Depression In Rats Research Articles

GRP94 in cerebrospinal fluid may contribute to a potential biomarker of depression: Based on proteomics

The present study was designed to investigate potential biomarkers of depression and targets of antidepressants from the perspective of hippocampal endoplasmic reticulum stress (ERS) based on cerebrospinal fluid (CSF) proteomics. Firstly, a six-week depression model was established and treated with fluoxetine (FLX). We found antidepressant-FLX could ameliorate depression-like behaviors and cognition in depressed rats caused by chronic unpredictable mild stress (CUMS). FLX significantly increased neuronal numbers in dentate gyrus (DG) and CA3 regions of hippocampus. CSF proteome data revealed thirty-seven differentially expressed proteins (DEPs) co-regulated by CUMS and FLX, including GRP94 and EIF2α. Results of Gene Oncology (GO) annotation and KEGG pathway enrichment for DEPs mainly included PERK-mediated unfolded protein response, endoplasmic reticulum, and translational initiation. The expression levels of GRP94, p-PERK, p-EIF2α, CHOP and Caspase-12 were increased in hippocampus of CUMS rats, and FLX worked the opposite way. FLX had strong affinity and binding activity with GRP94 protein, and four key proteins on the PERK pathway (PERK, EIF2α, p-EIF2α, CHOP). We proposed that FLX may exert antidepressant effects and neuroprotective action by alleviating excessive activation of the hippocampal PERK pathway and reducing neuronal deficits in depressed rats. PERK, EIF2α, p-EIF2α, and CHOP may be potential targets for antidepressant-FLX. GRP94 in CSF may be a potential biomarker of depression and the therapeutic effects of antidepressants.

Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model.

To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on 1H-NMR metabolomics techniques, and to explore the potential mechanisms of exercise for the treatment of depression. Rats were randomly divided into blank control group (C), CUMS control group (D), pre-exercise with CUMS group (P), CUMS with aerobic exercise group, CUMS with resistance exercise group (R), and CUMS with aerobic + resistance exercise group (E). The corresponding protocol intervention was applied to each group of rats. Body weight, sucrose preference and open field tests were performed weekly during the experiment to evaluate the extent of depression in rats. Plasma samples from each group of rats were collected at the end of the experiment, and then the plasma was analyzed by 1H-NMR metabolomics combined with multivariate statistical analysis methods to identify differential metabolites and perform metabolic pathway analysis. (1) Compared with the group D, the body weight, sucrose preference rate, and the number of crossings and standings in the different types of exercise groups were significantly improved (p < 0.05 or p < 0.01). (2) Compared to group C, a total of 15 differential metabolites associated with depression were screened in the plasma of rats in group D, involving 6 metabolic pathways. Group P can regulate the levels of 6 metabolites: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group A can regulate the levels of 6 metabolites: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose and acetoacetic acid. Group R can regulate the levels of 6 metabolites: choline, lactate, inositol, glucose, phosphocreatine and acetoacetic acid. Group E can regulate the levels of 5 metabolites: choline, citric acid, glucose, acetone and acetoacetic acid. The different types of exercise groups can improve the depressive symptoms in CUMS rats, and there are common metabolites and metabolic pathways for their mechanism of effects. This study provides a powerful analytical tool to study the mechanism of the antidepressant effect of exercise, and provides an important method and basis for the early diagnosis, prevention and treatment of depression.

Do Autistic and Depressed Rats Express the Same Type of Maternal Care?

Autism is a neurodevelopmental disorder that is more frequently diagnosed in men. Nevertheless, through current diagnostic tools, women have also been found to be affected by this disorder, but in different ways. Few studies have been conducted regarding unique periods of life, such as motherhood. Yet, extant literature has already described the existence of a comorbidity between autism and postpartum depression. Thus, this study aimed to compare the maternal care sphere between two animal models of these diseases. Lactating rats were subdivided into three groups (n = 8 animals/group): 1) control dams; 2) maternal separation (MS) dams, separated from their litter for 3 h daily from lactating day (LD) 2–12 for postpartum depression induction; and 3) valproic acid (VPA) dams, which were the pups of dams treated with 400 mg/kg of VPA (i.p.) on gestational day 12.5 for autism induction. Maternal care tests were performed during lactation and, after weaning, dams were euthanized for the analysis of dopaminergic system on the prefrontal cortex. The results showed an impairment of maternal care of MS dams and an improvement of VPA dams, as well as alterations on dopaminergic system that corroborates the behavior data. These findings indicate that VPA dams express better maternal care, even with cognitive and socialization difficulties. This is probably due to a hyper-focus, as opposed to MS dams, which mimic the maternal care dysfunction expressed by women with postpartum depression.

