Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine4 (5-HT4) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation and blockade of PrL 5-HT4 receptors on working memories by T-maze rewarded alternation and Morris water maze tests in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. The lesion induced working memory deficits, decreased dopamine levels in the limbic-related brain regions, changed normalized δ, high θ, α, β, low and high γ power of the PrL, and upregulated expression of PrL 5-HT4 receptor. Intra-PrL injection of 5-HT4 receptor agonist BIMU8 or antagonist GR113808 did not impact working memories in sham rats, but improved working memory deficits in the lesioned rats. Intra-PrL injection of BIMU8 or GR113808 had no effect on monoamine levels in the limbic-related brain regions or normalized low and high γ power of the PrL in sham rats. However, in the lesioned rats, intra-PrL injection of BIMU8 significantly increased dopamine and 5-HT levels in the medial prefrontal cortex, amygdala and dorsal hippocampus, while intra-PrL injection of GR113808 significantly increased dopamine levels in these brain regions and increased normalized low and high γ power of the PrL. These results suggest that 6-OHDA lesion in rats induces working memory deficits, while activation or blockade of PrL 5-HT4 receptors improves the deficits in the lesioned rats, which possibly due to the changes of monoamine levels in the limbic-related brain regions and network activity of neurons in the PrL.

The management and therapy of bone cancer pain (BCP) remain formidable clinical challenges. Curcumin and its analogues have been shown to have anti-inflammatory and analgesic properties. In the present study, we investigated the efficacy of curcumin analogue NL04 (NL04) in modulating inflammation in spinal dorsal horn (SDH), thereby exploring its potential to reduce central sensitization of BCP in a rat model. Differing doses of NL04 and curcumin were administered intrathecally either once (on day 12 of BCP) or over seven consecutive days (from day 6-12 of BCP). Results indicated that the ED50 for NL04 and curcumin ameliorating BCP-induced mechanical hyperalgesia is 49.08 mu g/kg and 489.6 mu g/kg, respectively. The analgesic effects at various doses of NL04 lasted between 4 and 8 h, with sustained administration over a week maintaining pain relief for 1-4 days, while also ameliorating locomotor gait via gait analysis and reducing depressive and anxiety-like behaviors via open-field and light-dark transition tests. The analgesic effects at various doses of curcumin lasted 4 h, with sustained administration over a week maintaining pain relief for 0-2 days. ELISA, Western blotting, qPCR, and immunofluorescence assays substantiated that intrathecal administration of NL04 on days 6-12 of BCP dosedependently lowered spinal IL-1 beta and IL-18 levels and significantly reduced the expression of IKK beta genes and proteins, as well as the downstream cleavage of the trans-Golgi network (TGN). Whole-cell patch-clamp results demonstrated that NL04 inhibits potassium ion efflux in rat primary spinal neurons. Thus, NL04 exhibits significant analgesic effects in a BCP rat model by downregulating IKK beta expression and inhibiting neuronal potassium ion efflux, which, in turn, suppresses the activation of NLRP3 inflammasomes and reduces IL-1 beta production, potentially ameliorating pain management in BCP.

