Depression Model Group Research Articles

Anxiolytic and antidepressant effects of agarwood inhalation and its mechanism

This study used m-chloropheniperazine(MCPP) and chronic unforeseeable mild stress(CUMS) to induce the rat models of anxiety and depression, respectively. The behaviors of rats were observed by the open field test(OFT), light-dark exploration test(LDE), tail suspension test(TST), and forced swimming test(FST), and the antidepressant and anxiolytic effects of agarwood essential oil(AEO), agarwood fragrant powder(AFP), and agarwood line incense(ALI) were explored. The enzyme-linked immunosorbent assay(ELISA) was used to determine the levels of 5-hydroxytryptamine(5-HT), glutamic acid(Glu), and γ-aminobutyric acid(GABA_A) in the hippocampal area. The Western blot assay was used to determine the protein expression levels of glutamate receptor 1(GluR1) and vesicular glutamate transporter type 1(VGluT1), exploring the anxiolytic and antidepressant mechanism of agarwood inhalation. The results showed that compared with the anxiety model group, the AEO, AFP, and ALI groups decreased the total distance(P<0.05), decreased the velocity of movements(P<0.05), prolonged the immobile time(P<0.05), and reduced the distance and velocity of the rat model of anxiety in the dark box(P<0.05). Compared with the depression model group, the AEO, AFP, and ALI groups increased the total distance and average velocity(P<0.05), reduced the immobile time(P<0.05), and reduced the forced swimming and tail suspension time(P<0.05). In terms of transmitter regulation, the AEO, AFP, and ALI groups decreased the level of Glu in the rat model of anxiety(P<0.05) and increased the levels of GABA_A and 5-HT(P<0.05), while the AEO, AFP, and ALI groups all increased the level of 5-HT in the rat model of depression(P<0.05) and decreased the levels of GABA_A and Glu(P<0.05). At the same time, the AEO, AFP, and ALI groups all increased the protein expression levels of GluR1 and VGluT1 in the hippocampus of the rat models of anxiety and depression(P<0.05). In conclusion, AEO, AFP, and ALI exert anxiolytic and antidepressant effects, and the mechanism might be related to the regulation of the neurotransmitter and the protein expression of GluR1 and VGluT1 in the hippocampus.

Effects of mitophagy on aerobic exercise intervention for depression in rats

Objective: This experiment was designed to observe the effects of aerobic exercise on depressive behavior in rats induced by chronic unpredictable mild stress (CUMS), and to explore the possible mechanism by detecting the proteins related to mitochondrial autophagy. Methods: SD rats were randomly divided into three groups: blank control group (C, n=12), depression model group (D, n=12) and post-depression exercise group (D+E, n=12). Group D and D+E were modeled with CUMS for 28 days, and group D+E underwent aerobic exercise intervention for 4 weeks after model establishment. Then the behavior of rats was evaluated. The concentrations of whole brain dopamine and norepinephrine were determined by ELISA kits. The morphology and structure of mitochondria in the frontal lobe were observed with the transmission electron microscope (TEM). Mitochondrial autophagy lysosomes were localized by immunofluorescence colocalization. The expressions of LC3 and P62 proteins in the frontal lobe were measured with Western Blotting. The relative content of mitochondrial DNA was detected using Real-time PCR. Results: ①Compared with group C, the sucrose preference ratio in group D was decreased significantly(P＜0.01); Compared with group D, the sucrose preference ratio in group D+E was increased significantly (P＜0.01). ②In the open field experiment, compared with group C, group D had a significant decrease in activity, average speed and total distance (P＜0.05); Compared with group D, the average rate of activity in group D+E was significantly higher (P＜0.05). ③ELISA results showed that the levels of whole brain dopamine and norepinephrine were significantly lower in group D rats than those in group C (P＜0.05). ④Under transmission electron microscopy, compared with group C, group D had different degrees of mitochondrial swelling, decreased crest density, and intermembrane space dilation.; Compared with group D, a significant increase in mitochondrial autophagosomes and autophagic lysosomes was observed in neurons in group D+E. Increased co-localization of mitochondria with lysosomes in the D+E group could be observed under fluorescence microscopy. ⑤Compared with group C, the expression of P62 was increased significantly(P＜0.05), and LC3II/LC3I ratio was decreased significantly (P＜0.05) in group D; Compared with group D, LC3II/LC3I ratio was significantly higher in group D+E than that in group D (P＜0.05). ⑥Compared with group C, the relative number of mitochondrial DNA in the frontal lobe of group D was increased significantly (P＜0.05). Conclusion: Aerobic exercise has a significant improvement effect on depression induced by CUMS in rats, and its mechanism may be related to the upregulation of the level of linear autophagy.

Effect of Running Exercise on Brain Functional Magnetic Resonance Characteristics of College Students with Depression.