Development of a novel UHPLC-MS/MS method for the quantification of corynoxeine: Application to pharmacokinetics and tissue distribution studies in normal and chronic unpredictable mild stress-induced depression rats

Corynoxeine, a natural active alkaloid found in Genus Uncaria, has been reported to have anti-depressant effects. In this study, a sensitive and efficient ultra-high performance liquid chromatography tandem mass spectrometry method for quantifying corynoxeine in rat plasma and tissues was established, validated and applied to investigate the pharmacokinetics and tissue distribution differences between normal rats and chronic unpredictable mild stress (CUMS)-induced depression model rats following oral administration. All bio-samples were prepared by methanol protein precipitation method with theophylline as internal standard (IS). Chromatographic separation was conducted on an Agilent ZORBAX Eclipse Plus C18 column using mobile phase A (acetonitrile) and B (0.1% formic acid in water) in gradient elution mode with a flow rate of 0.3 mL/min. Mass spectrometric detection was performed in multiple-reaction monitoring mode with positive electrospray ionization source. The transitions of m/z 383.0→160.2 for corynoxeine and m/z 181.1→124.0 for IS were chosen for quantification. The method showed good linearity, stability, accuracy, precision, recovery, and non-significant matrix effect, which were within the acceptable ranges. The pharmacokinetic results revealed that the absorption and bioavailability of corynoxeine in depression rats decreased compared to normal rats. The tissue distribution of corynoxeine trended to be mostly in the intestine and stomach and the distribution of this compound in intestine tissue of depression rats was significantly increased compared to the normal rats. The pharmacokinetics and tissue distribution profiles of corynoxeine were altered in CUMS-induced depression rats compared to normal rats and these experimental findings could provide beneficial information to the mechanism research and clinical applications of corynoxeine.

Ononin ameliorates depression-like behaviors by regulating BDNF-TrkB-CREB signaling in vitro and in vivo

Ethnopharmacological relevanceOnonin is a flavonoid compound found in several medicinal plants, including Astragalus membranaceus, Sophora flavescens, and Ononis spinosa. These plants have been traditionally used in various parts of the world for their medicinal properties, including anti-inflammatory, antioxidant, and antitumor effects. Major depression is a common, long-lasting, and recurrent psychiatric disorder with a high suicide rate. Naturally occurring flavonoids treat depression via poorly understood mechanisms. Aim of the studyThe present study aimed to determine whether ononin conferred an antidepressant-like effect in PC12 cell models and chronic mild stress (CMS)-induced depressive rat models and to explore its possible mechanisms. Materials and methodsDepression-related behaviors were measured using sucrose preference, tail suspension and open-field tests. Furthermore, to explore these mechanisms, we employed in vitro and in vivo assay methods, including neurite outgrowth, western blotting, quantitative RT-PCR, and staining methods. ResultsTreatment with ononin or BDNF significantly increased PC12 cells' neuronal growth and differentiation. Furthermore, ononin promotes the activation of TrkB and growth factors and upregulates the PI3K/Akt and BDNF/TrkB/CREB signaling pathways. The in vitro results were consistent with CMS-induced depressive rat models, in which ononin treatment significantly decreased depression-like behaviors and activated TrkB, growth factors, and BDNF/TrkB/CREB signaling pathways in the frontal cortex and hippocampus. Depression-induced microscopic alterations in the frontal cortex and hippocampus of rats with CMS-induced depression were also mitigated following ononin treatment. ConclusionBased on these findings, we suggest that ononin is a promising antidepressant candidate for treating depression.