AIM: To evaluate the effect of bone morphogenetic protein-6 (BMP-6) on transforming growth factor (TGF)-β2-induced epithelial-mesenchymal transition (EMT) in retinal pigment epithelium (RPE). METHODS: Adult retinal pigment epithelial cell line (ARPE-19) were randomly divided into control, TGF-β2 (5 µg/L), and BMP-6 small interfering RNA (siRNA) group. The cell morphology was observed by microscopy, and the cell migration ability were detected by Transwell chamber. The EMT-related indexes and BMP-6 protein levels were detected by Western blotting. Furthermore, a BMP-6 overexpression plasmid was constructed and RPE cells were divided into the control group, TGF-β2+empty plasmid group, BMP-6 overexpression group, and TGF-β2+BMP-6 overexpression group. The EMT-related indexes and extracellular regulated protein kinases (ERK) protein levels were detected. RESULTS: Compared with the control group, the migration of RPE cells in the TGF-β2 group was significantly enhanced. TGF-β2 increased the protein expression levels of α-smooth muscle actin (α-SMA), fibronectin and vimentin but significantly decreased the protein levels of E-cadherin and BMP-6 (P<0.05) in RPE. Similarly, the migration of RPE cells in the BMP-6 siRNA group was also significantly enhanced. BMP-6 siRNA increased the protein expression levels of α-SMA, fibronectin and vimentin but significantly decreased the protein expression levels of E-cadherin (P<0.05). Overexpression of BMP-6 inhibited the migration of RPE cells induced by TGF-β2 and prevented TGF-β2 from affecting EMT-related biomarkers (P<0.05). CONCLUSION: BMP-6 prevents the EMT in RPE cells induced by TGF-β2, which may provide a theoretical basis for the prevention and treatment of proliferative vitreoretinopathy.

Introduction: Dendritic cells (DCs) play critical roles in the pathogenesis of myasthenia gravis (MG), and a series of DC-based experimental strategies for MG have recently been developed. However, the definite roles of different DC subsets in the mechanism of MG have scarcely been covered by previous studies. The present study aimed to investigate the levels of three main DC subsets, plasmacytoid DCs (pDCs) (CD303 positive) and two distinct subsets of conventional DCs (cDCs), namely CD1c+ cDCs and CD141+ cDCs, in MG patients and analyze related clinical features. Methods: From January 2016 to December 2020, 160 newly diagnosed MG patients and matched healthy controls (n = 160) were included in the study, and their clinical data were collected. The blood samples from MG patients before treatment and controls were collected for flow cytometry analysis. A total of 14 MG thymoma, 24 control thymoma, and 3 thymic cysts were used to immunostain the DC subsets. Results: The flow cytometry analysis showed a significantly higher frequency of circulating pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients than in healthy controls (p < 0.001 for all). Patients with early-onset MG (<50 years old) had a lower frequency of circulating pDCs but a higher frequency of circulating CD1c+ cDCs than those with late-onset MG (≥50 years old) (p = 0.014 and p = 0.025, respectively). The frequency of circulating pDCs was positively associated with the clinical severity of late-onset MG patients (r = 0.613, p < 0.001). 64.3% (9/14) of MG thymoma is of type B2 under the World Health Organization classification, which is higher than that in control thymoma (33.3%, 8/24) (p = 0.019). For type B2 thymoma, there were significantly more pDCs but fewer CD1c+ cDCs in MG thymoma than in the controls. Conclusion: The distribution of aberrant pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients displayed age- and thymoma-related differences, which may contribute to the impaired immune tolerance and lead to the onset of MG.

Supplementary Figure 2B from Inhibition of the p38 Kinase Suppresses the Proliferation of Human ER-Negative Breast Cancer Cells

