Therapeutic effects and mechanisms of fecal microbiota transplantation on EAE partly through HPA axis-mediated neuroendocrine regulation.

Background: The pathogenesis of multiple sclerosis (MS) may be closely related to immune regulation and inflammatory cytokines induced by specific flora. Repairing the intestinal flora may alter the immune response in MS patients, thus opening up novel approaches for the treatment of MS. Objective: We aimed to test the therapeutic effect of fecal microbiota transplantation (FMT) on experimental autoimmune encephalomyelitis (EAE) and the characteristics of intestinal microbiota composition changes, explore the potential mechanisms of FMT treatment. Methods: EAE animals were treated with FMT, with the therapeutic effects were evaluated by observing neurological scores and measuring serum levels of cortisol, IL-17, and TLR-2. Fecal microbiome 16S rRNA sequencing was used to profile changes in microbiota composition, and adrenalectomy pretreatment was used to test whether FMT effects were dependent on HPA axis function. Results: FMT improved neurological function and reduced serum IL-17 to levels that were close to the control group. FMT reestablished intestinal homeostasis by altering the structure of the intestinal flora, increasing the abundance of beneficial flora, and regulating intestinal metabolites. We found that the therapeutic effects of FMT depended partly on the efferent function of the HPA axis; surgical disruption of the HPA axis altered the abundance and diversity of the intestinal flora. Conclusion: FMT showed a neuroprotective effect on EAE by increasing the abundance of the beneficial flora, rebuilding intestinal homeostasis, reducing IL-17 and cortisol serum levels, and promoting serum TLR-2; the therapeutic effect of FMT on EAE is partly dependent on the HPA axis.

MMSMAPlus: a multi-view multi-scale multi-attention embedding model for protein function prediction.

Protein is the most important component in organisms and plays an indispensable role in life activities. In recent years, a large number of intelligent methods have been proposed to predict protein function. These methods obtain different types of protein information, including sequence, structure and interaction network. Among them, protein sequences have gained significant attention where methods are investigated to extract the information from different views of features. However, how to fully exploit the views for effective protein sequence analysis remains a challenge. In this regard, we propose a multi-view, multi-scale and multi-attention deep neural model (MMSMA) for protein function prediction. First, MMSMA extracts multi-view features from protein sequences, including one-hot encoding features, evolutionary information features, deep semantic features and overlapping property features based on physiochemistry. Second, a specific multi-scale multi-attention deep network model (MSMA) is built for each view to realize the deep feature learning and preliminary classification. In MSMA, both multi-scale local patterns and long-range dependence from protein sequences can be captured. Third, a multi-view adaptive decision mechanism is developed to make a comprehensive decision based on the classification results of all the views. To further improve the prediction performance, an extended version of MMSMA, MMSMAPlus, is proposed to integrate homology-based protein prediction under the framework of multi-view deep neural model. Experimental results show that the MMSMAPlus has promising performance and is significantly superior to the state-of-the-art methods. The source code can be found at https://github.com/wzy-2020/MMSMAPlus.

Analysis of public opinion on food safety in Greater China with big data and machine learning.

The Internet contains a wealth of public opinion on food safety, including views on food adulteration, food-borne diseases, agricultural pollution, irregular food distribution, and food production issues. To systematically collect and analyze public opinion on food safety in Greater China, we developed IFoodCloud, which automatically collects data from more than 3,100 public sources. Meanwhile, we constructed sentiment classification models using multiple lexicon-based and machine learning-based algorithms integrated with IFoodCloud that provide an unprecedented rapid means of understanding the public sentiment toward specific food safety incidents. Our best model's F1 score achieved 0.9737, demonstrating its great predictive ability and robustness. Using IFoodCloud, we analyzed public sentiment on food safety in Greater China and the changing trend of public opinion at the early stage of the 2019 Coronavirus Disease pandemic, demonstrating the potential of big data and machine learning for promoting risk communication and decision-making.

Correlation between ERα gene polymorphism and multiple sclerosis and neuromyelitis optica.