Cherry leaf decoction inhibits NMDAR expression and thereby ameliorates CUMS- induced depression-like behaviors through downregulation of α2δ-1

Depression is a complex and prevalent mental illness. Cherry leaf is a traditional Chinese herbal medicine, which has confirmed to exert a certain antidepressant effect, but its potential neural regulation mechanism is not clear. This paper aims to investigate the improved action of cherry leaf decoction (CLD) on chronic unpredictable mild stress (CUMS) rats and its potential neural regulation mechanism by verifying the role and function of NMDAR regulatory target α2δ-1 in depression due to CUMS. Male SD rats were subjected to random stressors persisting for 5 weeks to establish the CUMS depression rat model. CLD could effectively alleviate depression-like behaviors of CUMS rats in behavioral tests including sucrose preference test, forced swimming test, tail suspension test and open field test. After the administration of the CLD, the expression of corticotropic-releasing hormone (CRH) in the hypothalamus was inhibited. Moreover, the levels of CRH, adrenal cortical hormone (ACTH) and corticosterone (CORT) in serum also decreased significantly. CUMS upregulated the expressions of α2δ-1, N-methyl-d-aspartate receptor 1 (NR1), NR2A and NR2B, and enhanced the binding ability to of α2δ-1 and NR1, which were reversed by CLD. The results demonstrated that CLD could ameliorate depression-like behaviors due to CUMS, which was related to the fact that CLD down-regulated α2δ-1 level and interfered with α2δ-1 binding to NR1, thereby reducing NMDAR expression and ultimately inhibiting HPA axis activity.

Screening the components in multi-biological samples and the comparative pharmacokinetic study in healthy and depression model rats of Suan-Zao-Ren decoction combined with a network pharmacology

Ethnopharmacological relevanceSuanzaoren Decoction (SZRD) is a classic traditional Chinese prescription, which has been commonly used for treating insomnia, depression and other nerve system diseases for a long time. Aim of this studyThe present study aimed to explore the metabolic profiles in multi-biological samples and pharmacokinetic mechanism between healthy and depression model rats combined with a network pharmacology approach after administration of SZRD. Materials and methodsIn our study, an ultra-high performance liquid chromatography (UPLC)-Q-Exactive Orbitrap Mass Spectrometry method was firstly used to study the prototype components and metabolites of SZRD in plasma, brain, urine, and feces between healthy and depressed rats. The possible metabolic pathways were also speculated. Then a network pharmacological study was conducted on the components in the plasma of model rats. According to the above components screened by network pharmacology and the other reported representative active components, the comparative pharmacokinetic study was established for the simultaneous determination of mangiferin, spinosin, ferulic acid, liquiritin, formononetin. magnoflorine and isoliquiritin between healthy and depression model rats. Finally, molecular docking was used to validate the binding affinity between key potential targets and active components in pharmacokinetics. ResultsA total of 115 components were identified in healthy rats, and 101 components were identified in model rats. The prototype components and metabolites in plasma, brain, urine, and feces were also distinguished. The main metabolic pathways included phase I and phase II metabolic reactions, such as dehydrogenation, oxidation, hydroxylation, gluconaldehyde conjugation, glutathione conjugation and so on. These results provided a basis for the further study of antidepressive pharmacokinetic and pharmacological action in SZRD. Then, according to the degree value of network pharmacological study, it was predicted that 10 components and 10 core targets, which involved in the critical pathways such as neuroactive ligand-receptor interaction, cyclic adenosine monophosphate (cAMP) signaling pathway, serotonergic synapse, phosphatidylinositol-3 kinase (PI3K)-Akt signaling pathway, etc. Finally, the established pharmacokinetic method was successfully applied to compare the pharmacokinetic behavior of these 7 active components in plasma of healthy and depressed rats after oral administration of SZRD. It showed that except magnoflorine, the pharmacokinetic parameters of each component were different between healthy and depressed rats. Molecular docking analysis also indicated that the active compounds in pharmacokinetics could bind tightly to the key targets of network pharmacological study. ConclusionThis study may provide important information for studying the action mechanism of SZRD in treating depression.