目的 观察不同慢性束缚方案与青春期小鼠抑郁行为及学习记忆能力的相关性,探讨瘦素对慢性束缚应激造成的情绪障碍和学习记忆的影响及相关受体机制.方法 选取出生后3～4周龄健康雄性C57小鼠70只,连续10d低强度(2h)/高强度(4h)束缚应激,筛选理想的束缚模型,腹腔注射瘦素(LP),矿场实验(OFT)观察小鼠抑郁行为,Morris水迷宫检测小鼠的学习记忆能力,酶联免疫法检测血清LP水平,Western blotting实验检测海马和内侧前额叶皮层(mPFC)N-甲基D-天冬氨酸受体1(NMDAR1)和γ氨基丁酸受体(GABAR)的表达.结果 OFT实验中,高强度束缚(HCRS)组小鼠的中央区停留时间低于对照组[HCRS组:(95.2±17.3)s,对照组:(157.1±25.5)s,P＜0.01].HCRS+盐水组小鼠的中央区停留时间低于假手术组(分别为97.7±25.1和148.6±24.8;P＜0.01),HCRS+高浓度LP(H-LP,0.05mg/kg)组小鼠在中央区停留时间与假手术组小鼠接近.Morris水迷宫定位航行实验中,HCRS小鼠在四个象限的逃避潜伏期均低于对照组,HCRS+H-LP小鼠与假手术小鼠差异无统计学意义.Morris水迷宫空间探索实验的平均穿越站台次数,HCRS小鼠低于对照组(HCRS组:2.1±0.9,对照组:4.2±1.9;P＜0.05),HCRS+H-LP小鼠与sham小鼠差异无统计学意义.血清LP水平检测显示,HCRS组(4.2±1.3)低于对照组(10.4±2.9;P＜0.01),HCRS+H-LP组与假手术组差异无统计学意义.蛋白质印迹法结果显示,HCRS组小鼠的mPFC NMDR1表达水平低于对照组.应用高浓度LP后NMDR1表达水平接近正常水平.结论 HCRS可以造成青春期小鼠的情绪和学习记忆障碍,全身慢性应用高浓度LP能够改善HCRS导致的青春期小鼠抑郁样行为和学习记忆障碍,这可能与瘦素抑制mPFC NMDAR1表达水平降低有关.

BACKGROUND:The comorbidity between diabetes mellitus and depression was revealed, and diabetes mellitus increased the prevalence of depressive disorder, which ranked 13th in the leading causes of disability-adjusted life-years. Insulin resistance, which is common in diabetes mellitus, has increased the risk of depressive symptoms in both humans and animals. However, the mechanisms behind the comorbidity are multi-factorial and complicated. There is still no causal chain to explain the comorbidity exactly. Moreover, Selective serotonin reuptake inhibitors, insulin and metformin, which are recommended for treating diabetes mellitus-induced depression, were found to be a risk factor in some complications of diabetes.AIMS:Given these problems, many researchers made remarkable efforts to analyze diabetes complicating depression from different aspects, including insulin resistance, stress and Hypothalamic-Pituitary-Adrenal axis, neurological system, oxidative stress, and inflammation. Drug therapy, such as Hydrogen Sulfide, Cannabidiol, Ascorbic Acid and Hesperidin, are conducive to alleviating diabetes mellitus and depression. Here, we reviewed the exact pathophysiology underlying the comorbidity between depressive disorder and diabetes mellitus and drug therapy.METHODS:The review refers to the available literature in PubMed and Web of Science, searching critical terms related to diabetes mellitus, depression and drug therapy.RESULTS:In this review, we found that brain structure and function, neurogenesis, brain-derived neurotrophic factor and glucose and lipid metabolism were involved in the pathophysiology of the comorbidity. Obesity might lead to diabetes mellitus and depression through reduced adiponectin and increased leptin and resistin. In addition, drug therapy displayed in this review could expand the region of potential therapy.CONCLUSIONS:The review summarizes the mechanisms underlying the comorbidity. It also overviews drug therapy with anti-diabetic and anti-depressant effects.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors that mediate the effects of cardiac diseases. GPR30, also named G-protein-coupled estrogen receptor, shows beneficial effect on female patients with heart failure. This research aimed to probe the role and mechanism of GPR30 in myocardial hypertrophy. The model of cardiac hypertrophy was induced by infusion of angiotensin (Ang) II in mice, and was induced by Ang II treatment in neonatal rat cardiomyocyte (NRCM). The mouse model of myocardial hypertrophy was induced by angiotensin (Ang) Ⅱ, and the neonatal rat cardiomyocyte (NRCM) was induced by Ang Ⅱ treatment. GPR30 agonist G1 reduced cardiac hypertrophy induced by Ang II in mice, and reduced cardiac atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) induced by Ang II. Ang Ⅱ treatment of myocardial fibrosis in mice was suppressed after administration of G1. GPR30 deficiency produced the opposite results. Oxidative stress and apoptosis were enhanced in the mice heart induced by Ang II, which were suppressed by G1 administration, but were further exacerbated after GPR30 deficiency. The outcomes demonstrated that GPR30 participated in the regulation of cardiac hypertrophy and fibrosis. Activation of GPR30 ameliorated cardiac hypertrophy and fibrosis by reducing oxidative stress and apoptosis.

Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated β-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway. The activity of GSK-3β, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3β. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3β signaling pathway.

目的 探讨不同浓度米氮平对慢性束缚应激导致的青春期小鼠焦虑、抑郁样行为的改善作用,为青春期情绪障碍的治疗提供研究资料.方法 随机选取60只出生3～4周龄雄性C57小鼠,模型组给予连续10 d(4 h/d)束缚应激(CRS),治疗组分别连续腹腔注射低浓度(15 mg/kg)或高浓度(30 mg/kg)米氮平(10 d).分别采用矿场实验(OFT)检测焦虑样行为,悬尾实验(TST)和强迫游泳实验(FST)检测抑郁样行为,酶联免疫法检测血清米氮平水平.结果 OFT实验中,CRS小鼠在中央区停留时间为(106.1±36.64)s,低于对照组[(182.5±38.69)s](P＜0.01),应用高浓度米氮平(30 mg/kg)后该时间延长至(186.1±23.43)s,接近正常水平.TST实验中,CRS组静止时间为(176.2±104.5)s,高于对照组[(71.05±36.4)s](P＜0.01),应用高浓度米氮平(30 mg/kg)后时间缩短为(69.13±31.72)s(P＞0.05).FST 实验中,CRS组的漂浮时间为(304.6±87.96)s,高于对照组[(196.2±72.6)s](P＜0.01),应用高浓度米氮平(30 mg/kg)后,漂浮时间缩短为(188.8±49.05)s(P＞0.05).CRS导致小鼠血清 NE[(34.52±9.03)pg/ml)]和5-HT[(44.42±16.55)ng/ml]水平低于正常小鼠(P＜0.01),应用高浓度米氮平后恢复接近正常水平[NE:(105.93±21.42)pg/ml,5-HT:(133.56±32.31)ng/ml].结论 CRS可以造成青春期小鼠抑郁和焦虑样情绪障碍,全身慢性应用高浓度米氮平可改善其焦虑和抑郁的症状.

The microstructure evolution and creep fracture mechanism of Al2O3f/Mg-6Al-0.5Nd-1Gd at different creep stages have been investigated by high temperature creep apparatus, X-ray diffraction analysis, and scanning electron microscopy. The results show that the composite is composed of alpha-Mg, beta-Mg17Al12, Al2O3, Mg2Si, Al2Nd, and Al2Gd. MgO was generated on the fiber surface as a transition layer. According to the creep test results, the composites are suitable for working conditions below 110 MPa at 200 degrees C. The creep fracture mode of the composites depends on the interfacial bonding conditions between the matrix alloy and fiber, and the fracture mechanism is a combination of interfacial debonding and fiber fracture.