OBJECTIVE: To study the polymorphism distribution of estrogen receptor (ER) α gene and the correlation between different types of polymorphism in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. METHODS: Forty-six cases of MS and NMO diagnosed from June 2018 to December 2019 were collected. Peripheral venous blood samples were collected. The patient's gender, age of onset, course of disease, and other clinical data were recorded. Fifty-eight healthy volunteers of the same age and sex were selected. By means of Pvu II and Xba I restriction fragment length polymorphism enzyme recognition sites of ER α gene, polymerase chain reaction-restriction fragment length polymorphism analysis was conducted. RESULTS: There was no significant difference in the frequency distribution of ER α gene's PP, Pp, and pp genotype between MS and NMO case group and control group (P = .598). Frequency distribution of ER α gene's XX, Xx, and xx was statistically significant between MS and NMO case group and control group (P = .021). Among them, distribution of Xx and Xx gene frequency between patient group and the control group was statistically significant (P = .001, OR = 4.622, 95% CI: 1.803-11.852). There was no significant correlation between ER α genotypes and the onset age in patient group (P > .05). The difference was statistically significant in disease duration of XX and Xx genotype (P = .006). The comparison of Xx and xx genotype frequency distribution in gender exists a difference(P = .047, OR = 7.500, 95% CI: 1.023-54.996). CONCLUSIONS: Xba I gene polymorphisms in the ER α gene have correlation with MS and NMO. Xba I gene could be a risk factor of MS and NMO pathogenesis, especially the women with Xx genotype are more vulnerable. Xba I gene polymorphisms in the ER α gene may impact the disease duration of MS and NMO, or rather, the disease duration of Xx genotype persists longer than Xx genotype. Pvu II gene polymorphisms in the ER α gene has no correlation with MS and NMO.

Delayed Diagnosis of Wilson's Disease Report From 179 Newly Diagnosed Cases in China.

Objective: To analyze the initial symptom and the cause of the misdiagnosis of Wilson's Disease (WD) so as to enhance awareness of this condition and reduce diagnostic errors. Methods: The clinical data of 179 patients with the confirmed diagnosis of WD who were hospitalized in the First Affiliated Hospital of Guangdong Pharmaceutical University from October 2014 to September 2021 were analyzed. Those patients who had attended two or more hospitals, had been misdiagnosed as other diseases, or failed to get a clear diagnosis for 3 months and over before hospitalization were included in the group of clinical misdiagnosis or the group without a definite diagnosis. Results: One hundred twenty-nine cases (72.1%) were misdiagnosed, 39 cases (21.8%) failed to be diagnosed as a specific disease, and only 11 cases (6.2%) had been diagnosed as WD within 3 months at the early stage of the disease. WD was easily masqueraded as a variety of diseases, including all types of hepatitis, cirrhosis, splenomegaly, hepatomegaly, encephalitis, encephalopathy, peripheral neuropathy, psychosis, osteoarthrosis, nephrosis, anemia, and other illnesses. Conclusion: Wilson's Disease is prone to long-term misdiagnosis or unclear diagnosis. Early diagnosis and treatment are the most important determinations of the prognosis. Therefore, when facing patients with doubtful WD, it is valued to perform Kayser-Fleischer ring, copper metabolism, imaging examination, genetic tests, and radioactive copper test if necessary.

circRNA-binding protein site prediction based on multi-view deep learning, subspace learning and multi-view classifier.

Circular RNAs (circRNAs) generally bind to RNA-binding proteins (RBPs) to play an important role in the regulation of autoimmune diseases. Thus, it is crucial to study the binding sites of RBPs on circRNAs. Although many methods, including traditional machine learning and deep learning, have been developed to predict the interactions between RNAs and RBPs, and most of them are focused on linear RNAs. At present, few studies have been done on the binding relationships between circRNAs and RBPs. Thus, in-depth research is urgently needed. In the existing circRNA-RBP binding site prediction methods, circRNA sequences are the main research subjects, but the relevant characteristics of circRNAs have not been fully exploited, such as the structure and composition information of circRNA sequences. Some methods have extracted different views to construct recognition models, but how to efficiently use the multi-view data to construct recognition models is still not well studied. Considering the above problems, this paper proposes a multi-view classification method called DMSK based on multi-view deep learning, subspace learning and multi-view classifier for the identification of circRNA-RBP interaction sites. In the DMSK method, first, we converted circRNA sequences into pseudo-amino acid sequences and pseudo-dipeptide components for extracting high-dimensional sequence features and component features of circRNAs, respectively. Then, the structure prediction method RNAfold was used to predict the secondary structure of the RNA sequences, and the sequence embedding model was used to extract the context-dependent features. Next, we fed the above four views' raw features to a hybrid network, which is composed of a convolutional neural network and a long short-term memory network, to obtain the deep features of circRNAs. Furthermore, we used view-weighted generalized canonical correlation analysis to extract four views' common features by subspace learning. Finally, the learned subspace common features and multi-view deep features were fed to train the downstream multi-view TSK fuzzy system to construct a fuzzy rule and fuzzy inference-based multi-view classifier. The trained classifier was used to predict the specific positions of the RBP binding sites on the circRNAs. The experiments show that the prediction performance of the proposed method DMSK has been improved compared with the existing methods. The code and dataset of this study are available at https://github.com/Rebecca3150/DMSK.

