Stress In Rats Research Articles

Date palm spathe extract reverses chronic stress-induced changes in dendritic arborization in the amygdala and impairment of hippocampal long-term potentiation.

Chronic restraint stress induces anxiety-like behaviors and emotional abnormalities via an alteration of synaptic remodeling in the amygdala and the hippocampus. Given that the date palm spathe has been shown to have neuroprotective effects on different experimental models, this study aimed to address whether the date palm spathe extract (hydroalcoholic extract of date palm spathe [HEDPP]) can reduce chronic restraint stress-induced behavioral, electrophysiological, and morphological changes in the rat model. Thirty-two male Wistar rats (weight 200-220g) were randomly divided into control, stress, HEDPP, and stress+HEDPP for 14 days. Animals were submitted to restraint stress for 2h per day for 14 consecutive days. The animals of the HEDPP and stress+HEDPP groups were supplemented with HEDPP (125mg/kg) during these 14 days, 30min before being placed in the restraint stress tube. We used passive avoidance, open-field test, and field potential recording to assess emotional memory, anxiety-like behavioral and long-term potentiation in the CA1 region of the hippocampus, respectively. Moreover, Golgi-Cox staining was used to investigate the amygdala neuron dendritic arborization. Results showed that stress induction was associated with behavioral changes (anxiety-like behavioral and emotional memory impairment), and the administration of HEDPP effectively normalized these deficits. HEDPP remarkably amplified the slope and amplitude of mean-field excitatory postsynaptic potentials (fEPSPs) in the CA1 area of the hippocampus in stressed rats. Chronic restraint stress significantly decreased the dendritic arborization in the central and basolateral nucleus of the amygdala neuron. HEDPP suppressed this stress effect in the central nucleus of the amygdala. Our findings indicated that HEDPP administration improves stress-induced learning impairment and memory and anxiety-like behaviors by preventing adverse effects on synaptic plasticity in the hippocampus and amygdala.

Postmenopausal Status Exacerbates Stress-Related Neurological Disorders in Rats

Aims: This study was aimed at assessing the effects of social instability stress (SIS) and immobilization stress (IS) in postmenopausal (PM) conditions. Postmenopause is a physiological state often associated with mild neuronal disorders (NDs) such as anxiety and irritability. The aging of the worldwide population, coupled with multiple stressors, can lead to significant public health concerns, including severe NDs.
 Place and Duration of Study: Tests and analyses were carried out within the confines of the Laboratory of Animal Physiology of the University of Yaoundé I (Cameroon) for 3 months. 
 Study Design: To induce PM syndrome, an 84-day ovariectomized Wistar rat model was used.
 Methodology: Random sampling of 4 groups of 6 rats, each aged between 8 and 10 weeks, was used. SIS and IS were induced during PM installation. Behavioral status, biochemical, and histopathological analyses were carried out.
 Results: SIS combined with IS exacerbates NDs induced by low estrogen levels. Furthermore, ovariectomized stressed rats are more depressed and anxious than the control. They presented severe hippocampal inflammation, oxidative stress, and memory impairment owing to low levels of ACh and reduced neuronal expression in the hippocampus. Overall, PM status makes NDs linked to stress worse in rats.
 Conclusion: Stress promotes oxidative stress, neuroinflammation, and neuronal death, leading to greater affective and cognition disorders when estrogen levels are low. Thus, there is a need to focus on the management of stress during menopausal life.