Background: Emerging evidence suggests that long non coding RNA (lncRNA) small nucleolar RNA host gene 4 (SNHG4) has become a new insight into lipopolysaccharide (LPS) - induced microglia inflammation, its role in neonatal pneumonia (NP) remains to be largely unrevealed.Methods: RT-qPCR was used to determine SNHG4 and METTL3 expression in the serum from NP patients and normal volunteers, as well as in WI-38 cells treated with LPS. The SNHG4 overexpression vector (pcDNA-SNHG4) was transfected into LPS - treated cells. CCK-8, Transwell, annexin V-FITC/PI and ELISA assays were used to determine cell proliferation, migration, apoptosis and contents of IL-6, TNF-α, SOD and MDA, respectively. The level of SNHG4 in the promoter region of METTL3 was assessed with RIP assay. m6A quantitative analysis illustrated the m6A level with or without SNHG4 overexpression or METTL3 silencing. Bioinformatics analysis and RIP-PCR were used to predict and validate YTHDF1 - mediated m6A levels on signal transducer and activator of transcription 2 (STAT2) mRNA in METTL3 inhibited cells. Then rescue experiments were performed to explore effects of SNHG4 and METTL3 or STAT2 on LPS-treated cell functions. Subsequently, in vivo functional experiments were performed to investigate the role of SNHG4 in LPS induced pneumonia in mice. Results: SNHG4 was downregulated and METTL3 was upregulated in NP patients and LPS-treated cells. SNHG4 overexpression facilitated cell proliferation, migration and SOD concentration, and inhibited apoptosis and IL-6, TNF-α and MDA contents. Mechanistically, SNHG4 bound with METTL3 and downregulated METTL3 expression. Besides, total m6A modification level was lower in the SNHG4 overexpressed or METTL3 inhibited cells. METTL3 interference reduced m6A levels of STAT2 mRNA, decreased STAT2 mRNA stability and promoted STAT2 translation level. METTL3 or STAT2 upregulated reversed the effects of SNHG4 overexpression on LPS - treated cell functions. Conclusions: This study reveals that SNHG4 promotes LPS induced inflammation in human lung fibroblasts and mouse lung tissues in vitro and in vivo by inhibiting METTL3 - mediated m6A level of STAT2 mRNA, which may provide a potential therapeutic mechanism for NP.

The specific Nd/Gd mass ratios were designed for optimizing the microstructure of the Mg–8Al–Nd–Gd alloys, and the strengthening mechanism of Al-Gd-Nd phase in the creep process was revealed. The Mg–8Al-1.0Gd-1.0Nd (T6) at Gd/Nd ratio of 1:1 exhibited excellent tensile creep resistance at 423 K/60 MPa, owing to the diffusely distributed Al2RE and the fine Al11Nd3 particles, which hindered the motion of dislocations and grain boundary sliding. The stead-state creep rate and creep strain of the alloy were 1.03 × 10−8 s−1 and 0.312%, respectively, which were superior to that of AZ91 alloy. It could be verified that Gd showed little aging precipitation strengthening effect, while it made the typical rod-like Al11Nd3 evolved into dot-like phase. A TEM thin foil was extracted by focused ion beam (FIB), and the result showed that Nd occupied the Gd sites to form Al2(Nd + Gd) solid solution. The TEM bright-field image was taken along the B = [1¯1¯01]Mg zone axis with diffraction condition g = 101¯1¯ and Two-beam dark field image with diffraction condition g = 112¯0, which demonstrated the activation of and dislocations during creep deformation.

采用光学显微镜(OM)、扫描电镜(SEM)、EDS能谱分析等研究了 Mg-6Al-1Nd-1Gd合金固溶与时效处理后的显微组织及在200℃和70 MPa条件下的高温压缩蠕变行为.结果表明:固溶+时效处理后Mg-6Al-1Nd-1Gd合金的β-Mg17Al12相几乎完全消失,金属间化合物为Al2RE(Nd、Gd)相,且在晶界产生偏聚.蠕变后,热处理后合金的金属间化合物有所增加,T4态合金金属间化合物体积分数增加最多,高温蠕变抗力最好,蠕变量及稳态蠕变速率分别为1.8％及2.333×10-8s-1,较铸态时的4.45％及5.817×10-8 s-1 分别降低了 59.6％和59.9％.

目的 观察不同强度的运动训练对青春期大鼠学习记忆能力的影响以及和血清瘦素水平的关系,为研究青春期学习记忆能力的提高提供依据.方法 选择30只45～50日龄大鼠,随机分为低强度运动组、中等强度运动组和对照组,每组10只,连续一周低强度或中等强度跑台运动训练,Morris水迷宫观察大鼠学习记忆,酶联免疫法检测血清瘦素(Lep)水平.结果 中等强度运动训练组大鼠Morris水迷宫实验四个象限的平均逃避潜伏期分别为(44.8±5.0)s,(49.3±5.2)s,(39.3±4.7)s和(37.7±2.8)s,均短于正常组大鼠(P＜0.01),中等强度运动训练组大鼠穿越站台次数为5.2±1.8,高于正常组大鼠(2.6±0.4),差异均具有统计学意义(P＜0.01).中等强度运动组大鼠的血清Lep水平[(15.1±4.5) pg/ml]高于正常组大鼠[(12.8±3.7) pg/ml](t=2.47,P＜0.05).结论 中等强度的运动训练能够提高青春期大鼠的学习记忆能力,这可能与血清Lep含量的增加有关.