In order to effectively reduce the incidence of depression in college students, the author proposes a method to influence brain functional magnetic resonance through running exercise. Aiming at the effect of running exercise on the brain functional magnetic resonance characteristics of depression in college students, through the comparison experiment between the MDD group and the HC group and the retrospective analysis of the sugar water preference experiment in rats, explore it in depth. Experimental results show that under the running exercise for six consecutive weeks, the average body weight of the rats in the depression model group was significantly lower than that in the blank control group, and the health status was significantly better than that in the blank group. Running exercise can effectively affect and reduce the incidence of depression in college students.

Magnetic resonance imaging features of hippocampus and mechanism of neurocognitive dysfunction for antiepileptic drugs in treatment of depression rats

ABSTRACT To explore the effects of antiepileptic drug sodium valproate on magnetic resonance imaging (MRI) images, neurological cognition, and JAK1/STAT3 pathway in hippocampus of rats with depression, 30 Sprague Dawley (SD) rats were included. The depression model (DM) was prepared through the chronic stress restraint test. Some model rats were injected with 10 mg/kg sodium valproate into abdominal cavity before modeling (RT group)), and healthy rats were selected as controls (healthy control (HC) group). Depth of split brain was greatly increased in DM group, and nitrogen-acetyl aspartic acid (NAA)/creatine (Cr), glutamic acid (Glu)/Cr, and choline (Cho)/Cr ratios were greatly reduced (P < 0.05). Behavioral test results showed that sugar water preference rate, escape latency, and divergence index in DM group were greatly reduced (P < 0.05), and cumulative immobility time, target quadrant stay time, and number of crossings in forced swimming and tail suspension were prolonged dramatically (P < 0.05), with no difference between the two groups (P > 0.05). Expression levels of interleukin 1β (IL-1β) and interleukin 6 (IL-6) in hippocampus of DM group were obviously increased (P < 0.05), and expression levels of JAK1 and STAT3 were decreased visibly (P < 0.05), with no difference between the two (P > 0.05). In summary, anti-epileptic drug sodium valproate effectively improves hippocampal volume characteristics and memory and neurocognitive dysfunction of depression models.

Simultaneous Quantification of Four Ginsenosides in Rat Plasma and Its Application to a Comparative Pharmacokinetic Study in Normal and Depression Rats Using UHPLC-MS/MS.

A sensitive method has been developed for simultaneous determination of ginsenoside Rh1 (G-Rh1), ginsenoside Rb1 (G-Rb1), ginsenoside Rc (G-Rc), and ginsenoside Rd (G-Rd) in rat plasma of normal and depression model group after oral administration of their solutions by using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-QQQ-MS). The biological samples were prepared by protein precipitation. Ginsenoside Rg3 (G-Rg3) was used as an internal standard (IS). MS analysis was performed under the multiple reaction monitoring (MRM) with electron spray ionization (ESI) operated in the negative mode. The method showed good linearity over a wide concentration range (R2 > 0.999) and obtained lower limits of quantification (LLOQ) of 5 ng/mL. The whole analysis procedure could be completed in as short as 16.5 min. The intraday precisions, interday precisions, and stabilities were less than 10%. The extraction recoveries from rat plasma were exceeded 86.0%. The results indicated that there were significant differences between the two groups on pharmacokinetics parameters; the absorptions of four analytes in the depression group were higher than those in the normal group because the liver metabolism and internal environment of the model rats had been affected.

Blue light regulates the expression of brain derived neurotrophic factor in the habenula nucleus of depression-like rats induced by light deprivation

Objective: To investigate the regulatory effect of blue light on the expression of brain derived neurotrophic factor (BDNF) in the habenula nucleus of depression-like rats induced by light deprivation. Methods: male SD rats were exposed to white light (white light control group, 20 rats) and constant darkness (depression model group, 60 rats), respectively. 18 days later rats in depression model group were randomly divided into three groups: depression model group (treated with constant darkness), blue light group (treated with blue light) and red light group (treated with red light). Rats in white light control group were kept in white light. All rats exposed to light were in a standard 12∶12 h Light/Dark condition at 20 lx for 36 days. Sucrose preference test was applied to evaluate depression-like symptoms of rats. The c-fos+cells in the habenula nucleus, intergeniculate leaflet and ventral lateral geniculate nucleus were detected. The phosphoylation of cAMP-response element binding protein (CREB) and the relative BDNF protein level in the habenula nucleus were measured. Results: Sucrose intake per kg body weight increased in rats exposed to blue light and returned to the level of control group (P>0.05). Sucrose intake per kg body weight in red light group and depression model group were lower than control group (P<0.05). More c-fos+cells were detected in the habenula nucleus, intergeniculate leaflet and ventral lateral geniculate nucleus from blue light group than those from depression model group (P<0.05). The relative BDNF protein level and the phosphoylation of CREB in the habenula nucleus from blue light group were higher than those from depression model group (P<0.05). Conclusion: Blue light could relieve depression-like symptoms in light-deprived rats. Exposure to blue light could activate neurons in the habenula nucleus to which intrinsically photosensitive retinal ganglion cells projected. Blue-light-mediated antidepressant effect might involve in the activation of CREB/BDNF signal transduction pathways in the habenula nucleus.

