/NLRP3-mediated inflammation in the lateral habenula nucleus (LHb) are key factors in the development of depression. This study sought to investigate the potential of EA in mitigating depression-like symptoms induced by chronic stress through mechanisms such as enhancing GABAB levels, regulating synaptic plasticity in the LHb, and suppressing NF-κB/NLRP3-mediated inflammation. MethodsSprague-Dawley rats were exposed to chronic unpredictable mild stress (CUMS) in order to create a model of depression. Subsequently, the weight and behavioral assessments of all rats were monitored, and samples of the lateral habenula and serum were collected. The protein expression levels were analyzed using western blotting. The 5-hydroxytryptophan (5-HT), Dopamine (DA), and Norepinephrine (NE) in the LHb and serum were measured using ELISA. The alterations in GABAB and NF-κB in the LHb were observed through immunofluorescence. The neuronal damage in the LHb was assessed using Nissl staining. ResultsEA upregulated the expression of GABAB in the LHb of rats subjected to CUMS. Subsequent behavioral assessments indicated that blocking GABAB attenuated the antidepressant effects of EA in CUMS-exposed rats. Furthermore, EA enhanced synaptic plasticity in the LHb of CUMS-exposed rats and mitigated NF-κB/NLRP3-mediated inflammatory responses, with these effects potentially being reversed by GABAB inhibition. ConclusionThrough the promotion of GABAB levels, regulation of synaptic plasticity within the LHb, and inhibition of NF-κB/NLRP3-mediated neuroinflammation in the same region, electroacupuncture at Shangxing and Fengfu acupoints demonstrates efficacy in mitigating depression-like behaviors induced by CUMS.

Exosomes Derived from DPA-treated UCMSCs Attenuated Depression-like Behaviors and Neuroinflammation in a Model of Depression Induced by Chronic Stress.

Depression is characterized by both neuroinflammation and neurodegeneration. Exosomes (Exo) have been shown to function as inhibitors of inflammation and promoters of neurogenesis. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid, can combat depression by increasing levels of docosapentaenoic acid (DPA). This study explored the effects of DPA on the therapeutic potential of Exo derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in glia-induced neuroinflammation associated with depression. Exposure to chronic unpredictable mild stress (CUMS) over six weeks induced depression- and anxiety-like behaviors, while decreasing the levels of serotonin and dopamine. Molecularly, CUMS increased the concentrations of the microglial M1 markers Iba1, iNOS, and IL-1β, while reducing the M2 markers Arg1, CD206, and IL-10 in the prefrontal cortex and hippocampus. However, Exo therapy reversed these effects. Moreover, DPA treatment of Exo demonstrated superior efficacy in alleviating depressive behaviors, neurotransmitter deficiencies, and M1 microglial activation. In vitro, Exo suppressed LPS-stimulated BV2 cell viability and M1 microglial activation, while mitigating the SH-SY5Y cell apoptosis triggered by treatment with the conditioned medium from LPS-activated BV2 cells. Furthermore, administration of DPA enhanced this effect. Mechanically, DPA enhanced Exo function by upregulating miR125b-5p expression, thereby targeting the MyD88/TRAF6/NF-κB signaling pathway. In summary, Exo exhibited antidepressant effects by suppressing M1 microglial neuroinflammation, while DPA treatment provided a more potent therapeutic effect on depression-like changes through the upregulation of miR125b-5p targeting the MyD88/TRAF6/NF-κB pathway.

Asiaticoside improves depressive-like behavior in mice with chronic unpredictable mild stress through modulation of the gut microbiota.