Effects of comfort food diet on the penile morphology of stressed rats

PurposeTo investigate the effects of chronic stress, associated or not with comfort food, on the morphology of the penis. Materials & methodsThirty-two adult Wistar rats were divided into four experimental groups: Control group (C), receiving standard rat chow, and under normal conditions; Stressed group (S), receiving standard chow, and submitted to stressful situations; Control + comfort food group (C + CF), receiving standard chow and comfort food, and under normal conditions; and Stressed + comfort food group (S + CF), receiving standard chow and comfort food, and submitted to stressful situations. At 10 weeks of age, food supply and stress were initiated. All groups had ad libitum access to standard chow and water, and groups receiving comfort food also had access to Froot Loops®. Chronic stress was induced by restriction, animals were contained daily in polypropylene tubes for 2 h, for eight weeks. After eight weeks all animals were killed; penises were removed for histomorphometric analysis. ResultsBody mass was similar among the groups. Food intake in S + CF group was lower than in other groups. Concerning food preference, groups C + CF and S + CF preferred comfort food over the standard chow, with this preference being higher in S + CF than in C + CF. The area of the corpora cavernosa without tunica albuginea was lower in group S + CF than in group C. Most interestingly, the surface density of connective tissue in the corpora cavernosa was higher in groups S and S + CF compared to group C. In contrast, smooth muscle surface density was markedly lower in S + CF compared to groups C and C + CF, while group S also had reduced smooth muscle in comparison to group C. ConclusionChronic stress caused a morphological alteration on penile histomorphometry. Also, stress increased the preference for comfort foods which caused more deleterious effects in some parameters.

Chronic Stress Decreases Lactation Performance.

The ability to provision offspring with milk is a significant adaptive feature of mammals that allows for considerable maternal regulation of offspring beyond gestation, as milk provides complete nutrition for developing neonates. For mothers, lactation is a period of marked increases in energetic and nutritive demands to support milk synthesis; because of this considerable increase in demand imposed on multiple physiological systems, lactation is particularly susceptible to the effects of chronic stress. Here, we present work that explores the impact of chronic stress during lactation on maternal lactation performance (i.e., milk quality and quantity) and the expression of key milk synthesis genes in mammary tissue using a Sprague-Dawley rat model. We induced chronic stress using a well-established, ethologically relevant novel male intruder paradigm for 10 consecutive days during the postpartum period. We hypothesized that the increased energetic burden of mounting a chronic stress response during lactation would decrease lactation performance. Specifically, we predicted that chronic exposure to this social stressor would decrease either milk quality (i.e., composition of proximate components and energy density) or quantity. We also predicted that changes in proximate composition (i.e., lipid, lactose, and protein concentrations) would be associated with changes in gene expression levels of milk synthesis genes. Our results supported our hypothesis that chronic stress impairs lactation performance. Relative to the controls, chronically stressed rats had lower milk yields. We also found that milk quality was decreased; milk from chronically stressed mothers had lower lipid concentration and lower energy density, though protein and lactose concentrations were not different between treatment groups. Although there was a change in proximate composition, chronic stress did not impact mammary gland expression of key milk synthesis genes. Together, this work demonstrates that exposure to a chronic stressor impacts lactation performance, which in turn has the potential to impact offspring development via maternal effects.

Spinal alarmin HMGB1 and the activation of TLR4 lead to chronic stress-induced nociceptive hypersensitivity in rodents

Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among others. However, the mechanisms underlaying these chronic stress-induced behavioral disorders have not been yet elucidated. This study was designed to understand the role of high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) in chronic stress-induced nociceptive hypersensitivity. Chronic restraint stress induced bilateral tactile allodynia, anxiety-like behaviors, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) and activation of spinal microglia. Moreover, chronic stress enhanced HMGB1 and TLR4 protein expression at the dorsal root ganglion, but not at the spinal cord. Intrathecal injection of HMGB1 or TLR4 antagonists reduced tactile allodynia and anxiety-like behaviors induced by chronic stress. Additionally, deletion of TLR4 diminished the establishment of chronic stress-induced tactile allodynia in male and female mice. Lastly, the antiallodynic effect of HMGB1 and TLR4 antagonists were similar in stressed male and female rats and mice. Our results suggest that chronic restraint stress induces nociceptive hypersensitivity, anxiety-like behaviors, and up-regulation of spinal HMGB1 and TLR4 expression. Blockade of HMGB1 and TLR4 reverses chronic restraint stress-induced nociceptive hypersensitivity and anxiety-like behaviors and restores altered HMGB1 and TLR4 expression. The antiallodynic effects of HMGB1 and TLR4 blockers in this model are sex independent. TLR4 could be a potential pharmacological target for the treatment of the nociceptive hypersensitivity associated with widespread chronic pain.