The present study aimed to investigate whether the cerebellar fastigial nucleus (FN) is involved in post-stroke depression (PSD), and to observe the effect of direct cerebellar-hypothalamic γ-aminobutyric acid (GABA)ergic and glutamatergic projections on PSD, in order to understand the mechanisms underlying the cerebellar modulation of mood and emotion. Healthy Sprague-Dawley rats were randomly divided into five groups: Sham-operated, Stroke, PSD, FN lesion, and decussation of superior cerebellar peduncle (XSCP) lesion groups. Sham surgery was performed in animals of the Sham group (n=6). The rats in the other four groups (n=6 for each group) underwent middle cerebral artery occlusion. The rats were examined twice a week in an open field test. In addition, the expression of cytokines in hippocampal tissues, and the content of glutamate and GABA in the lateral hypothalamic area (LHA) were measured. The results showed that scores corresponding to the behavioral signs of depression were decreased in the PSD, FN lesion and XSCP lesion groups. In addition, the mRNA levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in the hippocampus of the PSD, FN lesion and XSCP lesion groups were significantly increased. The GABA and glutamate content in the LHA were also decreased significantly in the PSD, FN lesion and XSCP lesion groups. Taken together, the findings of the present study indicated that the cerebellar FN may be involved in PSD through the direct cerebellar-hypothalamic glutamatergic and GABAergic projections.

Objectives: This study aimed to investigate the effect of serotonin6 (5-HT6) receptors in the dorsal hippocampus (dHip) on the regulation of Parkinson's disease (PD)-associated anxiety. Methods: We examined whether intra-dHip injection of both 5-HT6 receptor agonist and antagonist was involved in the regulation of anxiety-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle by the open-field and elevated plus maze (EPM) tests. Four weeks after injection of 6-OHDA, the concentrations of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in relative related brain regions were measured by reverse-phase high-performance liquid chromatography. Results: In sham-operated rats, intra-dHip injection of both 5-HT6 receptor agonist WAY208466 (3 and 6 µg/rat) and antagonist SB258585 (4 µg/rat) increased the percentage of time spent in the center area in the open-field test and percentages of open arm entries and open arm time in EPM test, indicating that induced anxiolytic effects. In the lesioned rats, WAY208466 (1.5, 3 and 6 µg/rat) produced anxiolytic responses, whereas SB258585 (2 and 4 µg/rat) produced anxiogenic effects. Neurochemical results showed that intra-dHip injection of WAY208466 (6 µg/rat) decreased NA level in the amygdala, and SB258585 (4 µg/rat) increased DA levels in the dHip and vHip in sham-operated rats, whereas WAY208466 increased DA levels in the dHip, vHip, and amygdala in the lesioned rats. Discussion: dHip 5-HT6 receptors are involved in the regulation of anxiety-like behaviors, which may be mediated through different neurochemical mechanisms, and the dHip is an important site involved in these effects. Abbreviation: PD: Parkinson's disease;6-OHDA: 6-hydroxydopamine; dHip: dorsal hippocampus; vHip: ventral hippocampus; 5-HT: serotonin; MFB: medial forebrain bundle; DA: dopamine; NA: noradrenaline; EPM: elevated plus-maze; GABA: gamma-aminobutyric acid; BLA: basolateral amygdala.

