Identification of differentially expressed genes in the medial prefrontal cortex of rats subjected to chronic unpredictable mild stress and treated with electroacupuncture.

Major depressive disorder is a chronic mental health condition that seriously impacts afflicted individuals. Although electroacupuncture has proven to be an effective therapy for depression, its underlying biological mechanism remains largely unknown. In this study, we aimed to investigate the effects of electroacupuncture on depression-like behavior and to identify potential target genes related to those effects. To achieve this, we subjected rats to chronic unpredictable mild stress (CUMS) and used sucrose preference, forced swimming, and open-field tests to determine their depression-like behavior in the absence or after receipt of electroacupuncture treatment. RNA sequencing technology was then used to reveal the differentially expressed genes associated with depression and electroacupuncture treatment effects in the medial prefrontal cortex (mPFC). Repeated electroacupuncture treatments at the Baihui (GV20) and Taichong (LR3) acupoints significantly alleviated depression-like behavioral defects in the animals. Genomic RNA sequencing revealed several significant changes in the mPFC transcriptome of rats that received treatment. Through differential gene expression analysis, we found that electroacupuncture reversed the CUMS-induced downregulation of 46 genes and upregulation of 13 genes. Among the differentially expressed genes, Casr, Bdkrb2, Gnb3, and Ccl1 were found to be associated with depression and electroacupuncture treatment effects. In conclusion, we verified that electroacupuncture treatment has an effective antidepressant effect, and the underlying mechanism involves multiple systems and targets.

Effects of chronic unpredictable mild stress on gut sensation and function in male mice.

Stress has been linked to the development of irritable bowel syndrome (IBS), and various methods have been explored to model IBS in combination with other stimuli. However, it remains unclear whether stress alone can induce IBS in animals. This study aimed to investigate the impact of chronic unpredictable mild stress (CUMS) on gastrointestinal sensation and function in mice and assess the potential of CUMS as a modeling approach for IBS. To evaluate the mice's behavior, we conducted open field test, sucrose preference test and weighed the mice, revealing that CUMS indeed induced anxiety and depression in the mice and caused weight loss. Further analyses, including fecal analysis, a total gastrointestinal transport test, and a colon propulsion test, demonstrated that CUMS led to abnormal defecation and disruptions in gastrointestinal motility in the mice. Additionally, the abdominal withdrawal reflex test indicated an increase in visceral sensitivity in CUMS-exposed mice. Histological examination using hematoxylin and eosin staining revealed no significant histological alterations in the colons of CUMS-exposed mice, but it did show a minor degree of inflammatory cell infiltration. In summary, the findings suggest that CUMS can replicate IBS-like symptoms in mice, offering a novel top-down approach to modeling IBS.

Hypothalamic Gene Expression in a Rat Model of Chronic Unpredictable Mild Stress Treated with Electroacupuncture.

Depression is characterized by the loss of pleasure and a depressed mood, and it is a common mental disorder in the twenty-first century. Multiple gene imbalances, which are considered pathological factors in depression, were detected in the brain. Electroacupuncture is an effective therapeutic approach for depression that has minimal side effects. As a crucial structure in the hypothalamus-pituitary-adrenal, the hypothalamus plays a key role in depression. Our study focused on the transcriptome level in the hypothalamus of depressive rats. After chronic unpredictable mild stress, the rats exhibited depressive-like behaviors, such as decreased sucrose consumption in the SPT, increased time in the central area of the OFT and increased immobility in the FST. Moreover, electroacupuncture alleviated depressive behaviors. Because of the importance of the hypothalamus in depression, we next detected gene expression in the hypothalamus. A total of 510 genes (125 upregulated genes and 385 downregulated genes) were detected in the hypothalamus of depressive rats. 15 of the 125 upregulated genes and 63 of the 385 downregulated genes could be altered by electroacupuncture, which suggests the antidepressant effect of electroacupuncture. Our study also provided the evidence that regulation of transcriptome in the hypothalamus might be a potential mechanism of electroacupuncture treatment.

Gamma auditory steady-state response as a promising electrophysiological biomarker for depression: an in vivo study with chronic unpredictable mild stress (CUS)-induced rats.