URB597 attenuates stress-induced ventricular structural remodeling by modulating cytokines, NF-kB and JAK2/STAT3 pathways in female and male rats.

Endocannabinoids act as a stress response system simultaneously the modulation of this system has emerged a novel approach for the therapy of cardiovascular disorders. We investigated the protective effects of the chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on morphology, pro-inflammatory and anti-inflammatory cytokine, the cytoplasm-nuclear distribution of JAK2/STAT3, NF-kB, and Nrf2/HO-1 signaling in the left ventricle of female and male rats exposed to chronic unpredictable stress. Our results show that URB597 treatment exhibits an antidepressant-like effect, decreases the heart/body weight ratio, prevents the hypertrophy of cardiomyocytes, and reduces the increased level of IL-6 in the wall of the left ventricle of stressed female and male rats. The phosphorylation levels of JAK2 and STAT3 in the ventricle of male rats treated with URB597 declined, whereas in female rats the decrease of STAT3 was observed. In addition, URB597 reduced increased NF-κB in both females and males and increased the expression of Nrf2 and HO-1 protein in the cytosol of male rats whereas did not affect their levels in females. The cardioprotective effects of URB597 could be linked to the ability to inhibit the JAK2 in males and the STAT3 inflammatory signaling pathways in both females and males.

Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety

BackgroundAnxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. MethodsHere, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. ResultsWe found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. LimitationsA single dose of histamine receptor antagonist was used. ConclusionsTogether, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

Gut microbiota-based metabolites of Xiaoyao Pills (a typical Traditional Chinese medicine) ameliorate depression by inhibiting fatty acid amide hydrolase levels in brain

Ethnopharmacological relevanceTraditional Chinese medicines (TCMs) are often prepared in oral dosage forms, making TCMs interact with gut microbiota after oral administration, which could affect the therapeutic effect of TCM. Xiaoyao Pills (XYPs) are a commonly used TCM in China to treat depression. The biological underpinnings, however, are still in its infancy due to its complex chemical composition. Aim of the studyThe study aims to explore XYPs’ underlying antidepressant mechanism from both in vivo and in vitro. Materials and methodsXYPs were composed of 8 herbs, including the root of Bupleurum chinense DC., the root of Angelica sinensis (Oliv.) Diels, the root of Paeonia lactiflora Pall., the sclerotia of Poria cocos (Schw.) Wolf, the rhizome of Glycyrrhiza uralensis Fisch., the leaves of Mentha haplocalyx Briq., the rhizome of Atractylis lancea var. chinensis (Bunge) Kitam., and the rhizome of Zingiber officinale Roscoe, in a ratio of 5:5:5:5:4:1:5:5. The chronic unpredictable mild stress (CUMS) rat models were established. After that, the sucrose preference test (SPT) was carried out to evaluate if the rats were depressed. After 28 days of treatment, the forced swimming test and SPT were carried out to evaluate the antidepressant efficacy of XYPs. The feces, brain and plasma were taken out for 16SrRNA gene sequencing analysis, untargeted metabolomics and gut microbiota transformation analysis. ResultsThe results revealed multiple pathways affected by XYPs. Among them, the hydrolysis of fatty acids amide in brain decreased most significant via XYPs treatment. Moreover, the XYPs' metabolites which mainly derived from gut microbiota (benzoic acid, liquiritigenin, glycyrrhetinic acid and saikogenin D) were found in plasma and brain of CUMS rats and could inhibit the levels of FAAH in brain, which contributed to XYPs’ antidepressant effect. ConclusionsThe potential antidepressant mechanism of XYPs by untargeted metabolomics combined with gut microbiota-transformation analysis was revealed, which further support the theory of gut-brain axis and provide valuable evidence of the drug discovery.