Energy metabolism disorder and functional magnetic resonance imaging of the medial prefrontal cortex in mice with chronic unpredictable mild stress

To analyze spontaneous activities and energy metabolism in the medial prefrontal cortex (mPFC) of mice with chronic unpredictable mild stress (CUMS) and explore the correlation of these changes with the mTORC1 signaling pathway. Normal C57Bl/6 mice were randomly divided into control group (n=16) and depression model group (n= 16), and the mice in the latter group were subjected to 8 weeks of modeling with CUMS. Behavioral tests including open field test, sucrose consumption test, tail suspension test and forced swimming test were performed, and the changes in prefrontal gray matter volume and the amplitude of low frequency fluctuation (ALFF) in the mice were detected with functional magnetic resonance imaging. The CUMS mice were then randomized into two groups for treatment with ketamine (n=8) or saline (n=8). The mPFC tissues of the mice were collected for detecting the phosphorylation levels of mTORC1-related proteins with Western blotting and ATP level and NADP +/NADPH ratio with ELISA in the 3 groups. Compared with the control mice, CUMS mice exhibited a distinct depressive phenotype with significantly decreased sucrose preference (P < 0.05) and shortened total distances (P < 0.01) and central exercise distances (P < 0.05) in the open field test without obvious changes of immobile time in tail suspension test and forced swimming test (P>0.05). Prefrontal gray matter volume and mALFF increased (P < 0.01), and the phosphorylation level of mTORC1- related proteins, ATP level and NADP +/NADPH ratio all decreased significantly (P < 0.05) in CUMS mice. After ketamine treatment, the phosphorylation level of mTORC1-related proteins and ATP level increased significantly in CUMS mice (P < 0.05), but the increase of NADP +/NADPH ratio was not statistically significant. The mPFC of CUMS mice shows increased spontaneous activities but lowered productivity efficiency, indicating the presence of energy metabolism disorder in the mPFC, which is related with reduced mTORC1 phosphorylation and can be alleviated by activating the mTORC1 pathway with ketamine.

Behavioral and Biochemical Effects of KXS on Postmyocardial Infarction Depression.

BackgroundDepression and coronary heart disease (CHD) often occur together in clinical practice. As a traditional Chinese medicine, Kai-Xin-San (KXS) has been widely used for the treatment of emotion-related disorders. In the present study, we aimed to explore whether KXS had both antidepressive effects and cardioprotective functions in a rat model of myocardial ischemia (MI) with depression.MethodsA total of 50 SD rats were randomly assigned into five groups as follows: normal control (control group), celiac injection of isopropyl adrenaline (ISO) (MI group), depression (depression group), MI+ depression (model group) and MI+ depression treated with intragastric administration of 370 mg/kg KXS (KXS group). MI was induced by subcutaneous injection of 85 mg/kg ISO. Depression was developed by a 7-week chronic mild stress (CMS) challenge. Behavioral test was conducted before and during the experiment. Echocardiography and biochemical analysis were carried out after 7 weeks of CMS challenge.ResultsAfter 7 weeks of experiment, depression-like behaviors were observed in all the groups except for control and KXS groups, and KXS treatment dramatically increased open-field test scores and sucrose consumption (P < 0.01 vs. model group). Echocardiography and biochemical analysis showed that KXS treatment could improve levels of ejection fraction (EF) and fractional shortening (FS), which were reduced by depression and ISO challenge. Meanwhile, KXS treatment significantly decreased the levels of creation kinase MB (CK-MB) and lactate dehydrogenase (LDH), which were increased in the model group. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), catalase (CAT) were increased, while the malondialdehyde (MDA) activity was significantly decreased in the KXS group. Moreover, KXS treatment reduced the levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in myocardial tissue compared with the model group.ConclusionsKXS had antidepressant-like activity and offered cardioprotective effects against ISO-induced myocardial infarction with depression.

