Project description:Objective: To elucidate the potential effects of stressful factors for depression on the hippocampal, frontal cortex and pituitary gland genome-wide transcriptomes at the molecular level, we evaluated the transcriptomic profiles of depression rats under chronic restraint stress (CRS). Methods: Forty-eight rats were randomly divided into control, model, fluoxetine and acupuncture groups. Experimental period was 28 days. Open-field test, Sucrose preference and body weight were investigated respectively at the experiment before and after the experiment. The experiment having been finished, solexa sequencing technology (Illumina Nextseq 500/151nt) was applied to investigate and verify the altered hippocampal, frontal cortex and pituitary gland genome-wide transcriptome analysis in rats of all groups. Results: Based on the data from RNA-seq analysis, it revealed that compared the expression of genes in the control group with model group in the respective of three brain tissues, 101, 134, 148 differential expression genes were found in the hippocampus, frontal cortex and pituitary gland, respectively; compared the expression of genes in the fluoxetine group with model group in the respective of three brain tissues, 41, 46, 87 differential expression genes were found in the hippocampus, frontal cortex and pituitary gland, respectively; compared the expression of genes in the acupuncture group with model group in the respective of three brain tissues, 107, 89, 179 differential expression genes were found in the hippocampus, frontal cortex and pituitary gland, respectively. Furthermore, we used the GO (Gene ontology) analysis and KEGG (Kyo-To conservation of Genes and Genomes) pathway analysis for these differentially expressed genes. We found that the results of these two analyses were consistent, both mainly related to monoamine neurotransmitters, inflammation and immune response in control group VS model group. It is noted that this phenomenon also appears in fluoxetine group compared with model group, acupuncture group VS model group. Importantly, the antidepressant effect of acupuncture was more extensive, which was more consistent with the pathogenesis of depression induced by CRS in rats. Conclusions: Our study represents the first detailed analysis of the hippocampal, frontal cortex and pituitary gland genome-wide transcriptomes in depression rats under CRS by RNA-seq technology. The results of this study revealed multiple DEGs and possible mechanisms specifying the function of hippocampal, frontal cortex and pituitary gland in depression rats induced by CRS. These results provide a basis for further investigation of the signaling mechanisms that affect central nervous system output related to stress-sensitive depressive disorder development. Overall design: Forty-eight rats were randomly divided into control, model, fluoxetine and acupuncture groups. The rat model of depression was established by subjecting to chronic restraint stress (6h/day) for 28 days. Rats in acupuncture group were acupunctured at GV20 (Baihui) and GV29 (Yintang) one hour before the CRS procedures every day. Rats in fluoxetine group were administered with fluoxetine (10mg/kg) by gavage one hour before the CRS procedures every day. Open-field test, Sucrose preference and body weight were investigated respectively at the experiment before and after the experiment. The experiment having been finished, the hippocampal, frontal cortex and pituitary gland were harvested, and their RNA profiles were generated by deep sequencing, in triplicate, using Illumina Nextseq 500/151nt.
Project description:Major depressive disorder (MDD) is a chronic disease that adversely affects mood and cognition. In this study, we randomly divided the rats into control group (C), model group (M), fluoxetine group (F), and acupuncture group (A), used open-field test to ascertain whether acupuncture affects chronic restraint stress (CRS) induced depression-like behaviors of rats, and explored the antidepressant mechanism of acupuncture at the molecular level of transcriptome in the frontal cortex of CRS rats by RNA-sequencing (RNA-seq). According to differentially expressed genes (DEG) analysis, we identified 134, 46, and 89 response genes differentially expressed in C versus M, F versus M, and A versus M, respectively. Through Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we identified the gene sets involved in extracellular space, inflammatory response, Toll-like receptor signaling pathway, chemokine signaling pathway, and TNF signaling pathway. In this study, RNA-seq technology was used to investigate the frontal cortex genome-wide transcriptomes in depression rats under CRS, which suggested that the antidepressant effect of acupuncture is effective and has a multitarget characteristic, which may be related to amino acid metabolism and inflammatory pathways, especially the Toll-like receptor signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway.
Project description:The persistence of anxiety and the deficit of fear memory extinction are both phenomena related to the symptoms of a trauma-related disorder, such as post-traumatic stress disorder (PTSD). Recently we have shown that single acute restraint stress (2?h) in rats induces a late anxiety-related behavior (observed ten days after stress), whereas, in the present work, we found that the same stress impaired fear extinction in animals conditioned ten days after stress. Fourteen days of environmental enrichment (EE) prevented the deleterious effect of stress on fear memory extinction. Additionally, we observed that EE prevented the stress-induced increase in AMPA receptor GluA1 subunit phosphorylation in the hippocampus, but not in the basolateral amygdala complex and the frontal cortex, indicating a potential mechanism by which it exerts its protective effect against the stress-induced behavioral outcome.
Project description:A wide range of stress-related pathologies such as post-traumatic stress disorder are considered to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic-pituitary-adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to 10 days of restraint alone (60 minutes daily), forced swim alone (30 minutes daily) or daily sequential exposure to restraint (60 minutes) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim with sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC) and hippocampus (HPC). Sequential exposure to restraint and swim increased interleukin (IL)-1? in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL-6 and tumour necrosis factor-? responses in the HPC and PFC, respectively, which did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL-1? response evoked by swim exposure imposed immediately after the sixth day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL-1? response after swim in comparison to acutely-exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds: (i) independent of HPA axis habituation; (ii) likely requires more daily sessions of stress to develop; and (iii) IL-1? displays a greater tendency to habituate after repeated stress challenges compared to other stress-reactive cytokines.