Asiaticoside, the main active ingredient of Centella asiatica, is a pentacyclic triterpenoid compound. Previous studies have suggested that asiaticoside possesses neuroprotective and anti-depressive properties, however, the mechanism of its anti-depressant action not fully understood. In recent years, a growing body of research on anti-depressants has focused on the microbiota-gut-brain axis, we noted that disruption of the gut microbial community structure and diversity can induce or exacerbate depression, which plays a key role in the regulation of depression. Behavioral experiments were conducted to detect depression-like behavior in mice through sucrose preference, forced swimming, and open field tests. Additionally, gut microbial composition and short-chain fatty acid (SCFA) levels in mouse feces were analyzed 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS). Hippocampal brain-derived neurotrophic factor (BDNF) and 5-hydroxytryptamine receptor 1A (5-HT1A) expression in mice was assessed by western blotting. Changes in serum levels of inflammatory factors, neurotransmitters, and hormones were measured in mice using ELISA. This study revealed that oral administration of asiaticoside significantly improved depression-like behavior in chronic unpredictable mild stress (CUMS) mice. It partially restored the gut microbial community structure in CUMS mice, altered SCFA metabolism, regulated the hypothalamic-pituitary-adrenal axis (HPA axis) and inflammatory factor levels, upregulated BDNF and 5-HT1A receptor protein expression, and increased serum serotonin (5-hydroxytryptamine, 5-HT) concentration. These findings reveal that asiaticoside exerts antidepressant effects via the microbiota-gut-brain axis. These results suggested that asiaticoside exerts antidepressant effects through the microbiota-gut-brain axis in a CUMS mouse model.

Chronic stress in adulthood results in microvascular dysfunction and subsequent depressive-like behavior

Depression is a prevalent mental disorder characterized by unknown pathogenesis and challenging treatment. Recent meta-analyses reveal an association between cardiovascular risk factors and an elevated risk of depression. Despite this, the precise role of vascular injury in depression development remains unclear. In this investigation, we assess vascular system function in three established animal models of depression— chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS) and maternal separation (MS)—utilizing ultrasonography and laser Doppler measurement. All three model animals exhibit anhedonia and despair-like behavior. However, significant microvascular dysfunction (not macrovascular) is observed in animals subjected to CUMS and CSDS models, while such dysfunction is absent in the MS model. Statistical analysis further indicates that microcirculation dysfunction is not only associated with depression-like behavior but is also intricately involved in the development of depression in the CUMS and CSDS models. Furthermore, our study has proved for the first time that endothelial nitric oxide synthase-deficient (eNOS+/−) mice, which is a classic model of vascular endothelial injury, showed depression-like behavior which occurred two months later than microvascular dysfunction. Notably, the mitigation of microvascular dysfunction successfully reverses depression-like behavior in eNOS+/− mice by enhancing nitric oxide production. In conclusion, this study unveils the pivotal role of microvascular dysfunction in the onset of depression induced by chronic stress in adulthood and proposes that modulating microvascular function may serve as a potential intervention in the treatment of depression.

Breakdown of the blood-brain barrier in depressed mice induced by chronic unpredictable mild stress

BackgroundRecent studies have suggested potential impairment of the blood-brain barrier (BBB) in depression. However, due to the limited research and variability in animal models, further investigation using diverse and stable models is necessary. MethodsA male mouse model of depression was established using the chronic unpredictable mild stress (CUMS) protocol. Following model establishment, depression-like behaviors were assessed using the sucrose preference test, tail suspension test, and forced swimming test. Morphological changes in the hippocampus were examined through hematoxylin-eosin staining. BBB permeability was evaluated using the Evans blue leakage test, fluorescein sodium (NaF) leakage test, and serum S100B content assessment. Gene and protein expression levels of BBB-related proteins in the hippocampus were determined via real-time PCR, western blotting, and immunofluorescence assays. ResultsCUMS exposure induced depression-like behaviors, including reduced body weight gain, diminished sucrose preference, and prolonged immobility in both the tail suspension test and forced swimming test. While no significant pathological changes were observed in the hippocampus of either group, increased BBB permeability was noted in the CUMS group, as evidenced by enhanced NaF leakage into the brain parenchyma and elevated serum S100B levels. Gene expression analysis revealed downregulation of angiogenesis-related genes and tight junction proteins in the CUMS group. Additionally, protein levels of tight junction proteins Claudin-5 and ZO-1 were lower in the CUMS group compared to controls. LimitationsThis study is limited to a male mouse model, and the BBB in females is worth exploring in the future. ConclusionsIncreased BBB permeability and decreased expression of tight junction proteins Claudin5 and ZO-1 were observed in mice with CUMS-induced depression.

Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury Exacerbates Neurological Dysfunctions.

Nearly half of mild traumatic brain injury (mTBI) patients continue to experience residual neurological dysfunction, which may be attributed to exposure to stress. Ferroptosis, a newly discovered form of cell death, is increasingly recognized for its involvement in the pathophysiology of TBI. Understanding the mechanisms by which stress influences mTBI, particularly through ferroptosis, is crucial for the effective treatment and prevention of mTBI patients who are sensitive to stressful events. In our study, a mouse mTBI model was established. An acute restraint stress (RS) and a chronic unpredictable mild stress (CUMS) model then were applied to make acute and chronic stress, respectively. We found acute RS significantly delayed the recovery of reduced body weight and short-term motor dysfunctions and exacerbated cell insults and blood-brain barrier leakage caused by mTBI. Further studies revealed that acute RS exacerbates neuronal ferroptosis, pyroptosis, and apoptosis by promoting iron overloading in the neocortex following mTBI. Interestingly, the inhibition of ferroptosis with iron chelators, including deferoxamine and ciclopirox, reversed pyroptosis and apoptosis. Moreover, CUMS aggravated neurological dysfunctions (motor function, cognitive function, and anxiety-like behavior) and exacerbated brain lesion volume. CUMS also exacerbates ferroptosis, pyroptosis, and apoptosis by intensifying iron deposition, along with decreasing the expression of neuronal brain-derived neurotrophic factor and glucocorticoid receptor in the neocortex post mTBI. These effects were also mitigated by iron chelators. Our findings suggest that alleviating ferroptosis induced by iron deposition may represent a promising therapeutic approach for mTBI patients who have experienced stressful events.

CUMS induces depressive-like behaviors and cognition impairment by activating the ERS-NLRP3 signaling pathway in mice

Background and objectiveEndoplasmic reticulum stress (ERS), as a primary defense mechanism against stress, is closely related to mental disorders, but its pathogenesis is still unclear. This research seeks to explore the influence of ERS-nucleotide-bound oligomerized domain-like receptor protein 3 (NLRP3) signaling on mice's depressive-like behaviors and cognitive impairment. Design and methodWe carried out a study on 32 male C57BL/6J mice to investigate how chronic unpredictable mild stress (CUMS) can give rise to depressive-like behaviors and cognitive dysfunction, randomly dividing them into control, model, inhibitor, and agonist groups. We utilized ELISA to quantify dopamine (DA) and 5-hydroxytryptamine (5-HT) levels. Using Nissl and hematoxylin and eosin (H&E) staining, we assessed the number and morphology of hippocampal neurons and cells. Western blot and immunofluorescence staining detected the changes in ERS and inflammation-related pathways in the hippocampus. ResultsCUMS could induce ERS and activate NLRP3 inflammasome, causing neuronal damage and histopathological changes, eventually leading to depressive-like behaviors and cognitive impairment in mice. The abnormal activation of NLRP3 inflammasome could be restored by ERS blocker 4-phenyl butyric acid (PBA), thus reducing neuronal damage, and ameliorating depressive-like behaviors and cognitive disorder in mice. ConclusionOur study demonstrates a previously unknown link between ERS and NLRP3 inflammasome in CUMS mice. The ERS-NLRP3 signaling pathway may be activated by CUMS, potentially resulting in mice exhibiting depressive-like behaviors and cognitive dysfunction. Theoretical foundations for elucidating the pathogenesis of depression, as well as its prevention and treatment, will be established through the results.