Input-output relation of midbrain connectomics in a rodent model of depression

BackgroundThe symptoms associated with depression are believed to arise from disruptions in information processing across brain networks. The ventral tegmental area (VTA) influences reward-based behavior, motivation, addiction, and psychiatric disorders, including depression. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB), is an emerging therapy for treatment-resistant depression. Understanding the depression associated anatomical networks crucial for comprehending its antidepressant effects. MethodsFlinders Sensitive Line (FSL), a rodent model of depression and Sprague-Dawley rats (n = 10 each) were used in this study. We used monosynaptic tracing to map inputs of VTA efferent neurons: VTA-to-NAc nucleus accumbens (NAc) (both core and shell) and VTA-to-prefrontal cortex (PFC). Quantitative analysis explored afferent diversity and strengths. ResultsVTA efferent neurons receive a variety of afferents with varying input weights and predominant neuromodulatory representation. Notably, NAc-core projecting VTA neurons showed stronger afferents from dorsal raphe, while NAc shell-projecting VTA neurons displayed lower input strengths from cortex, thalamus, zona incerta and pretectal area in FSL rats. NAc shell-projecting VTA neurons showed the most difference in connectivity across the experimental groups. LimitationsLack of functional properties of the anatomical connections is the major limitation of this study. Incomplete labeling and the cytotoxicity of the rabies virus should be made aware of. ConclusionsThese findings provide the first characterization of inputs to different VTA ascending projection neurons, shedding light on critical differences in the connectome of the midbrain-forebrain system. Moreover, these differences support potential network effects of these circuits in the context of MFB DBS neuromodulation for depression.

Fecal metabolomics combined with metagenomics sequencing to analyze the antidepressant mechanism of Yueju Wan

BackgroundYueju Wan (YJW), defined in Danxi's Mastery of Medicine, has Qi-regulating and Qi-promoting effects. YJW has frequently been applied in the clinic for the treatment of depression. Substantial evidence has shown that depression is related to metabolic abnormalities of the gut microbiota, and traditional Chinese medicine (TCM) can treat depression by adjusting gut microbiota metabolism. The antidepressant effect of YJW is well established, but thus far, whether its mechanism of action is achieved by regulating the intestinal flora has not been elucidated. MethodsIn this study, chronic unpredictable mild stress (CUMS) along with isolated feeding created a rat depression model, and YJW was administered for intervention. Rats were put through behavioral tests to determine their level of depression, and ELISA was utilized for measuring the level of monoamine neurotransmitters (MNTs) in the hippocampus. Metagenomic gene sequencing analysis was used to study the effect of depression on the intestinal flora in rats and the regulatory mechanism of YJW on the intestinal flora. Furthermore, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was utilized for fecal metabolomics studies to further reveal the antidepressant mechanism of YJW. The antidepressant mechanism of YJW was explored and further verified by Western blot analysis. ResultsDifferent doses of YJW improved the depressive state of rats and raised the levels of MNTs in the hippocampus. The results of metagenomic sequencing indicated that the YJW recovered the structure and diversity of the intestinal flora in depressed rats. Metabolomics revealed sustained changes in 21 metabolites after the treatment of YJW, suggesting that YJW can play an antidepressant role by improving abnormal metabolic pathways. The results of correlation analysis suggested that YJW might mediate Eubacterium, Oscillibacter, Roseburia, Romboutsia and Bacterium to regulate purine metabolism, tryptophan metabolism, primary bile acid biosynthesis, and glutamate metabolism and exert antidepressant effects. Western blot analysis showed that YJW reduced the content of IL-1β in the hippocampus, inhibited the activation of the NLRP3 inflammasome in the hippocampus of rats, and increased the content of ZO-1 in the colon of rats. ConclusionYJW can alleviate depressive symptoms in depressed rats, and its mechanism is connected to improving intestinal flora and regulating body metabolism.

Tailoring Efficient Fluorogenic Tactic for Ultrasensitive Detection of Dopamine in Urine and Rat Brain through Real-Time and In Situ Formation of High-Performance Fluorophore.

Owing to the predominance of dopamine (DA) in controlling mental health, planning an innovative method for DA detection with simplicity and high efficacy is conducive to the assessment of neurological disorders. Herein, an efficient fluorogenic tactic has been elaborated for ultrasensitive detection of DA with remarkably enhanced turn-on response. Utilizing a twisted intramolecular charge-transfer (TICT)-suppressing strategy, a highly emissive azocine derivative 11-hydroxy-2,3,6,7,11,12,13,14-octahydro-1H,5H,10H-11,14a-methanoazocino[5',4':4,5]furo[2,3-f]pyrido[3,2,1-ij]quinolin-10-one (J-Aza) is generated via a one-step reaction between DA and 8-hydroxyjulolidine. It is marvelous that J-Aza not only possesses ideal fluorescence quantum yield (ΦF) as high as 0.956 but also exhibits bathochromic shifted fluorescence (green emissive) and stronger anti-photobleaching capacity superior to traditional azocine-derived 1,2,3,4-tetrahydro-5H-4,11a-methanobenzofuro[2,3-d]azocin-5-one (Aza) with moderate ΦF, blue fluorescence, and poor photostability. By confining the TICT process, the detection limit to DA can be reduced to 80 pM, which is competitive in contrast to previously reported fluorescence methods. Encouraged by the instant response (within 90 s), wide linear range (0.1-500 nM), great selectivity, and excellent sensitivity, this fluorogenic method has been used for the real-time measurement of DA contents in practical urine samples with satisfactory results. Furthermore, the cerebral DA level in the reserpine-induced depression rat model has also been evaluated by our designed method, demonstrating its potent analytical applicability in the biosensing field.