Antidepressant effect of 4-Butyl-alpha-agarofuran via HPA axis and serotonin system

Depression is a leading cause of disability worldwide and the psychiatric diagnosis most commonly associated with suicide. 4-Butyl-alpha-agarofuran (AF-5), a derivative of agarwood furan, is currently in phase III clinical trials for generalized anxiety disorder. Herein, we explored the antidepressant effect and its possible neurobiological mechanisms in animal models. In present study, AF-5 administration markedly decreased the immobility time in mouse forced swim test and tail suspension test. In the sub-chronic reserpine-induced depressive rats, AF-5 treatment markedly increased the rectal temperature and decreased the immobility time of model rats. In addition, chronic AF-5 treatment markedly reversed the depressive-like behaviors in chronic unpredictable mild stress (CUMS) rats by reducing immobility time of forced swim test. Single treatment with AF-5 also potentiated the mouse head-twitch response induced by 5-hydroxytryptophan (5-HTP, a metabolic precursor to serotonin), and antagonized the ptosis and motor ability triggered by reserpine. However, AF-5 had no effect on yohimbine toxicity in mice. These results indicated that acute treatment with AF-5 produced serotonergic, but not noradrenergic activation. Furthermore, AF-5 reduced adrenocorticotropic hormone (ACTH) level in serum and normalized the neurotransmitter changes, including the decreased serotonin (5-HT) in hippocampus of CUMS rats. Moreover, AF-5 affected the expressions of CRFR1 and 5-HT2C receptor in CUMS rats. These findings confirm the antidepressant effect of AF-5 in animal models, which may be primarily related to CRFR1 and 5-HT2C receptor. AF-5 appears to be promising as a novel dual target drug for depression treatment.

LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats through regulating DNA methylation in hippocampus

Objective: In this study, we aimed to analyze the effects and underlying mechanisms of LPM570065 on behavioral phenotypes in rats with generalized anxiety disorder (GAD).Methods: The chronic unpredictable mild stress (CUMS) rats were used to observe the results of LPM570065. Total 72 male Sprague Dawley rats were divided into control, vehicle (0.5% CMC-Na), LPM570065 (32 mg/kg) and diazepam (3 mg/kg) groups, 12 rats in each group. Anxiety-like behaviors of rats were observed by elevated zero maze test and novelty-suppressed feeding test. Depressive-like behaviors of rats were detected by forced swimming test. DNA methylation in hippocampi of rats were measured by reduced representation bisulfite sequencing (RRBS). In hippocampi of rats, expressions of DNA methyltransferase (DNMT) 1 and DNMT3a proteins were measured by western blot, and density of dendritic spines was observed by Golgi staining.Results: Compared with the control group, the weights of rats were obviously decreased (p < 0.001) and the rats showed anxiety-like and depressive-like behaviors (p < 0.001) in the vehicle group. Compared with the vehicle group, the weights of rats were significantly increased (p < 0.001) and the anxiety-like and depressive-like behaviors were improved (p < 0.001) in the LPM570065 group. The results of RRBS showed that there were 49964 promoters showed hypermethylation in the LPM570065 treatment rats contrasted to the vehicle treatment rats. In addition, these promoters were enriched in signal transduction and immune function. Furthermore, the expressions of DNMT1 and DNMT3a were significantly decreased, the density of dendritic spines was significantly increased in hippocampi of LPM570065 treatment rats compared with the vehicle treatment rats.Conclusions: LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats, and its mechanism is possible associated with downregulating DNA methylation in hippocampus.

The effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and BDNF changes in chronically stressed adolescent rats

Chronic stress during the pre-pubertal period has adverse effects in developing neuropsychiatric disorders such as depression and anxiety. The administration of supplements with antioxidant properties may alleviate depression and anxiety behavior. This study investigated the effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and changes in brain-derived neurotropic factor (BDNF) in adolescence rats subjected to chronic stress. In order to assess the effects of chronic stress, adolescent rats were grouped into one non-stressed control group (non-stress) and four different experimental groups. The other animals were subjected to stress and orally received normal saline (Control-stress), 15 mg/kg yeast (Stress-15), 30 mg/kg yeast (Stress-30) and 45 mg/kg yeast (Stress-45). Anxiety and depression-like behavior, BDNF levels, and oxidative stress markers were evaluated. The rats exposed to stress exhibited anxiogenic and depression-like behavior as well as lower levels of BDNF and higher levels of oxidative markers compared with non-stressed rats (P<0.05). However, the oral supplementation of sake yeast decreased anxiogenic and depression-like behavior and oxidative indices, and also increased BDNF levels compared to stressed rats treated with saline in a dose-dependent manner (P<0.05). In sum, stress caused anxiety and depression behavior, increased oxidative indices, and reduced BDNF levels while sake yeast alleviated adverse effects of stress on anxiety and depression behaviors, decreased oxidative markers, and increased BDNF levels.