Metabolomics analysis of the antidepressant prescription Danzhi Xiaoyao Powder in a rat model of Chronic Unpredictable Mild Stress (CUMS)

Ethnopharmacological relevanceDanzhi Xiaoyao Powder (DZXY) is a classical prescription, that has been extensively used in traditional Chinese medicine (TMC) to treat depression for many years. However, the mechanism of DZXY is still unclear. Aim of the studyThe aim was to investigate the mechanism of the antidepressant effect of DZXY on a rat model of chronic unpredictable mild stress (CUMS). Materials and methodsForty male SD (Sprague-Dawley) rats with similar open field test (OFT) results were randomLy divided into a control group (n = 10) and an experimental group (n = 30). A depression model was established in the experimental group using the CUMS method. After the CUMS model was established successfully, the rats were randomLy divided into a depression model group and a DZXY group. The DZXY group was fed DZXY, while the depression model group and control group were given an equal amount of 0.5% sodium carboxymethyl cellulose suspension. Intragastric administration was performed once daily for 14 consecutive days. Animal weight, the sugar preference test, the open field test and the forced swimming test were used to evaluate the modeling effect and the antidepressant effect of DZXY. After the experiment, the plasma of rats was collected and the changes in plasma metabolites were analyzed by UPLC/Q-TOF-MS. The UPLC/Q-TOF-MS spectra data were evaluated by pattern recognition analysis to determine the changes in endogenous metabolites in the rat plasma samples. ResultsThe results of the behavioral investigation showed that the rat model of depression was successfully replicated and that DZXY had an antidepressant effect. Using the UPLC-MS/MS metabolomics platform, partial least squares (PLS) and orthogonal partial least squares (OPLS), metabolic profile models (R2 and Q2 ≥ 0.5) of rat plasma were successfully constructed. The model could distinguish among the control group, the depression model group and the DZXY group. Finally, 38 differential metabolites were identified in the plasma. According to KEGG (http://www.kegg.jp) pathway analysis, amino acid metabolism, lipid metabolism, purine metabolism, the prolactin signaling pathway and bile secretion were enriched and represented the main metabolic pathways influenced in the plasma. ConclusionsThis study successfully established a CUMS depression model. A total of 38 differential metabolites associated with depression were identified in the plasma of rats, 24 of which were modulated by DZXY. These results suggest that DZXY can improve excitability and play an antidepressant role by regulating phenylalanine metabolism, arachidonic acid metabolism, porphyrin metabolism, D-arginine and D-ornithine metabolism, steroid hormone biosynthesis, unsaturated fatty acid biosynthesis and steroid biosynthesis.

Reduction of depression-like behavior in rat model induced by ShRNA targeting norepinephrine transporter in locus coeruleus

Depression may be associated with reduced monoamine neurotransmission, particularly serotonin and norepinephrine (NE). Reuptake of NE by the norepinephrine transporter (NET) is the primary mechanism by which many of the antidepressants are high-affinity substrates for NET. This study aimed to examine the effect of lentivirus-mediated shRNA targeting NET in locus coeruleus (LC) on depression-like behaviors of rats. We randomly assigned 60 male Wistar rats to 6 experimental groups: (1) Control group: without chronic unpredictable mild stress (CUMS) and without NET-shRNA treatment; (2) shRNA group: without CUMS + NET-shRNA; (3) CUMS group: 3-week CUMS without NET-shRNA; (4) CUMS + nonsense shRNA group; (5) CUMS + amygdala (Amy)-shRNA group; (6) CUMS+ locus coeruleus (LC)-shRNA group. First, recombinant lentiviral vector expressing shRNA (ShRNA-629, ShRNA-330, ShRNA-1222, ShRNA-1146 or ShRNA- negative control) against NET were produced, and their efficiency in knocking down of NET in PC12 cells were assessed by Q-PCR and western blot analysis. Second, shRNA was injected into the rat LC bilaterally to investigate whether it could prevent the depressive-like behavior induced by 3-week CUMS. Third, we tested the depressive-like behavior of the rats in the forced swimming test, the open field test, the sucrose preference test, as well as the body weight gain at the end of the seventh week. Finally, the protein expressions of NET was measured by western blot and the NE levels were measured by high performance liquid chromatography. Q-PCR and western blot showed that the ShRNA-1146 had the best interference efficiency targeting on NET in PC12 cells (p < 0.01). Compared to the depression model group, the immobility time in the forced swimming test was significantly reduced (p < 0.01), but the sucrose preference and the total scores in the open field test were significantly increased (all p < 0.01) in the group treated with shRNA in LC. Furthermore, compared with the depression model group, NET levels were significantly decreased (p < 0.01), but NE levels were significantly increased in the group treated with shRNA in LC (p < 0.05). Our findings suggest that Lentivirus-mediated shRNA targeting NET in LC downregulated NET both in vitro and in vivo, resulting in a significant decrease in depressive-like behavior of rats.