Widely targeted metabolomics unveils baicalin-induced hippocampal metabolic alternations in a rat model of chronic unpredictable mild stress

Baicalin has various neuroprotective effects in models of nervous system disease. Our study has shown baicalin could alleviate depressive-like behaviors in a neuroendocrine mouse model. But the systematic metabolic characteristic and particular targets of baicalin in regulating depressive behaviors have never been investigated. Therefore, this study aims to reveal the hippocampal metabolic profiling of chronic unpredictable mild stress (CUMS) induced depressive rats and the potential metabolic variations after baicalin treatment. We first used the sucrose preference test and open field test to access the antidepressant effects of baicalin. Then, metabolites of the hippocampus after baicalin therapy were monitored by widely-targeted metabolomics based on ultra-performance liquid chromatography-tandem mass spectrometry technology. Finally, the potential mechanism associated with neurogenesis obtained from metabolomics was verified by immunohistochemistry. The results showed that baicalin(40,80 mg/kg) could significantly alleviate depressive behaviors induced by CUMS as demonstrated by an increase in sucrose preference and movement distance and stand-up times in open field test. In the metabolomic analysis, a total of 733 metabolites were identified after baicalin treatment including 15 differential metabolites such as organic acid and its derivatives, heterocyclic compounds, fatty acid, bile acids, amino acid and its metabolites, and so on. Enrichment for differential metabolites showed that the differential metabolites might be involved in the process of folate and cofactor biosynthesis, cholesterol metabolism, primary bile acid biosynthesis, tyrosine metabolism and dopaminergic synapse. Moreover, immunohistochemical analysis confirmed baicalin could facilitate hippocampal neurogenesis of depressive rats in CUMS model. These results suggested baicalin might exert antidepressant effects through regulating the differential metabolites which might play a crucial role in inhibiting oxidative stress and improving neurogenesis. Our findings wish to discover the potential mechanism of baicalin on depression from the metabolomics perspective and promote its clinical application.

Extracellular Vesicles from Neural Stem Cells Carry microRNA-16-5p to Reduce Corticosterone-induced Neuronal Injury in Depression Rats

ObjectiveDepression is a common mental illness. Neural stem cell-derived extracellular vesicles (NSC-EVs) are involved in repairing neuronal injury. We estimated the mechanism of miR-16-5p in depression rats. MethodsEVs were extracted from NSCs. The depression rat model was established by corticosterone (CORT) induction and treated with NSC-EVs. The depression behavioral/pathological changes in rats were assessed using forced swimming test, open field test, sucrose consumption test and western blotting. The neuronal apoptosis in hippocampal tissue were detected. CORT-induced PC12 cell model was established. EV uptake by PC12 cells was measured and PC12 cell apoptosis was detected. The downstream targets of miR-16-5p were predicted and verified. The expressions of miR-16-5p and MYB in rats, PC12 cells, and EVs were measured. Functional rescue experiments were conducted to verify the role of miR-16-5p and MYB in PC12 cell apoptosis. ResultsCORT induction increased neuronal apoptosis in hippocampal tissue and induced depression-like behaviors in rats, while NSC-EV treatment improved depression-like behaviors and apoptosis in rats. In PC12 cells, NSC-EVs decreased CORT-induced PC12 cell apoptosis. NSC-EVs carried miR-16-5p into PC12 cells. miR-16-5p knockdown in EVs partially reversed the inhibitory effects of NSC-EVs on CORT-induced PC12 cell apoptosis. miR-16-5p targeted to inhibit MYB to repress CORT-induced PC12 cell apoptosis. In vivo experiments further verified that NSC-EVs reduced neuronal injury in CORT-induced depression rats via the miR-16-5p/MYB axis. ConclusionNSC-EVs-mediated alleviation on neuronal injury by carrying miR-16-5p to target MYB was highly likely one of the mechanisms by which NSC-EVs mediated miR-16-5p in neuroprotection of depression rats.