Role of miR-124-3p in regulatory mechanisms of Gpm6a expression in the hippocampus of chronically stressed rats.

The neuronal membrane glycoprotein M6a (GPM6A) belongs to the family of myelin proteolipid protein and plays a role in neuronal remodeling and plasticity. Decreased expression of GPM6A mRNA is observed in the hippocampal tissue of suicide victims who suffered from depression and after chronic stress exposure in animals. The regulatory mechanisms that impact expression of GPM6A under chronic stress or in pathological conditions are not well understood. Previously, miRNAs miR-133b, miR-124-3p, and miR-9-5p have been shown to regulate the expression of Gpm6a mRNA under normal conditions. Here, we employed the paradigm of chronic-restraint stress in rats and using quantitative polymerase chain reaction (qPCR) showed down-regulation of expression of Gpm6a and the brain-derived neurotrophic factor (Bdnf) genes at mRNA level as well as miR-133b, and miR-124-3p, but not miR-9-5p in the hippocampus of chronically stressed rats. Furthermore, we observed alterations in the expression of histone deacetylase (Hdac5) and myocyte enhancer factor 2C (Mef2c) mRNAs. Our data suggest that chronic stress influences Gpm6a expression by miR-124-mediated impact on the expression of Hdac5 and Mef2c. Upon miR-124 over-expression in hippocampal neurons cultured in vitro, we observed enhanced neuronal arborization as evaluated by Sholl analysis, increased Gpm6a and Mef2c expression, and decreased Hdac5 expression. Moreover, treatment of hippocampal neurons cultured in vitro with BDNF resulted in an elevation in the miR-124-3p expression, a decrease in the miR-9-5p expression but did not affect miR-133b. This was accompanied by augmented expression of Gpm6a and Mef2c mRNAs and significantly lower levels of Hdac5 mRNA. Altogether, these results indicate that the regulatory mechanism that influence expression of Gpm6a under chronic stress involves miR-124-mediated impact on the expression of Hdac5 and Mef2c and a role of BDNF in the activation of Gpm6a expression.

The impact of chronic stress on intracellular redox balance: A systems level analysis.

Chronic psychosocial stress is implicated in the onset and progression of noncommunicable diseases, and mechanisms underlying this relationship include alterations to the intracellular redox state. However, such changes are often investigated in isolation, with few studies adopting a system level approach. Here, male Wistar rats were exposed to 9.5 weeks of chronic unpredictable mild stress and redox status assays were subsequently performed on cardiac, hepatic, and brain tissues versus matched controls. The stressed rats displayed an anxious phenotype, with lowered plasma corticosterone levels (p= 0.04 vs. Controls) and higher plasma epinephrine concentrations (p= 0.03 vs. Controls). Our findings showed organ-specific redox profiles, with stressed rats displaying increased myocardial lipid peroxidation (p= 0.04 vs. Controls) in the presence of elevated nonenzymatic antioxidant capacity (p= 0.04 vs. Controls). Conversely, hepatic tissues of stressed rats exhibited lowered nonenzymatic antioxidant capacity (p< 0.001 vs. Controls) together with increased superoxide dismutase (SOD) activity (p= 0.05 vs. Controls). The brain displayed region-specific antioxidant perturbations, with increased SOD activity (p= 0.01 vs. Controls) in the prefrontal cortex of the stressed rats. These findings reveal distinct stress-related organ-specific vulnerability to redox perturbations and may provide novel insights into putative therapeutic targets.

Electroacupuncture intervention on stress-induced cardiac autonomic imbalance in rats involves corticotropin-releasing hormone system activity.