Effects of neurogenesis in the dentate gyrus (DG) of hippocampus on depression-like behaviors in WKY rats

To observe the effects of the neurogenesis in the dentate gyrus (DG) of the hippocampus on depression-like behaviors in adult Wistar Kyoto (WKY) rats. There were three groups in total (n = 10): ① the control (Wistar) group: 9-week-old Wistar rats were treated with saline for 3 weeks (10 mg/kg, intragastric administration); ② the depression model (WKY) group: WKY rats of the same age, tested for depression-like behaviors, were as a rat model of depression, and were treated with saline for 3 weeks (10 mg/kg, intragastric administration); ③ the positive control (AMI+WKY) group: WKY rats of the same age were treated with amitriptyline for 3 weeks (10 mg/kg, intragastric administration). The neurogenesis in hippocampus was detected by immunofluorescence staining for Ki67 (a neuronal proliferation marker) and DCX (an immature neuronal marker). The depression-like behaviors were assessed by sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). ① When compared with Wistar rats, the number of Ki67+ cells and DCX+ cells of the DG in WKY rats were decreased by 33.0% (P＜0.01) and 39.2% (P＜0.01), respectively; amitriptyline treatment significantly increased the number of Ki67+cells and DCX+ cells in the DG by 43.8% (P＜0.01) and 46.7% (P＜0.01), respectively, as compared with WKY rats. ② When compared with control group, WKY rats showed a significant decrease in sucrose preference (P＜0.01), less total horizontal distance (P＜0.01) and less time entered the center field (P＜0.01) in the OFT, the immobility time in the FST was increased significantly (P＜0.01). Amitriptyline treatment significantly improved the depression-like behaviors in WKY rats. ① The proliferation and differentiation of hippocampal neural stem cells in adult WKY rats are significantly lower than those of Wistar rats, suggesting that the neurogenesis in adult WKY rats is impaired. ②Amelioration of impaired hippocampal neurogenesis can partially reverse the depression-like behaviors in adult WKY rats.

Cerebellar Fastigial Nucleus Stimulation in a Chronic Unpredictable Mild Stress Rat Model Reduces Post-Stroke Depression by Suppressing Brain Inflammation via the microRNA-29c/TNFRSF1A Signaling Pathway.

BackgroundWe previously reported that cerebellar fastigial nucleus stimulation reduced post-stroke depression in a rat model by reducing inflammation. This study aimed to investigate the molecular inflammatory signaling pathways associated with cerebellar fastigial nucleus stimulation in an established rat model of post-stroke depression.Material/MethodsTwenty-four Sprague-Dawley rats included a sham group (N=6), an untreated stroke group (N=6), an untreated post-stroke depression model group (PSD) (N=6), and the model group treated with cerebellar fastigial nucleus stimulation (FNS) (N=6). The rat stroke model involved occlusion of the middle cerebral artery occlusion (MCAO). Post-stroke depression model was established using chronic unpredictable mild stress treatment and was verified using an open field test. Real-time polymerase chain reaction (PCR) and Western blot compared expression levels of microRNA-29c (miR-29c), miR-676, TNFRSF1A, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in cerebellar tissue. U251 human glioblastoma cells and SH-SY5Y human neuroblastoma cells were studied in vitro.ResultsCerebellar fastigial nucleus stimulation reduced behaviors associated with depression in the rat model, upregulated the expression of miR-29c, and reduced the expression of TNFRSF1A and inflammatory cytokines, and mildly reduced neuronal apoptosis. Bioinformatics data analysis identified a regulatory relationship between miR-29c and TNFRSF1A. SH-SY5Y cells treated with a miR-29c mimic, or TNFRSF1A short interfering RNA (siRNA), identified a negative regulatory relationship between TNFRSF1A and miR-29c.ConclusionsIn a rat model, cerebellar fastigial nucleus stimulation reduced the expression of TNFRSF1A by upregulating miR-29c expression, which suppressed the expression of inflammatory cytokines, resulting in reduced severity of post-stroke depression.

Dynamic monitoring of depressive behavior induced by nonylphenol and its effect on synaptic plasticity in rats