At present, role of the lateral habenula (LHb) calcium-permeable AMPA receptors (CP-AMPARs) in depression is not understood, particularly in Parkinson's disease-related depression. Here we found that lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors, and intra-LHb injection of CP-AMPAR antagonist Naspm produced antidepressant-like effects in SNc sham-lesioned and SNc-lesioned rats, however, the doses inducing these effects in SNc-lesioned rats were lower than that of SNc sham-lesioned rats. Blockade of LHb CP-AMPARs decreased the firing rate of the neurons and increased release of dopamine and serotonin in the medial prefrontal cortex (mPFC) in both groups, but the duration of Naspm action on the firing rate and release of the transmitters were prolonged in SNc-lesioned rats. These changes in SNc-lesioned rats were involved in increased expression of βCaMKII and p-GluR1-S831 in the LHb. Intra-LHb injection of Naspm inhibited dopaminergic neurons in the anterior ventral tegmental area and serotonergic neurons in the dorsal raphe nucleus and excited dopaminergic neurons in the posterior ventral tegmental area (pVTA) and serotonergic neurons in the median raphe nucleus (MRN), and lesioning the GABAergic rostromedial tegmental nucleus (RMTg) decreased the percentages of excited pVTA dopaminergic neurons and MRN serotonergic neurons. Our findings indicate that blockade of LHb CP-AMPARs produces antidepressant-like effects, which attribute to decreased firing activity of LHb neurons and increased levels of dopamine and serotonin in the mPFC, and provide further evidence that LHb CP-AMPARs regulate the firing activity of pVTA dopaminergic neurons and MRN serotonergic neurons indirectly via the RMTg.

The medial prefrontal cortex (mPFC) receives direct and indirect projections from the ventral hippocampus (VH) and plays an important role in the regulation of anxiety. However, the effect of the mPFC dopamine D-1 receptor on anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH has not been described. Here, we examined the effects of SKF38393, a selective dopamine D-1 receptor agonist, on anxiety-like behaviors induced by NMDA receptor inhibition in the VH and neuron firing activity of mPFC. Injection of MK-801 (6 mu g/0.5 mu l) into the VH produced anxiety-like behaviors in the elevated plus maze and open field tests, increased the firing activity of pyramidal neurons in the mPFC, and decreased the level of dopamine in the mPFC. Injection of SKF38393 (0.5 mu g/0.5 mu l) into the mPFC produced anxiolytic effects, and normalized the hyperactive firing activity of mPFC pyramidal neurons induced by MK-801, whereas in both normal and anxiety-like rats caused by MK-801, injection of SKF38393 into the mPFC decreased the firing activity of mPFC interneurons but did not affect the dopamine content in the mPFC. The present data demonstrate that decreased D-1 receptor activation in the mPFC may mediate anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH. The balance of D-1 receptor activity between pyramidal neurons and intemeurons is a crucial factor in maintaining normal conditions, and inhibitory glutamatergic activity in the VH induces hyperactivity of mPFC pyramidal neurons through decreases in dopamine release and in the amount of D-1 receptor activation on mPFC pyramidal neurons, which may be a critical factor for anxiety disorders.

Nuciferine, a bioactive component extracted from the lotus leaf, has been reported to have various anti-inflammatory effects. In the present study, we aimed to investigate the anti-inflammatory effects and mechanism of nuciferine on lipopolysaccharide (LPS)-stimulated BV2 microglia cells. The anti-inflammatory activity of nuciferine was measured by ELISA to detect the inflammatory mrdiators secretion in LPS-simulated BV2 microglia cells. The results demonstrated that nuciferine significantly inhibited LPS-induced TNF-α, IL-1β, PGE2 and NO secretion. LPS-induced NF-κB activation was also suppressed by nuciferine. Further studies showed that nuciferine increased the expression of PPAR-γ. Functional aspects were analyzed using PPAR-γ specific inhibitor GW9662, which attenuated the LPS-induced secretion of proinflammatory mediators, such as TNF-α, IL-1β, PGE2, and NO. In conclusion, these results suggested that nuciferine activated PPAR-γ, which subsequently inhibited LPS-induced inflammation in BV2 cells.