Gamma oscillations play a functional role in brain cognitions. Recently, auditory steady-state response (ASSR) has been reported abnormally in depression clinically, particularly in the low-gamma band. However, clinical electroencephalography research has challenges obtaining pure signals straight from the source level, making information isolation and precise localization difficult. Besides, the ASSR deficits pattern remains unclear. Herein, we focused on the origin of ASSR-primary auditory cortex (A1), the central node in the auditory pathway. We assessed the evoked-power and phase-synchronization using local field potentials (LFP) in depression (n = 21) and control (n = 22) rats. Subsequent processing of the received auditory information was examined using event-related potentials (AEPs). Results showed that depressed rats exhibited significant gamma ASSR impairments in peak-to-peak amplitude, inter-trial phase coherence, and signal-to-noise ratio. These deficits were more pronounced during 40-Hz auditory stimuli in right-A1, indicating severe gamma network abnormalities in the right auditory pathway. Besides, increased N2 and P3 amplitudes in depression group were found, indicating excessive inhibitory control and contextual processing. Taken together, these ASSR abnormalities have a high specificity of more than 90% and high sensitivity of more than 80% to distinguish depression under 40-Hz auditory stimuli. Our findings provided an abnormal gamma network in the auditory pathway, as a promising diagnostic biomarker in the future.

The potential beneficial effects of Lactobacillus plantarum GM11 on rats with chronic unpredictable mild stress- induced depression.

OBJECTIVE: The main purpose of the present study was to assess the beneficial effect of Lactobacillus plantarum GM11 (LacP GM11), screened from Sichuan traditional fermented food, in depressive rats induced by chronic unpredictable mild stress (CUMS). METHODS: Male SPF SD rats were randomly assigned to 3 groups: the control group, CUMS group and CUMS + LacP GM11 group (n = 10). The rats in the CUMS and LacP GM11 groups received CUMS stimulation for 42 d. The behavioral tests and levels of monoamine neurotransmitter, glucocorticoid hormone and brain-derived neurotrophic factor (BDNF) in the serum and hippocampus were measured. The effects of LacP GM11 on the mRNA and protein expression of BDNF and cAMP response element binding protein (CREB) in the hippocampus were also investigated. RESULTS: After supplementation for 21 d, LacP GM11 was associated with alleviation of depressive-like behavior, not anxiety-like behavior, in depressive rats. LacP GM11 increased the levels of 5-hydroxytryptamine (5-HT) and BDNF and decreased the level of cortisol (CORT) in the serum and hippocampus in depressed rats. In addition, treatment with LacP GM11 also increased the mRNA and protein expression of BDNF and CREB in the hippocampus. CONCLUSIONS: This work has revealed that LacP GM11 has potential beneficial effects on depression. This effect might be related to alleviating monoamine neurotransmitter deficiency, HPA axis hyperfunction and CREB-BDNF signaling pathway downregulation. This study demonstrates that LacP GM11 could be a potential therapeutic approach to treat depression and other mental health problems.

Level of Cytokines and C3 Complement in the Blood of Rats under Conditions of Chronic Unpredictable Stress of Different Durations.

The parameters of the cytokine profile and functional activity of the complement system in the blood of rats were studied during different time periods of chronic unpredictable mild stress using a model of sequentially alternating low-intensity stress effects for 1, 2, 3, and 4 weeks. In the dynamics of observation, a general tendency towards multidirectional fluctuations in the concentration of cytokines was revealed: an increase in IL-10, but a decrease in IL-4 in comparison with the control. Statistically significant changes in the level of IL-10 were noted after 2, 3, and 4 weeks, IL-4 - after 2 and 4 weeks of stress loads. The percentage of lysis of the C3 component in rats gradually increased by the 2nd week of chronic stress, but then decreased and practically did not differ from the control values (intact animals) by the end of the study. These results illustrate the specificity of changes in the indicators of the C component of the complement system and the cytokine profile of the blood reflecting activity of the cellular and humoral components of the immune response in rats exposed to repeated stress factors of different origins and duration.

Disruption of IDO signaling pathway alleviates chronic unpredictable mild stress-induced depression-like behaviors and tumor progression in mice with breast cancer.