The etiology of depression is not known, it is thought that endocrine-disrupting chemicals (EDCs) contribute to the disease. Results of our previous research have shown that nonylphenol (NP), a well-known EDC, has neurotoxic effects, however, whether NP can induce depressive behavior by affecting synaptic plasticity has not yet been clearly elucidated. The depressive behavior induced by subchronic exposure to NP and its effect on the neuronal synaptic plasticity in rats are dynamically observed. Thirty Sprague-Dawley rats were randomly divided into 3 groups: control group (C, corn oil), NP group (NP, 4 mg/kg), and depression model group (D, corticosterone 20 mg/kg). There were 8 rats in each group. The depressive behavior of rats was tested by sucrose preference test, open-field test, and forced swimming test once a month for 3 months. The serum levels of brain-derived neurotrophic factor (BDNF) and corticosterone were detected by ELISA assay, and cellular morphological changes were observed by hematoxylin-eosin (HE) staining. The number of nerve cells, the length of dendrites, and the density of dendritic spines were observed by Golgi staining, and the synaptic cleft width, the postsynaptic density (PSD) thickness, and the synaptic interface curvature were observed by transmission electron microscope. Compared with the control group, the consumption of sucrose solution decreased in the NP group at the 2nd and 3rd month compared to the 1st month (F = 9.887, P = 0.002). The number of central square entries, the central square duration, and the total distance of movement were all decreased, and the decreasing degrees at the 3rd month were greater than those at the 1st month (F = 21.191, P < 0.001; F = 9.836, P = 0.002). The time of immobility for the NP group at the 1st month was higher than that in the control group (F = 6.912, P = 0.002). The expression of BDNF in the NP-treated group was higher than the control, while the expression of corticosterone in the NP-treated group was lower than the control. In the NP group, the cytoplasm of nerve cells contracted and appeared disordered. The neuron arrangement was disordered, and the number of cells, the length of the apex, the length of the basal dendrites, and the dendritic spine density were all lower in the NP group than those in the control group. The PSD thickness, the synaptic cleft width, and synaptic interface curvatures were all decreased in the NP group when compared to the control group. Subchronic exposure to 4 mg/kg NP led to depressive behavior in rats, and the depressive behavior and alterations in synaptic plasticity were more obvious with longer exposure time.

MicroRNA-27a participates in the pathological process of depression in rats by regulating VEGFA.

The present study aimed to determine the expression of vascular endothelial growth factor A (VEGFA) and microRNA (miRNA/miR)-27a in hippocampal tissues, and serum from a depression model of rats. In addition, the present study aimed to understand the mechanism of regulation of miR-27a in depression. A total of 40 male rats were selected, and divided into the control and depression model groups. The rats in the model group were subjected to 14 types of stimulations to model depression. By determining the body weight, syrup consumption rate and open field test score, the extent of depression in the rats was evaluated. Quantitative-polymerase chain reaction was used to determine the expression of VEGFA mRNA and miR-27a in hippocampal tissues, and serum. ELISA was used to measure the content of VEGFA protein in serum, while western blotting was employed to determine the expression of VEGFA protein in hippocampal tissues. A dual luciferase assay was carried out to identify the interactions between VEGFA mRNA and miR-27a. The rats in the depression model group showed depression symptoms and the depression model was successfully constructed. Rats with depression had lower VEGFA mRNA and protein expression in the hippocampus, and peripheral blood compared with the control group. Rats in the depression model group had reduced levels of miR-27a in the hippocampus and peripheral blood, which may be associated with the levels of VEGFA. miR-27a was able to bind with the 3′-untranslated region of VEGFA mRNA to regulate its expression. The present study demonstrated that miR-27a expression in hippocampal tissues and blood from rats with depression is upregulated, while the expression of VEGFA mRNA and protein is downregulated. miR-27a may participate in the pathological process of depression in rats by regulating VEGFA.

慢性应激抑郁大鼠模型心脏电生理变化与5-羟色胺、生长相关蛋白-43影响的研究

目的：探讨慢性应激抑郁大鼠模型5-羟色胺(5-HT)对心脏局部组织生长相关蛋白-43(GAP-43)及动作电位的影响。方法：随机将20只大鼠分为对照组和抑郁组，对抑郁组大鼠进行连续21天的慢性应激。应用电生理仪纪录心率、心房、心室局部组织动作电位时间(APD)，对左心室心尖部行5-HT及GAP-43免疫染色。结果：抑郁组大鼠慢性应激后的糖水消耗试验、自主活动得分均明显低于对照组，差异有显著统计学意义(P < 0.01)。抑郁组大鼠心率高于对照组，差异有统计学意义(P < 0.05)。抑郁组大鼠心房、心室组织动作电位时间低于对照组大鼠，差异有统计学意义(P < 0.05)。抑郁组大鼠心室组织5-羟色胺及GAP-43递质含量高于对照组大鼠，差异有统计学意义(P < 0.01)。结论：慢性应激所致的抑郁导致交感神经平衡紊乱及5-羟色胺及GAP-43递质含量增多，明显缩短大鼠心房、心室动作电位时程，破坏了心室电生理一致性，这可能是抑郁导致心律失常的机制之一。 Objective: To explore electrophysiologic characteristics of action potential and serotonin, growth-associated protein-43 (GAP-43) of heart location tissue in chronic stress mice. Methods: Twenty rats were randomly divided into two groups, 10 rats exposed to 21 consecutive days of unpredicted chronic mild stress as depression models, and 10 rats as normal controls. After intraperitioneal injection of choral hydrate (0.3 ml/100 mg), heart rats, atrial and ventricular local tissue field action potential duration (fAPD) were recorded by electrophysiological technology. Immunohistochemical stain, quantitative analysis of 5-HT and GAP-43 in the local heart tissue of depression group and control group were achieved by computerized image system. Results: There was significantly difference in glucose consume, total activity, heart rats between the two groups (p < 0.01, p < 0.05). The atrium and ventricular local tissue APD in depression model group were lower than that in normal group (p < 0.05). the positive index(PI) of 5-HT and GAP-43 increased in the local tissue of heart in depression model group, the PI of depression model group was much higher than in control group (p < 0.01). Conclusions: The increased heart rate, decreased fADP in atrial and ventricular tissue and increased PI of 5-HT and GAP-43 are the typical electrophysiologic characteristics of chronic depressive mice models made by unpredicted chronic mild stress method, stress depression may lead to arrhythmia through abnormal sympathetic nerve tension and serotonin change.