Autonomic imbalance is a core aspect of stress response that strongly correlates to cardiovascular diseases. Enhanced activity of the central corticotropin-releasing hormone (CRH) system may result in autonomic imbalance to cause cardiovascular responses in a stress state. Electroacupuncture at PC6 acupoints has been demonstrated to prevent and treat cardiovascular diseases. In this study, we aim to demonstrate the protective role of electroacupuncture at PC6 in ameliorating cardiac autonomic imbalance and investigate the underlying mechanisms in immobilization stress rats. Four groups were subjected. Immobilization stress was applied to three groups. And the rats in two electroacupuncture-intervened groups exerted electroacupuncture at PC6 or tail respectively. Then, we performed ECG recording for heart rate variability (HRV) analysis, and rats were sacrificed after experiments for biological analysis. HRV analysis indicated that electroacupuncture at PC6 improved the enhanced low-frequency band of the power spectrum (LF), the reduced high-frequency band of the power spectrum (HF), and the enhanced LF/HF ratio caused by immobilization stress. Besides, electroacupuncture at PC6 significantly decreased phosphorylated tyrosine hydroxylase expression and increased acetylcholine esterase expression in heart of immobilization stress rats. Furthermore, electroacupuncture at PC6 significantly decreased CRH level and CRH 1 type receptor and CRH 2 type receptor (CRHR2) expressions in the rostral ventrolateral medulla (RVLM), and CRH level and CRHR2 expression in the nucleus of the solitary tract (NTS) of immobilization stress rats. Our findings suggest that electroacupuncture at PC6 can ameliorate stress-induced cardiac autonomic imbalance by modulating the CRHergic input in the RVLM and NTS.

Alteration of the gut microbiome and correlated metabolism in a rat model of long-term depression.

This study aims to investigate the composition and function of the gut microbiome in long-term depression using an 8-week chronic unpredictable mild stress (CUMS) rat model. Animals were sacrificed after either 4 weeks or 8 weeks under CUMS to mimic long-term depression in humans. The gut microbiome was analyzed to identify potential depression-related gut microbes, and the fecal metabolome was analyzed to detect their functional metabolites. The correlations between altered gut microbes and metabolites in the long-term depression rats were explored. The crucial metabolic pathways related to long-term depression were uncovered through enrichment analysis based on these gut microbes and metabolites. The microbial composition of long-term depression (8-week CUMS) showed decreased species richness indices and different profiles compared with the control group and the 4-week CUMS group, characterized by disturbance of Alistipes indistinctus, Bacteroides ovatus, and Alistipes senegalensis at the species level. Additionally, long-term depression was associated with disturbances in fecal metabolomics. D-pinitol was the only increased metabolite in the 8-week CUMS group among the top 10 differential metabolites, while the top 3 decreased metabolites in the long-term depression rats included indoxyl sulfate, trimethylaminen-oxide, and 3 alpha,7 alpha-dihydroxy-12-oxocholanoic acid. The disordered fecal metabolomics in the long-term depression rats mainly involved the biosynthesis of pantothenate, CoA, valine, leucine and isoleucine. Our findings suggest that the gut microbiome may participate in the long-term development of depression, and the mechanism may be related to the regulation of gut metabolism.

Abnormal compositions of gut microbiota and metabolites are associated with susceptibility versus resilience in rats to inescapable electric stress

BackgroundIncreasing evidence suggests the role of gut microbiota in resilience versus vulnerability after stress. However, the role of gut microbiota and microbiome-derived metabolites in resilience versus susceptibility in rodents exposed to stress remains unclear. MethodsAdult male rats were exposed to inescapable electric stress under the learned helplessness (LH) paradigm. The composition of gut microbiota and metabolites in the brain and blood from control (no stress) rats, LH resilient rats, and LH susceptible rats were examined. ResultsAt the genus level, the relative abundances of Asaccharobacter, Eisenbergiella, and Klebsiella in LH susceptible rats were significantly higher than that of LH resilient rats. At the species level, the relative abundances of several microbiome were significantly altered between LH susceptible rats and LH resilient rats. Furthermore, there were several metabolites in the brain and blood altered between LH susceptible rats and LH resilient rats. A network analysis showed correlations between the abundance of several microbiome and metabolites in the brain (or blood). LimitationsDetailed roles of microbiome and metabolites are unclear. ConclusionsThese findings suggest that abnormal compositions of the gut microbiota and metabolites might contribute to susceptibility versus resilience in rats subjected to inescapable electric foot shock.