Women with breast cancer (BC) are often combined with psychological disorder such as depression and anxiety. Depression is associated or correlated with increased toxicity and severity of physical symptoms. However, the mechanism of BC progression related to the regulation of emotion-related circuitry remains to be further explored. The study aims to investigate indoleamine 2,3-dioxygenase (IDO) pathway mechanism underlying stress-induced progression of BC. BC cell line 4T1 was subcutaneously inoculated into BALB/c mice, and they then received daily chronic unpredictable mild stressors (CUMS) for 12 weeks. Depression-like behavior tests were conducted, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and novelty suppressed feeding test (NSF). The levels of 5-Hydroxytryptamine (5-HT) and inflammatory factors, IL-6, CXCL1, IL-10 and IL-4 were measured by enzyme linked immunosorbent assay (ELISA) of mouse serum. Immunohistochemical staining was performed to detect Ki67- or FOXP3-positive tumor cells. The status of IDO signaling pathway was assessed by immunoblotting analysis. CUMS induced depression-like behaviors, decreased the level of 5-HT, promoted tumor progression, enhanced the immunohistochemical staining of Ki-67, and promoted the activation of IDO signaling pathway in BC mice. The IDO signaling pathway was disrupted in mice by lentiviral transduction of shRAN-IDO. Lentivirus-mediated IDO knockdown attenuated CUMS-induced depression-like behaviors, increased the level of 5-HT, inhibited tumor progression, and reduced the immunohistochemical staining of Ki-67 in BC mice. The present study suggests that disruption of IDO signaling pathway alleviates CUMS-induced depression-like behaviors and inhibits tumor progression in BC mice.

Activation of mTORC1 Signaling Cascade in Hippocampus and Medial Prefrontal Cortex Is Required for Antidepressant Actions of Vortioxetine in Mice.

BACKGROUND: Although thought of as a multimodal-acting antidepressant targeting the serotonin system, more molecules are being shown to participate in the antidepressant mechanism of vortioxetine. A previous report has shown that vortioxetine administration enhanced the expression of rapamycin complex 1 (mTORC1) in neurons. It has been well demonstrated that mTORC1 participates in not only the pathogenesis of depression but also the pharmacological mechanisms of many antidepressants. Therefore, we speculate that the antidepressant mechanism of vortioxetine may require mTORC1. METHODS: Two mouse models of depression (chronic social defeat stress and chronic unpredictable mild stress) and western blotting were first used together to examine whether vortioxetine administration produced reversal effects against the chronic stress-induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex (mPFC). Then, LY294002, U0126, and rapamycin were used together to explore whether the antidepressant effects of vortioxetine in mouse models of depression were attenuated by pharmacological blockade of the mTORC1 system. Furthermore, lentiviral-mTORC1-short hairpin RNA-enhanced green fluorescence protein (LV-mTORC1-shRNA-EGFP) was adopted to examine if genetic blockade of mTORC1 also abolished the antidepressant actions of vortioxetine in mice. RESULTS: Vortioxetine administration produced significant reversal effects against the chronic stress-induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and mPFC. Both pharmacological and genetic blockade of the mTORC1 system notably attenuated the antidepressant effects of vortioxetine in mice. CONCLUSIONS: Activation of the mTORC1 system in the hippocampus and mPFC is required for the antidepressant actions of vortioxetine in mice.

18ß-Glycyrrhetinic Acid Ameliorates Neuroinflammation Linked Depressive Behavior Instigated by Chronic Unpredictable Mild Stress via Triggering BDNF/TrkB Signaling Pathway in Rats.

Evidence shows that inflammatory responses may encompass the onset of severe depressive illness. Traditionally used licorice contains 18ß-glycyrrhetinic acid (18ßGA), which has been demonstrated to reduce inflammation and oxidative stress. This study investigates the antidepressant effects of 18ßGA and the underlying mechanism in rats exposed to chronic unpredictable mild stress (CUMS). Wistar rats were exposed to CUMS for 36 consecutive days to establish depression. 18ßGA (10, 20, and 50 mg/kg) or fluoxetine was given once daily (from day 30 to day 36). Thereafter, behavior parameters (sucrose preference test, forced-swimming test, open-field test, body weight), pro-inflammatory cytokines, neurotransmitters, adrenocorticotropic hormone (ACTH), corticosterone (CORT), and liver biomarkers were studied. Immunohistochemistry and western blot analyses were conducted to investigate the protein's expression. 18ßGA (20 and 50 mg/kg) treatment increased sucrose intake, locomotion in the open-field test, decreased immobility time in the forced swim test, and improved body weight in CUMS-exposed rats. The therapy of 18ßGA dramatically declined cytokines, ACTH and CORT and improved 5HT and norepinephrine in CUMS rats. Furthermore, BDNF and TrkB proteins were down-regulated in CUMS group, which was increased to varying degrees by 18ßGA at doses of 20 and 50 mg/kg. Therefore, 18ßGA ameliorates depressive-like behavior persuaded by chronic unpredictable mild stress, decreases neuroinflammation, liver biomarkers, stress hormones, and improves body weight, brain neurotransmitter concentration via activating on BDNF/TrkB signaling pathway in both PFC and hippocampus in rats.