Chronic unpredicted mild stress-induced depression alter saxagliptin pharmacokinetics and CYP450 activity in GK rats.

Background. This study was to explore the pharmacokinetics of saxagliptin (Sax) in Goto–Kakizaki (GK) rats complicated with depression induced by chronic unpredicted mild stress (CUMS). The comorbidity of diabetic patients with depression is becoming more and more epidemic. Whether depression mental disorder alters the pharmacokinetics of hypoglycemic drugs in diabetes patients is not clear.Methods. Five-week-old male GK rats were kept in the cage for 7 weeks in a specific pathogen free (SPF)-grade lab until the emergence of diabetes and were then divided into two groups: control group and depression model group. Rats in the CUMS-induced depression group were exposed to a series of stressors for 8 weeks. Plasma serotonin and dopamine levels and behavior of open-field test were used to confirm the establishment of the depression model. All rats were given 0.5 mg/kg Sax orally after 8 weeks and blood samples were collected at different time points. The Sax concentration was assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The CYP450 activity of the liver microsomes was determined by using cocktails of probe drugs in which the activities of CYP enzymes were assessed through the determination of the production of the probe drugs.Results. Statistically significant differences in Sax pharmacokinetics were observed for area under curve, clearance, peak concentration, peak time and mean residence time between the depression rats and the control rats, while no statistical differences were observed for half-time and distribution volume by HPLC-MS/MS analysis. The CYP450 activity had different changes in the depression group.Conclusions. These results indicated that CUMS-induced depression alters the drug metabolic process of Sax and CYP450 activity of the liver microsomal enzymes in GK rats.

Effect of vanillin inhalation on brain derived neurotrophic factor in depressed model rats

Objective To evaluate the relieving effects of vanillin sinffing on depression-like behaviors in depressed rats and to explore the possible underlying mechanism. Methods Depression animal model established by chronic unpredictable medium intensity stress combined with isolation and destroy the olfactory bulb. The depressed rats were divided randomly into vanillin inhalation group, fluoxetine hydrochloride group, depression model group, olfactory bulbectomy with the vanillin inhalation treatment group and sham-operated group. Nervous behavioral changes had been observed at different time after the administration of 5 weeks. The concentration of brain derived neurotrophic factor(BDNF) in the brain homogenate and the positive expression of BDNF in hippocampus had been also measured. Results Two weeks after the intervention, the immobility time of vanillin group((12.78±7.50)s) was lower than that of the model group((57.33±32.16)s)(P<0.05). The consumption of saccharose in vanillin group((52.88±25.18)g) was higher than that of model group((37.40±19.33)g)(P<0.05). BDNF of the brain homogenate in vanillin group (0.54±0.13) was significantly increased compared with model group (0.36±0.06) (P<0.01). When compared with the OBX group (0.40±0.06), similar result was obtained. Immunohistochemistry and the average density of image analysis revealed that the expression of BNDF of hippocampal CA3 in vanillin group (0.40±0.03)was significantly increased compared with model group (0.25±0.04) and OBX group(0.28±0.03)(P<0.01). Conclusion Vanillin inhalation significantly relieves depression-like behaviors in depression rats .The possible mechanism may increase hippocampal neurogenesis by raising brain derived neurotrophic factor in brain. Key words: Vanillin; Olfactory pathway; Depressive disorder; Brain derived neurotrophic factor

The possible relationship between expressions of TRPC3/5 channels and cognitive changes in rat model of chronic unpredictable stress

