Chronic Stress-induced Depression Model Research Articles

SARM1 deficiency induced depressive-like behavior via AMPKα/p-eEF2 axis to synapse dysfunction

Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signaling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signaling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.

The improvement effect of exercise on rats with chronic stress-induced depression-like behavior: a discussion based on the kynurenine pathway.

To observe the effects of 4 weeks of voluntary wheel running on depressive-like behavior in a rat chronic stress-induced depression model to explore the anti-depressive mechanism of exercise. In this observational study, 36 Sprague-Dawley rats were randomly divided into control, stress model, and stress exercise groups (12 rats/group). The control group received no intervention, and the stress model and stress exercise group rats underwent chronic mild unpredictable stress and isolation. The stress exercise group rats also underwent 4 weeks of voluntary wheel running. Behavioral changes and hippocampal protein and mRNA expression levels were detected. Voluntary wheel running significantly increased horizontal and vertical movements, sucrose intake, and the sucrose preference percentage and reduced immobility time in the forced swimming test in depression model rats. The hippocampal tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and quinolinic acid levels were significantly decreased, while the IL-4, IL-10, and kynurenic acid levels were significantly increased. Kynurenine-3-monooxygenase and 3-hydroxyanthranilate-3, 4-dioxygenase mRNA levels were downregulated, and kynurenine aminotransferase mRNA was upregulated. Voluntary wheel running improved depressive-like behavior in depression model rats. The mechanism may be related to a kynurenine pathway metabolite level imbalance, which has neurotoxic and neuroprotective effects, caused by long-term voluntary wheel running.

Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis

BackgroundGut microbiota plays a critical role in the pathogenesis of depression and are a therapeutic target via maintaining the homeostasis of the host through the gut microbiota–brain axis (GMBA). A co-decoction of Lilii bulbus and Radix Rehmannia Recens (LBRD), in which verbascoside is the key active ingredient, improves brain and gastrointestinal function in patients with depression. However, in depression treatment using verbascoside or LBRD, mechanisms underlying the bidirectional communication between the intestine and brain via the GMBA are still unclear. PurposeThis study aimed to examine the role of verbascoside in alleviating depression via gut-brain bidirectional communication and to study the possible pathways involved in the GMBA. MethodsKey molecules and compounds involved in antidepressant action were identified using HPLC and transcriptomic analyses. The antidepressant effects of LBRD and verbascoside were observed in chronic stress induced depression model by behavioural test, neuronal morphology, and synaptic dendrite ultrastructure, and their neuroprotective function was measured in corticosterone (CORT)-stimulated nerve cell injury model. The causal link between the gut microbiota and the LBRD and verbascoside antidepressant efficacy was evaluate via gut microbiota composition analysis and faecal microbiota transplantation (FMT). ResultsLBRD and Verbascoside administration ameliorated depression-like behaviours and synaptic damage by reversing gut microbiota disturbance and inhibiting inflammatory responses as the result of impaired intestinal permeability or blood-brain barrier leakiness. Furthermore, verbascoside exerted neuroprotective effects against CORT-induced cytotoxicity in an in vitro depression model. FMT therapy indicated that verbascoside treatment attenuated gut inflammation and central nervous system inflammatory responses, as well as eliminated neurotransmitter and brain–gut peptide deficiencies in the prefrontal cortex by modulating the composition of gut microbiota. Lactobacillus, Parabacteroides, Bifidobacterium, and Ruminococcus might play key roles in the antidepressant effects of LBRD via the GMBA. ConclusionThe current study elucidates the multi-component, multi-target, and multi-pathway therapeutic effects of LBRD on depression by remodeling GMBA homeostasis and further verifies the causality between gut microbiota and the antidepressant effects of verbascoside and LBRD.

Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression.

Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression-targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFα, IL-1β and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression.