Combining network pharmacology and experimental verification to reveal the mechanism of Chaigui granules in the treatment of depression through PI3K/Akt/mTOR signaling pathways.

INTRODUCTION: Chaigui granules are a novel manufactured traditional Chinese antidepressant medicine, which is originated from the ancient classical prescription of Xiaoyaosan. It ameliorated depression-like behavior and concomitant symptoms in animal models. But its antidepressant mechanism is still unclear. Therefore, network pharmacology and molecular biology were used to explore underlying antidepressant mechanism in this study. METHODS: Firstly, network pharmacology was used to screen main active ingredients and potential targets in the treatment of depression with Chaigui granules, and to perform pathway enrichment analysis. Secondly, chronic and unpredictable mild stress-induced depression model rats were used, and behavioral tests were used to evaluate the antidepressant effect of Chaigui granules. Finally, the core targets and key pathways predicted by network pharmacology were validated by qRT-PCR and Western blot to determine the relevant gene and protein expression levels in rat hippocampus. RESULTS: The results of network pharmacology indicated that the PI3K/Akt signaling pathway may play a key role in antidepressant of Chaigui granules. The results of animal experiments showed that Chaigui granules significantly modulated behavioral indicators. Subsequently, the upregulation of relative mRNA levels of mTOR, Akt and PI3K and downregulation of GSK-3ß and FoxO3a were observed in rat hippocampus by molecular biology diagnosis. In addition, the decreased expression of Akt and mTOR in CUMS rats hippocampus was significantly reversed, and the expression levels of GSK-3ß and FoxO3a were upregulated. CONCLUSIONS: Based on the results of network pharmacology and animal experiment validation, Chaigui granules may reverse CUMS-induced depression-like behavior in rats through PI3K/Akt/mTOR signaling pathway.

Total saponins of panax ginseng via the CX3CL1/CX3CR1 axis attenuates neuroinflammation and exerted antidepressant-like effects in chronic unpredictable mild stress in rats.

Total saponins of Panax ginseng (TSPG) have antidepressant effects. However, the underlying antidepressant mechanism of TSPG remains not clear. This study aimed to predict the mechanism of TSPG by bioinformatics analysis and to verify it experimentally. Bioinformatics analysis showed that the antidepressant effects of TSPG may be related to inflammation, and CX3CL1/CX3CR1 may play a key mediating role. Wistar rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks, and TSPG (50 mg/kg/d, 100 mg/kg/d) was administered throughout the modeling period. It was found that TSPG improves depressive behavior and reduces neuropathic damage in the hippocampus in rats. Meanwhile, TSPG decreased mRNA and protein expression of pro-inflammatory cytokines and CX3CL1/CX3CR1 and inhibited P38 and JNK protein phosphorylation in the hippocampus. Rat astrocytes were employed to explore further the potential mechanism of TSPG in regulating CX3CL1/CX3CR1. The results showed that CX3CL1 small interfering RNA (siRNA-CX3CL1) and CX3CR1 inhibitor (JMS-17-2) had similar effects to TSPG, that is, reduced inflammatory response, reactive oxygen species (ROS), and phosphorylation of P38 and JNK proteins, while overexpression of CX3CL1 (pcDNA-CX3CL1) counteracted the above effects of TSPG. It is suggested that the antidepressant effect of TSPG may be achieved through inhibition of CX3CL1/CX3CR1.

Antidepressant-like effects of geniposide in chronic unpredictable mild stress-induced mice by regulating the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 networks.