Transient receptor potential canonical channel (TRPC) is a nonselective cation channel dominantly permeable to Ca2+. It consists of seven homologues, TRPC1–TRPC7, based on their sequence similarity. According to some researches, the expression of TRPC3/5 in hippocampus is related to the morphological changes of hippocampus, including axon length and dendritic spine density [1]. This study observed whether the expression of TRPC3/5 was changed in chronic unpredictable stress (CUS)-induced depression of rat model and can the altered TRPC3/5 expression affect the morphology of neurons in hippocampus of depressive rats as well as the cognitive ability. A total of 16 rats were equally and randomly divided into two groups: the control group and the depression model group, which underwent a process of CUS for three weeks. Western blot assay was conducted to test the content of TRPC3/5 in hippocampus, and Golgi-Cox staining was used to observe the morphological changes of neurons in hippocampus. Morris water maze (MWM) test was performed to observe the changes of spatial cognitive ability of rats while the long-term potentiation was applied to evaluate synaptic plasticity. Results showed that there was a difference in the expression of TRPC3/5 in hippocampal neurons, as well as the neuron morphology between control group and depression model group. At the same time the cognitive ability and synaptic plasticity were significantly changed. Results suggest that there is an association between expressions of TRPC3/5 and cognitive changes in CUS rat model, and the mechanism maybe that the different expressions of TRPC3/5 can cause morphological changes of the neurons in hippocampus, which has a profound impact on the spatial cognitive ability and synaptic plasticity.

Effect and mechanism of fluoxetine on electrophysiology in vivo in a rat model of postmyocardial infarction depression.

BackgroundMajor depression is diagnosed in 18% of patients following myocardial infarction (MI), and the antidepressant fluoxetine is shown to effectively decrease depressive symptoms and improve coronary heart disease prognosis. We observed the effect of fluoxetine on cardiac electrophysiology in vivo in a rat model of post-MI depression and the potential mechanism.Methods and resultsEighty adult male Sprague Dawley rats (200–250 g) were randomly assigned to five groups: normal control (control group), MI (MI group), depression (depression group), post-MI depression (model group), and post-MI depression treated with intragastric administration of 10 mg/kg fluoxetine (fluoxetine group). MI was induced by left anterior descending coronary artery ligation. Depression was developed by 4-week chronic mild stress (CMS). Behavior measurement was done before and during the experiment. Electrophysiology study in vivo and Western blot analysis were carried on after 4 weeks of CMS. After 4 weeks of CMS, depression-like behaviors were observed in the MI, depression, and model groups, and chronic fluoxetine administration could significantly improve those behaviors (P<0.05 vs model group). Fluoxetine significantly increased the ventricular fibrillation threshold compared with the model group (20.20±9.32 V vs 14.67±1.85 V, P<0.05). Expression of Kv4.2 was significantly reduced by 29%±12%, 24%±6%, and 41%±15%, respectively, in the MI group, CMS group, and model group, which could be improved by fluoxetine (30%±9%). But fluoxetine showed no improvement on the MI-induced loss of Cx43.ConclusionThe susceptibility to ventricular arrhythmias was increased in depression and post-MI depression rats, and fluoxetine may reduce the incidence of ventricular arrhythmia in post-MI depression rats and thus improve the prognosis. This may be related in part to the upregulation of Kv4.2 by fluoxetine.

CNP signal pathway up-regulated in rectum of depressed rats and the interventional effect of Xiaoyaosan.

To investigate the distribution and expression of C-type natriuretic peptide (CNP)/natriuretic peptide receptor B (NPR-B) in the rectum of a rodent depression model and the interventional effect of Xiaoyaosan (XYS). Male rats (n = 45) of clean grade (200 ± 20 g) were divided into five groups after one week of adaptive feeding: primary control, depression model, low dose XYS, middle dose XYS, and high dose XYS. The animal experiment continued for 3 wk. Primary controls were fed normally ad libitum. The rats of all other groups were raised in solitary and exposed to classic chronic mild unpredictable stimulation each day. XYS groups were perfused intragastrically with low dose, middle dose, and high dose XYS one hour before stimulation. Primary control and depression model groups were perfused intragastrically with normal saline under similar conditions as the XYS groups. Three weeks later, all rats were sacrificed, and the expression levels of CNP and NPR-B in rectum tissues were analyzed by immunohistochemistry, real-time polymerase chain reaction, and Western blotting. CNP and NPR-B were both expressed in the rectum tissues of all rats. However, the expression levels of CNP and NPR-B at both gene and protein levels in the depression model group were significantly higher when compared to the primary control group (n = 9; P < 0.01). XYS intervention markedly inhibited the expression levels of CNP and NPR-B in depressed rats. The expression levels of CNP and NPR-B in the high dose XYS group did not significantly differ from the expression levels in the primary control group. Additionally, the high and middle dose XYS groups (but not the low dose group) significantly exhibited lower CNP and NPR-B expression levels in the rectum tissues of the respectively treated rats compared to the untreated depression model cohort (n = 9; P < 0.01). The CNP/NPR-B pathway is upregulated in the rectum of depressed rats and may be one mechanism for depression-associated digestive disorders. XYS antagonizes this pathway at least partially.