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

The aim of this study was to repurpose a drug for the treatment of bipolar depression. A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Sex differences in cocaine self-administration by Wistar rats after predator odor exposure.

Traumatic stress disorders are defined in part by persistent avoidance of trauma-related contexts. Our lab uses a preclinical model of traumatic stress using predator odor (i.e., bobcat urine) in which some but not all rats exhibit persistent avoidance of odor-paired stimuli, similar to what is seen in humans. Bobcat urine exposure increases alcohol consumption in male Avoider rats, but it has not been tested for its effects on intake of other drugs. Here, we tested the effect of bobcat urine exposure on cocaine self-administration in adult male and female Wistar rats. We did not observe any effect of bobcat urine exposure on cocaine self-administration in male or female rats. We observed that (1) female rats with long access (6 hours) to cocaine self-administer more cocaine than long-access males, (2) long-access males and females exhibit escalation of cocaine intake over time, (3) stressed rats gain less weight than unstressed rats following acute predator odor exposure, (4) baseline cocaine self-administration is predictive of subsequent cocaine self-administration. The results of this study may inform future work on predator odor effects on cocaine self-administration.

A novel insight for high-rate and low-efficiency glucose metabolism in depression through stable isotope-resolved metabolomics in CUMS-induced rats

BackgroundExisting research has suggested that depression results in disorders of glucose metabolism in the organism which causing insufficient energy supply. However, the overall changes in glucose metabolism that arise from depression have not been clarified. MethodsIn this study, the depression-like behavior in chronically unpredictable mild stressed rats was investigated, and the fate of glucose was tracked through isotope tracing and mass spectrometry, with a focus on metabolite changes in cecal contents. ResultsAs indicated by the results, the isotopic results of cecal contents can indicate the metabolic end of the organism. Moreover, the TCA cycle activity was notably reduced, and the gluconeogenesis pathway was abnormally up-regulated in the CUMS-induced rats. The organism expedited other glucose metabolism pathways to make up for the insufficiency of energy. As a result, the activity of the inefficient glycolysis pathway was increased. LimitationsExisting research has only investigated the metabolism of 13C-glucose, and lipids and proteins have been rarely explored. ConclusionsThe chronic unpredictable mild stress can inhibit the entry of pyruvate into mitochondria in SD rats, such that the activity of TCA is reduced, and insufficient energy supply is caused. The organism is capable of expediting other glucose metabolism rate pathways to make up for the insufficiency of energy, whereas it still cannot compensate for the loss of energy. As a result, CUMS-induced rats exhibited high-rate and low-efficiency glucose metabolism.

The effects of curcumin and sertraline on stress-induced changes in the stomach tissues of rats.

Exposure to stressors can cause functional disorders and structural damage to the stomach. Sertraline (SER) is an antidepressant and curcumin (CUR) is a natural compound with many properties. The current study aimed to investigate the impacts of stress, SER, and CUR on the stomach tissue using stereological methods. In total, 24 male and 24 female Sprague-Dawley rats were divided into four groups. In the control group, the rats were not exposed to stress. However, the animals in stress, SER and, CUR groups were exposed to daily stress and were orally fed with distilled water, SER (10mg/kg/day), and CUR (100mg/kg/day), respectively. The volume, surface area, and number of nerve, parietal, and chief cells were evaluated by stereological methods. Results showed that stress increased the stomach and its mucosa and submucosa volumes, while it decreased the surface area of the mucosa. Furthermore, this disorder increased the number of neurons in the submucosa and myenteric plexuses while it decreased the number of parietal and chief cells. However, treating stressed rats with SER or CUR could prevent these changes. The results showed that the consumption of SER or CUR could be used as a preventive or adjunctive treatment for stressful situations.