Influence of electroacupuncture on nestin expression in hippocampus neural stem cells of the chronic stress induced depression model rats

目的 观察电针对慢性应激抑郁模型大鼠海马神经干细胞巢蛋白(Nestin)的影响.方法 将雄性SD大鼠按照数字表法随机分为健康组、模型组、电针组和氟西汀组,每组10只.采用慢性不可预知温和应激结合孤养的方法制备模型.电针组选取印堂穴和百会穴,接HANS LH202H型电针仪,频率2 Hz,电流强度0.6 mA,治疗30 min,每天1次,共21 d.氟西汀组大鼠按3.3 mg/kg腹腔注射氟西汀,每天1次,共治疗21 d.用游泳不动时间测行为学,用免疫组化检测海马神经干细胞Nestin的表达.结果 健康组、模型组、电针组、氟西汀组大鼠游泳不动时间分别为(14.40±2.17)s、(37.50±7.69)s、(30.10±4.53)s、(32.10±4.98)s.与健康组比较,模型组大鼠游泳不动时间显著延长(t=7.53,P＜0.01),海马神经干细胞Nestin阳性表达降低(P＜0.01).与模型组比较,电针组、氟西汀组大鼠游泳不动时间明显减少(F=4.89,P＜0.05),海马神经干细胞Nestin阳性表达增强(χ2=12.057,P＜0.01),电针组与氟西汀组之间差异无统计学意义(χ2=3.899,P＞0.05).结论 应激引起大鼠海马神经干细胞巢蛋白表达降低,而电针刺激可以促进抑郁模型大鼠海马神经干细胞增殖,改善慢性应激大鼠的行为表现.这可能是电针对慢性应激抑郁模型大鼠海马损伤的保护作用机制之一。

The effects of mangiterin on the improvement of behavior and expression of brain-derived neurotrophic factor in the hippocampus of chronic stress-induced depression model mice

Objective To explore the effects of mangiterin on behaviors and brain-derived neurotrophic factor(BDNF) of hippocampus in chronic stress depression mice. Methods 60 male mice were randomly divided into normol control group, model group, fluoxetin control group and mangiterin groups(low, medium and high dose), 10 mice in each group.All mice except normal control group were singly housed and subjected to chronic stress-induced depression model for 21 consecutive days.The behaviors of mice were detected by open-field test and tail-suspension test.The expression of BDNF in the hippocampus were assessed using western blot. Results Compared with the normal group, mice exposed chronic stress showed decreased body weight((5.33±1.20)g), crossing lines(102±18) and distances((3425±112)mm) notably decreased in open-field behavior test.The duration of immobility during tail-suspension was increased significantly.BDNF expression in the hippocampus(0.45±0.03) was downregulated significantly(P 0.05). Conclusion Mangiterin can ameliorate behavior impairment of chronic stress induced-depression mice and it may be related to the upregulation of BDNF expression in the hippocampus. Key words: Mangiterin; Chronic stress-induced depression; Brain-derived neurotrophic factor

Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San

To screen microRNAs with specific expression of in hippocampus of rats with chronic stress induced depression model, and observe the effect of traditional Chinese medicine Chaihu Shugan San on the expression of microRNA in hippocampus. SD rats were randomly divided into 3 groups: the normal control group, the model control group and the Chaihu Shugan San group. The depression model was replicated by unpredictable chronic mild stress combined with separation. Behavioral changes of the rats were observed by Open-field test and sucrose solution consumption test, and the expression of microRNAs in hippocampus was assayed by microRNA micro-array. Compared with the normal control group, there were 13 specific miRNAs in hippocampus in the model control group with the expression difference of more than 2 times. Among them, down-regulating miRNAs included miR298, miR-130b, miR-135a, miR-323, miR-503, miR-15b, miR-532, and miR-125a, and the up-regulation miRNAs included miR7a, miR-212, miR-124, miR-139, and miR-182. Among the 13 specific miRNAs, miR-125a and miR-182 recovered to normal after intervention with Chaihu Shugan San in the Chaihu Shugan San group. This study preliminarily found that 13 specific miRNAs in hippocampus are related to depression. Among them, miR-125a and miR-182 recover to normal after intervention with Chaihu Shugan San, which may be the target points of the antidepressant effect of Chaihu Shugan San. We shall further analyze the target genes and their mechanisms.