Evidence exists suggesting the anti-depressive activities of geniposide (GP), a major compound in Gardenia jasminoides Ellis. Accordingly, the present study attempts to explore the anti-depressive mechanism of GP in chronic unpredictable mild stress (CUMS)-induced depression-like behaviors of mice. CUMS-induced mice were given GP daily and subjected to behavioral tests to observe the effect of GP on the depression-like behaviors. It was noted that GP administration reduced depression-like behaviors in CUMS mice. Transcriptome sequencing was conducted in three control and three CUMS mice. Differentially expressed circRNAs, lncRNAs and mRNAs were then screened by bioinformatics analyses. Intersection analysis of the transcriptome sequencing results with the bioinformatics analysis results was followed to identify the candidate targets. We found that Gata2 alleviated depression-like behaviors via the metabolism- and synapse-related pathways. Gata2 was a target of miR-25-3p, which had binding sites to circ_0008405 and Oip5os1. circ_0008405 and Oip5os1 competitively bound to miR-25-3p to release the expression of Gata2. GP administration ameliorated depression-like behaviors in CUMS mice through regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks. Taken together, GP may exert a potential antidepressant-like effect on CUMS mice, which is ascribed to regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks.

α-Cyperone ameliorates depression in mammary gland hyperplasia and chronic unpredictable mild stress rat by regulating hormone, inflammation, and oxidative stress.

BACKGROUND: Hyperplasia of mammary gland (HMG) is caused by endocrine disorders, and patients are prone to anxiety and depression. α-Cyperone has a variety of pharmacological activities including antidepressant. The purpose of this study was to explore the effect and its possible mechanism of α-Cyperone on HMG-associated depression rats. METHODS: The depression model was constructed using chronic unpredictable mild stress (CUMS), while the HMG model was induced by estrogen, with or without α-Cyperone intervention. The effect of α-Cyperone on the depression-like phenotype of model rats was measured by sucrose preference test (SPT), forced swim test (FST), and open field test (OFT). Dendritic spines density in ventral medial prefrontal cortex (vmPFC) neurons was evaluated by Golgi staining. The second pair of nipple height, diameter, organ index, and oxidative stress-related factors were analyzed. Serum sex hormone concentration, histopathological changes, inflammatory factor expression, and p65 were evaluated by enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (HE) staining, real-time quantitative PCR and western blot, respectively. RESULTS: The sucrose preference rate, dendritic spine density decreased, and immobility time increased in CUMS rats; α-Cyperone reversed the effect of CUMS on depression-like behavior and dendritic spine density in rats. α-Cyperone reduced nipple height and diameter, uterine index, estradiol concentration, increased ovary, thymus, spleen index, progesterone, and testosterone concentration, relieved pathological damage, oxidative stress, depression-like behavior, and inflammatory reaction in HMG combine CUMS rats. In addition, α-Cyperone inhibited the phosphorylation of p65 in HMG and CUMS rats. CONCLUSIONS: α-Cyperone has an effective therapeutic effect on HMG combined with CUMS rats.

Optimization of Monobenzone-Induced Vitiligo Mouse Model by the Addition of Chronic Stress.

Vitiligo is a common primary, limited or generalized skin depigmentation disorder. Its pathogenesis is complex, multifactorial and unclear. For this reason, few animal models can simulate the onset of vitiligo, and studies of drug interventions are limited. Studies have found that there may be a pathophysiological connection between mental factors and the development of vitiligo. At present, the construction methods of the vitiligo model mainly include chemical induction and autoimmune induction against melanocytes. Mental factors are not taken into account in existing models. Therefore, in this study, mental inducement was added to the monobenzone (MBEH)-induced vitiligo model. We determined that chronic unpredictable mild stress (CUMS) inhibited the melanogenesis of skin. MBEH inhibited melanin production without affecting the behavioral state of mice, but mice in the MBEH combined with CUMS (MC) group were depressed and demonstrated increased depigmentation of the skin. Further analysis of metabolic differences showed that all three models altered the metabolic profile of the skin. In summary, we successfully constructed a vitiligo mouse model induced by MBEH combined with CUMS, which may be better used in the evaluation and study of vitiligo drugs.

Polygalae Radix Oligosaccharide Esters May Relieve Depressive-like Behavior in Rats with Chronic Unpredictable Mild Stress via Modulation of Gut Microbiota.