Project description:A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain's mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug-tianeptine-on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive- and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, two-dimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases.
Project description:Depression is a serious psychiatric disorder with an enormous socioeconomic burden, and it is commonly comorbid with pain, chronic fatigue, or other inflammatory diseases. Recent studies have shown that acupuncture is an effective therapeutic method for reducing depressive symptoms; however, the underlying mechanism remains unknown. In this study, we investigated the effects of acupuncture on chronic stress-induced depression-like behavior and its central neural mechanisms in the brain. We induced chronic restraint stress (CRS) in male C57BL/6 mice for 14 or 28 consecutive days. Acupuncture treatment was performed at KI10·LR8·LU8·LR4 or control points for 7 or 14 days. Depression-like behavior was assessed with the open field test. Then, brain neural activity involving c-Fos and serotonin-related mechanisms <i>via</i> the 5-HT1A and 5-HT1B receptors were investigated. Acupuncture treatment at KI10·LR8·LU8·LR4 points rescued the depressive-like behavior, while control points (LU8·LR4·HT8·LR2) and non-acupoints on the hips did not. Brain neural activity was changed in the hippocampus, cingulate cortex, motor cortex, insular cortex, thalamus, and the hypothalamus after acupuncture treatment. Acupuncture treatment increased expression of 5-HT1A receptor in the cortex, hippocampus, thalamus, and the hypothalamus, and of 5-HT1B in the cortex and thalamus. In conclusion, acupuncture treatment at KI10·LR8·LU8·LR4 was effective in alleviating the depressive-like behavior in mice, and this therapeutic effect was produced through central brain neural activity and serotonin receptor modulation.
Project description:The inbred LOU/C/Jall rat is currently described as a model of successful aging. These rats have a longer healthy median lifespan than other strains, do not develop obesity, diabetes, or tumor and more importantly they do not show cognitive decline with aging. This is the first study to examine gene expression changes in the inbred LOU/C/Jall rat hippocampus and frontal cortex. Microarray data from LOU/C/Jall rats aged of 5 months were compared to the one measured in rats aged of 26 month. We have identified a set of 15 genes in the hippocampus and 70 genes in the frontal cortex that could be grouped into several clusters of similar expression profiles and that are involved in biological functions, namely regulation of plasticity, inflammatory response, metabolic, catabolic and homeostatic processes, and transcription. Genes were mainly up-regulated in aged brain. Gene expression profil in hippocampus and cortex frontal of LOU/C/Jall rats strain. Rats were 3 and 26 months old.
Project description:Background:Fluoxetine (FLU) is the first-line and widely used medication for depression; however, FLU treatment is almost ineffective in 30%-40% of patients with depression. In addition, there are some problems in FLU treatment, such as delayed efficacy, large side effects, and poor tolerance. Chaihu Shugan San (CSS) is a classic and effective antidepressant Chinese herbal medicine that has been used in China for thousands of years. CSS or coadministration of CSS and FLU has become one of the most recommended methods in the treatment of depression in China. However, the specific pathways of CSS and coadministration of CSS and FLU for antidepressant are still unclear. Objective:This study was designed to evaluate the antidepressant effects of CSS and coadministration of CSS and FLU. Methods:The chronic unpredictable mild stress (CUMS) rat model was used to simulate depression. 120 healthy adult male Sprague-Dawley (SD) rats were randomly divided into seven groups: the control group, CUMS group, low-dose CSS group, high-dose CSS group, FLU group, coadministration of low-dose CSS and FLU group, and coadministration of high-dose CSS and FLU group. The rats in different groups were given different interventions. Then, the depression-like behavior and cognitive function were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and Y-maze test. What is more, the antidepressant mechanism of CSS and coadministration of CSS and FLU were studied through BDNF mRNA, ERK mRNA, CREB mRNA, BDNF, p-ERK/ERK, and p-CREB/CREB levels in the hippocampus and frontal cortex by Western blot and RT-PCR. Results:Compared with the CUMS group, CSS and coadministration of CSS and FLU could alleviate the depressive symptoms and improve cognitive function in CUMS rats (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (Discussion and Conclusion. Finally, we found that both CSS and coadministration of CSS and FLU play an antidepressant role, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway in the hippocampus and frontal cortex. Among them, the coadministration of CSS and FLU can enhance the antidepressant effect of CSS or FLU alone, and the underlying mechanism needs further investigation.
Project description:An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1?), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-?, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-? signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.
Project description:Depression, a psychiatric and dysthymic disorder, severely affects the learning, work and life quality. The main pathogenesis of depression is associated with central nervous system (CNS) dysfunction. Taurine has been demonstrated to exert protective effects on the brain development and can improve learning ability and memory. Our study investigated the antidepressant-like effects of taurine pre-treatment by examining the changes in depression-like behavior, hormones, neurotransmitters, inflammatory factors and neurotrophic factors in the hippocampus of a chronic unpredictable mild stress (CUMS)-induced depressive rat model. Taurine was found to inhibit the decrease of sucrose consumption and prevent the deficiency of spatial memory and anxiety in rats exposed to CUMS, suggesting a preventive effect of taurine on depression-like behavior. Furthermore, the decreased levels of 5-hydroxytryptamine, dopamine, noradrenaline; the increased levels of glutamate, corticosterone; and the decreased expressions of fibroblast growth factor-2, vascular endothelial growth factor and brain derived neurotrophic factor in depressive rats were hindered by taurine pre-administration. However, tumor necrosis factor-? and interleukin-1? levels were not significantly changed by taurine. The results demonstrated that the anti-depressive effect of taurine may be involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and the promotion of neurogenesis, neuronal survival and growth in the hippocampus.