Study on the mechanism of interleukin-6 in the colonic motility changes of depression rat model

[Abstract] Objective To study the changes of colonic motility in chronic stress-induced depression rat model, the association between interleukin 6 （IL-6） and depression and its effects on contraction of colonic smooth muscle in vitro. Methods There were 30 healthy adult Wistar rats, of which chronic stress-induced depression model was created in 15 rats and the other 15 rats were in control group. The ratio of sugar consumption to body weight and the percentage of sugar preference were tested in these two rats groups through sugar preference experiments. The behavioral changes of two rats groups were detected by open field test. Colonic motility was evaluated with simulated fecal discharge experiment, and the serum IL-6 level was measured with enzyme linked immunosorbent assay （ELISA）. IL-6 in colon tissue at mRNA level was determined by RT-PCR. The contraction ability of rat colonic smooth muscle was observed. The colonic smooth muscle of control group was treated with different concentration of IL-6, the effects of IL6 on normal colonic smooth muscle and its response to acetylcholine （Ach） were evaluated. Results In model group, the ratio of sugar consumption to body weight was 0. 12±0. 03, the percentage of sugar preference was 16. 17%-±2.61%, total walking distance was （741.54±341.10） cm and total times of upright was 15.69＋ 8.00, which were all significantly lower than those of control group （0.18±0.02, 25.54±2.32%, 1336.20 cm±698.80 cm and 24.87±7.90, respectively） （P= 0. 041, 0. 044, 0. 002 and 0. 001）. It took （109. 78±48.00） min for defecating in model group, which was significantly longer than that of control group （28.00±11.10） min （P=0. 002）. The IL6 levels were high both in the serum and colon tissue of model group rats. The response of colonic smooth muscle to Aeh was weaker in model group than that of control group （P=0. 035）. In model group, there were no significant difference in the response of colonic smooth muscle to IL-6 at 200, 500 and 1000 pg/ml （P =0. 935,0. 825, 0. 766）. After Ach added, there was significant difference in the response to Aeh between IL-6 at 500, 1000 pg/ml （R=1.14804-0. 1000 and 1. 1361±0. 1500） and control group only added with Ach （R= 1. 6100±0. 4500） （P= 0. 000 and 0. 004）. Conclusion IL-6 level increase in chronic stress-induced depression rat model and causes smooth muscle contraction disorder through reducing the sensitivity of intestinal smooth muscle to Ach. Key words: Stress; Depressive disorder; Disease models, animal; Colon; Kinetics; Interleukin-6

Abnormity of SOD, MDA and COX-2 in colon of depression rats

：Objective To investigatethe abnormity of superoxide dismutase (SOD), malondialdehyde (MDA) and cyclooxygenase-2(COX-2) in colon of rats caused by depression.Methods The chronic stress-induced model ofdepression of wistar rats was produced . The experimental animals were randomly dividedinto model control and normal control in the study. The levels of SOD and MDA were assayedwith ultraviolet spectrophotometry. The expression of COX-2 in colonic tissue was detectedwith immunohistochemistry.Results Enhanced colon inflammatory response and oxidativestress were observed in the chronic stress-induced depression model of rats, whichmanifested as the significant increase of MDA, as well as the expressions of COX-2 in thecolon tissue, while the colonic SOD activity was significantly decreased compared with thenormal control (MDA: 10.34±2.77 vs 2.55±0.70; COX-2: 53.26±8.16 vs 4.87±1.05;SOD:53.39±11.15 vs 84.45±22.31; P <0.01). Conclusion Depression can induce injurieson colon of rats, which was probably due to the abnormity of metabolism of oxygen freeradical (OFR) and arachidonic acid. Key words: Depression model; Superoxide dismutase; Malondialdehyde; Cyclooxygenase-2