Polygalae radix (PR) is a well-known traditional Chinese medicine that is used to treat depression, and polygalae radix oligosaccharide esters (PROEs) are the main active ingredient. Although gut microbiota are now believed to play key role in depression, the effects of PROEs on depression via modulation of gut microbiota remain unknown. In this article, we investigate the effect of PROEs on the gut microbiota of a depression rat and the possible mechanism responsible. The depression rat model was induced by solitary rearing combined with chronic unpredictable mild stress (CUMS). The depression-like behavior, the influence on the hypothalamic-pituitary-adrenal (HPA) axis, the contents of monoamine neurotransmitter in the hippocampus, and the quantity of short-chain fatty acids (SCFAs) in the feces were each assessed, and the serum levels of lipopolysaccharide (LPS) and interleukin-6 (IL-6) were measured by ELISA. Additionally, ultrastructural changes of the duodenal and colonic epithelium were observed under transmission electron microscope, and the gut microbiota were profiled by using 16S rRNA sequencing. The results show that PROEs alleviated the depression-like behavior of the depression model rats, increased the level of monoamine neurotransmitters in the brain, and reduced the hyperfunction of the HPA axis. Furthermore, PROEs regulated the imbalance of the gut microbiota in the rats, relieving intestinal mucosal damage by increasing the relative abundance of gut microbiota with intestinal barrier protective functions, and adjusting the level of SCFAs in the feces, as well as the serum levels of LPS and IL-6. Thus, we find that PROEs had an antidepressant effect through the restructuring of gut microbiota that restored the function of the intestinal barrier, reduced the release of intestinal endotoxin, and constrained the inflammatory response.

The Antidepressant Activity of a Taurine-Containing Derivative of 4-Phenylpyrrolidone-2 in a Model of Chronic Unpredictable Mild Stress.

This study investigates the therapeutic potential of a new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner's chronic unpredictable mild stress model of male Wistar rats was used as a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group with saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light-dark box, were used to assess the animals' conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to the intact animals. These results suggest that Compound I has reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

[Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway].

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1ß), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

Comparison of the chronic unpredictable mild stress and the maternal separation in mice postpartum depression modeling.

Postpartum depression (PPD) is a serious mental health concern of new mothers worldwide. In view of the particularity of puerpera, the research on pathogenesis and drug development of PPD are highly dependent on animal models. Although both maternal separation (MS) and chronic unpredictable mild stress (CUMS) modeling approaches have been used in PPD studies, the characteristics of the two rodent models have not been compared to explain which is more advantageous in PPD research. In this study, we applied 21-day MS and CUMS paradigms to induce mouse model of PPD and compared their differences in behavior, physiology and gut microbiota. As a result, the two models exhibited significant increases of immobility time in forced swim test (FST) and tail suspension test (TST), whereas sucrose preference index and pup weight were significantly decreased. Both displayed depression-like behaviors, and CUMS was more obvious, which demonstrated by the lower levels of 5-hydroxytryptamine (5-HT) and higher hypothalamic-pituitary-adrenal (HPA) axis related mRNA expression (corticotropin releasing hormone, corticotropin releasing hormone receptor 1) in CMUS group than that in MS group. The gut microbiota in MS and CUMS groups were significantly different in terms of the relative abundances of Bacteroidetes, Firmicutes, Proteobacteria. In conclusion, MS model and CUMS model have different performance in behavior and physiology. The CUMS model showed more obvious parameter changes, which may be more suitable for PPD induced by various social environmental factors.

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model.

Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP's metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.

Loureirin C and Xanthoceraside Attenuate Depression-Like Behaviors and Expression of Interleukin-17 in the Prefrontal Cortex Induced by Chronic Unpredictable Mild Stress in Mice.

Major depressive disorder (MDD) is the most prevalent and serious psychiatric disease involving inflammation. Loureirin C and Xanthoceraside are extracts of dragon's blood and Xanthoceras sorbifolia Bunge, respectively, which have neuroprotective and anti-inflammatory properties. In this study, we examined whether Loureirin C and Xanthoceraside attenuated depression-like behaviors and inflammation induced by chronic unpredicted mild stress (CUMS) in mice. Adult C57BL/6 J mice exposed to CUMS for 4 weeks showed depression-like behaviors characterized by hyperactivity in a novel environment, decreased interaction time in the social interaction test, prolongation of eating latency in the novelty suppressed feeding test, and increased immobility in the forced swimming test. CUMS increased the expression of interleukin-17 (IL-17) in the prefrontal cortex (PFC). One week after exposure to CUMS, the mice were treated with Loureirin C (0.64 mg/kg) or Xanthoceraside (1.28 mg/kg) once a day for 3 weeks during CUMS. Loureirin C and Xanthoceraside significantly attenuated CUMS-induced behavioral impairment. Furthermore, both Loureirin C and Xanthoceraside prevented IL-17 expression induced by CUMS in the PFC. This data suggests that Loureirin C and Xanthoceraside have antidepressant-like properties that may be associated with the inhibition of IL-17 expression.