HIF-1A regulates cognitive deficits of post-stroke depressive rats

Post-stroke depression (PSD) is a serious neuropsychiatric complication post stroke and leads to cognitive deficits. This study was conducted to explore the molecular mechanism of hypoxia-inducible factor-1α (HIF-1A) in cognitive dysfunction in rats with PSD. The rat model of PSD was established by middle cerebral artery occlusion, followed by 3 weeks of treatment with chronic unpredictable mild stress. The levels of miR-582–5p, HIF-1A, and neighbor of Brca1 gene (NBR1) in brain tissues were determined using RT-qPCR. The behaviors and cognitive capacity of rats were evaluated by various behavioral tests. PSD rats were injected with HIF-1A/miR-582–5p lowexpression vectors or NBR1 overexpression vectors via stereotactic method. The binding of HIF-1A to NBR1 or miR-582–5p was analyzed by chromatin immunoprecipitation and dual-luciferase assay. HIF-1A and NBR1 were highly expressed while miR-582–5p was poorly expressed in the brain of PSD rats. HIF-1A inhibition alleviated cognitive dysfunction of PSD rats. miR-582–5p was the upstream miRNA of HIF-1A, and HIF-1A specifically interacted with the NBR1 promoter to enhance NBR1 expression. miR-582–5p downregulation and NBR1 upregulation reversed the alleviative role of HIF-1A inhibition in cognitive dysfunction of PSD rats. In summary, HIF-1A inhibition may be a therapeutic target for cognitive dysfunction post PSD.

Effects of Chaihu Shugan San on Brain Functional Network Connectivity in the Hippocampus of a Perimenopausal Depression Rat Model.

In this study, we used Chaihu Shugan San (CSS), a traditional Chinese herbal formula, as a probe to investigate the involvement of brain functional network connectivity and hippocampus energy metabolism in perimenopausal depression. A network pharmacology approach was performed to discover the underlying mechanisms of CSS in improving perimenopausal depression, which were verified in perimenopausal depression rat models. Network pharmacology analysis indicated that complex mechanisms of energy metabolism, neurotransmitter metabolism, inflammation, and hormone metabolic processes were closely associated with the anti-depressive effects of CSS. Thus, the serum concentrations of estradiol (E2), glutamate (Glu), and 5-hydroxytryptamine (5-HT) were detected by ELISA. The brain functional network connectivity between the hippocampus and adjacent brain regions was evaluated using resting-state functional magnetic resonance imaging (fMRI). A targeted metabolomic analysis of the hippocampal tricarboxylic acid cycle was also performed to measure the changes in hippocampal energy metabolism using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CSS treatment significantly improved the behavioral performance, decreased the serum Glu levels, and increased the serum 5-HT levels of PMS + CUMS rats. The brain functional connectivity between the hippocampus and other brain regions was significantly changed by PMS + CUMS processes but improved by CSS treatment. Moreover, among the metabolites in the hippocampal tricarboxylic acid cycle, the concentrations of citrate and the upregulation of isocitrate and downregulation of guanosine triphosphate(GTP) in PMS + CUMS rats could be significantly improved by CSS treatment. A brain functional network connectivity mechanism may be involved in perimenopausal depression, wherein the hippocampal tricarboxylic acid cycle plays a vital role.

Depression in the next generation is related with maternal behaviors: A cross-comparison by alternating rat's mother care.

This study investigated the potential impacts of depressive rats' maternal behavior as an early life stress on the outcome of offspring as an adulthood. Offspring from the same mother were divided into two groups, half of them were fostered or remained by a depressive mother, and the other half remained or fostered by a control mother, respectively. The results showed that offspring fostered by depressive mothers presented significant depressive behaviors. Meanwhile, depressive mothers engaged in more grooming during the light cycle, but less off-the-pup behavior during the dark phase. In conclusion, offspring exposed to a postnatal depressive maternal environment developed a depressive-like behavior. Contrarily, postpartum maternal behaviors play an essential role, which might determine the outcome of the next generation. Furthermore, the appropriate timing of postpartum maternal caring sequences, which might eliminate prenatal stressful influences, was recognized and might be a promising approach for reducing children's predisposition to mental disorders in their life time.

Near-infrared light therapy ameliorates depression-induced intestinal dysfunction in rats possibly by activating PGC-1α/Nrf2 signaling and increasing hippocampal BDNF expression

To investigate the effect of near-infrared (NIR) light therapy on depression-induced intestinal dysfunction in rats and explore the possible mechanism. Thirty-two male SD rats were randomly divided into control group, model group, low-dose NIR light group and high-dose NIR light group. All the rats except for those in the control group were subjected to chronic restrained stress (CRS) for 4 weeks, and NIR light therapy of the head was administered in the two NIR light groups. The depression- like behaviors, intestinal functions, fecal water content and number of fecal pellets of the rats were evaluated. HE staining was used for detecting histopathological changes in the hippocampus and colon, and hippocampal expressions of BDNF, Nrf2 and PGC-1α were detected with Western blotting. The rats in the CRS model group showed significantly increased immobility time and visceral sensitivity in the behavioral tests, decreased fecal pellets and fecal water content, and lowered expressions of BDNF, Nrf2, and PGC-1α in the hippocampus (P<0.05). Histopathological examination of the CRS rats revealed loosely arranged hippocampal pyramidal cells, obvious neuronal damages, and obvious inflammatory cell infiltration in the colon with irregularly arranged mucosal glands and a high pathological score. High-dose NIR light therapy significantly lowered the immobility time and visceral sensitivity, increased the number of fecal pellets and fecal water content (P<0.05), and enhanced hippocampal expressions of BDNF, Nrf2, and PGC-1α (P<0.05) of the depressive rats. The rats receiving high-dose NIR light therapy also exhibited close arrangement of the hippocampal pyramidal cells with significantly reduced neuronal damage and colonic inflammatory cell infiltration, neatly arranged mucosal glands, and lowered pathological score. NIR light therapy can significantly improve depression-like behavior and intestinal function in rats possibly by ameliorating oxidative stress via the PGC-1α/Nrf2 signaling pathway and increasing BDNF level in the hippocampus.

Potential value of Interleukin-6 as a diagnostic biomarker in human MDD and the antidepressant effect of its receptor antagonist tocilizumab in lipopolysaccharide-challenged rats

Depression is a common mental disease with disastrous effect on the health and wealth globally. Focusing on the role for inflammation and immune activation in the pathogenesis of depression, many tries have been taken into effect targeting at the blockage of inflammatory cytokines, among which interleukin- 6 (IL-6) and its receptor antagonist tocilizumab attracts more attention, with inconsistent findings. Moderate to severe depressive disorder (MSDD) patients were enrolled and the serum concentrations of IL-6 and tumor necrosis factor-α (TNF-α) measured, their correlation with the Hamilton Depression Rating Scale-24 (HAMD-24) scores was analyzed, and their role in discriminating MSDD patients from the health controls were evaluated. Meanwhile, a depression rat model was established by intraperitoneal injection of LPS, and tocilizumab was administrated doing 50 mg/kg via intravenous injection. The behavioral performance was observed, the serum concentration of IL-6, TNF-α, and C-reactive protein (CRP) was measured, and the protein expression of IL-6 and TNF-α in the hippocampus were also detected. The activity of the Hypothalamic-pituitary-adrenal (HPA) axis was observed, and the protein expression levels in the hippocampus were detected via western blot. Moreover, the immunofluorescence staining (IF) technique was used to investigate the co-location of IL-6 and neuron (MAP2), astrocyte (GFAP), or microglial (IBA-1). The results showed that the serum IL-6 level was significantly increased in the MSDD patients and lipopolysaccharide (LPS)-challenged rats, with a significant correlation with the HAMD-24 scores or struggling time in the FST and corticosterone (CORT) abundance. Results of ROC analysis showed a significant diagnosis value of IL-6 in discriminating MSDD patients or depression rats from the controls in the present study. Tocilizumab could relieve the depression-like behaviors induced by LPS, together with a normal abundance of serum CORT and hypothalamic CRH expression. Moreover, tocilizumab could alleviate the “inflammatory storm” and impaired hippocampal synaptic plasticity in LPS-challenged depression rats, inhibiting the hyperactivation of astrocyte and microglia, decreasing the peripheral and central abundance of IL-6, CRP, and TNF-α, and balancing the hippocampal expression levels of synaptic plasticity-associated proteins and key molecular in Wnt/β-catenin signaling pathway. These results indicated a predictive role of IL-6 in discriminating depression from controls, and demonstrated an antidepressant effect of tocilizumab in LPS-challenged rats, targeting at the inflammatory storm and the subsequent impairments of hippocampal synaptic plasticity.

Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis

BackgroundAstrocytes play a vital role in offering functional support for neurons, which are related to the pathogenic mechanism of depression. Ginsenoside Rb1 (GRb1) is demonstrated with antidepressant-like activities. PurposeWe aimed to investigate whether GRb1 can inhibit mitophagy-mediated astrocytic pyroptosis to protect neurons in depression. Study DesignModel rats were subjected to chronic unpredictable mild stress (CUMS) for determining the in vivo antidepressant activity of GRb1. MethodsThe mitophagy-mediated antipyroptosis role of GRb1 was assessed in lipopolysaccharide (LPS) + ATP-stimulated astrocytes. The mechanism by which GRb1 protects synaptic plasticity was investigated using hippocampal neurons incubated in an astrocyte medium. The rat depressive-like behaviors were determined through sucrose preference, forced swimming, and the open-field tests. Escitalopram was used in the anti-depression control of GRb1. Cyclosporin A (CsA), a mitophagy inhibitor, and interleukin (IL)-1β were used to reverse the role of GRb1 in mitophagy and pyroptosis, respectively. ResultsGRb1 inhibited LPS-induced inflammation and activation in the astrocytes and repressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Also, GRb1 repressed LPS + ATP-promoted astrocytic pyroptosis. During GRb1 treatment, the activation of mitophagy with a decrease in ROS was observed in LPS + ATPs-stimulated astrocytes. CsA enhanced GRb1-decreased ROS and promoted astrocytic pyroptosis. The GRb1-treated astrocyte medium suppressed neuron death and increased neuron viability and synaptic density. Escitalopram and GRb1 improved the depressive-like behaviors of the rats. GRb1 activated mitophagy and inhibited astrocytic activation and pyroptosis in rats with depression. It also reduced impairments in synaptic structures and increased synaptic density in depressive-like rats. IL-1β increased astrocytic pyroptosis and reversed GRb1-enhanced synaptic plasticity in the rats exposed to CUMS. There were no statistical changes in depressive-like behaviors between GRb1 and Escitalopram groups. ConclusionGRb1 modulates mitophagy and the NF-κB pathway to inhibit astrocytic pyroptosis, thereby maintaining neurological homeostasis by repressing inflammation and enhancing synaptic plasticity.

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 needle in the haystack: Identifying and validating common genes of depression, insomnia, and inflammation

BackgroundInsomnia, inflammation, and depression are often co-occurring conditions. The mechanisms underlying these conditions remain unclear. Materials and methodsWe collected microarray datasets of depression and insomnia from GEO and analyzed them for differentially expressed genes (DEGs). We then overlapped the DEGs with a list of inflammatory response-related genes to identify genes associated with all three conditions. We next performed analyses of enrichment analyses, KEGG mapping, and protein-protein interaction to identify hub genes. Furthermore, we established a depression rat model with inflammation and insomnia to validate the potential genes. At last, a two-sample Mendelian randomization (MR) study was conducted to confirm the association of identified target genes with depression outcomes. ResultsWe obtained 32 common DEGs associated with the depression, insomnia and inflammatory, and found that the PI3K-AKT signaling pathway might be involved in the inflammatory response in insomnia and depression. CREB1, CYBB, FYN, and CCR5 were identified as targets for the next validation. In model rats, the CCR5 and PI3K-AKT pathways were significantly up-regulated, while the model group exhibited significantly lower hippocampal p-CREB protein expression. The MR study suggested a potential causal relationship between CREB1 and the risk of depression (OR = 1.11, p = 0.013). LimitationsThe identified potential genes and pathways require further laboratory and clinical evidence verification. ConclusionWe identified four potential inflammatory related-genes (CREB1, CYBB, FYN, and CCR5). CREB1 may be a potential inflammatory response-related biomarker and drug target for depression and insomnia, as validated by the followed rat model and MR study.