An Epidemiological Retrospective and Predictive Analysis of Rubella in Beijing, Haidian District of China.

BACKGROUND: This study is aimed to investigate the epidemiological characteristics of rubella in Beijing, Haidian District of China, from 2005 to 2020, providing scientific basis for controlling rubella and the congenital rubella syndrome. METHODS: Data were collected via the legal infectious disease report cards from medical institutions in Haidian, 2005-2020. The descriptive epidemiological methods plus statistical analysis were used to analyze the distribution of rubella in terms of population, time and region. RESULTS: In total, there were 994 cases of rubella in Beijing, Haidian District, with an average incidence of 1.81/100 000. In 2007, it was hit by rubella with the highest incidence up to 8.37/100 000, in the past 16 years. The peak incident of rubella was in spring (March to May). The majority of rubella patients were students and employees (70.1%) who are infected mainly due to the gathering. The majority of patients aged 15-29 years (63.4%). And the male-to-female ratio was 1.45 : 1. Rubella had a feature of spatial aggregation and appeared in all the regions in Haidian. According to Joinpoint regression model, rubella would still exist in the next 3 years with 2-5 new cases per year. CONCLUSIONS: Rubella showed a downshift trend from 2008 to 2014, then a sporadic distribution till 2020 in Haidian. Not completely eliminated yet, it is quite impending to improve people's awareness of preventing rubella and their health literacy mentally and physically in the whole population by means of the policy issuing from government.

Tuberculosis infection and epidemiological characteristics in Haidian District, Beijing, 2005-2018.

BACKGROUND: This study was aimed to investigate the epidemiological characteristic of pulmonary tuberculosis (PTB) in Haidian District, Beijing from 2005 to 2018 and to provide suggestions for controlling tuberculosis (TB) development. METHODS: Epidemiological data about TB were obtained by the Infectious Disease Reporting System at different levels of medical institutions in Haidian District of Beijing from 2005 to 2018. The epidemiological methods combined with χ2 test were used to analyze the distribution of TB in population, time, region and TB diagnosis. RESULTS: In total, 14,449 cases of TB patients were reported in Haidian District from 2005 to 2018 and the average annual morbidity was 31.67/10,000. Of the total cases, housework and unemployed people (20.73%; 2996/14,449) accounted for the highest proportion of occupational distribution, followed by students, accounting for 17.18% (2482/14,449). 2433 patients with the age of 65 years and over accounting for 16.83% (2433/14,449); Laboratory confirmed diagnosis of TB was 26.60% and the diagnostic delays accounted for 54.96%. CONCLUSIONS: From 2005 to 2018, TB incidence was falling gradually in Haidian District. However, particular attention should be paid to the elderly and student groups, and the policy publicity and education should be strengthened to reduce the diagnosis delay of TB.

Flavor quality evaluation system of Xinjiang milk knots by using SOM neural network and the fuzzy AHP.

Self-made milk knots in Xinjiang Kazakh ethnic group were used as material to establish the quality assessment system of flavor quality. The fuzzy analytic hierarchy process based on the optimal consistency matrix was used to evaluate the quality of the samples qualitatively and quantitatively. Its result is consistent with the cluster analysis of the SOM neural network. The results showed that the milk knot samples of Altay had differences with the milk knot samples of Yili. The comprehensive evaluation system is feasible and can evaluate the quality of milk knot samples by flavor characteristics. This can provide a reference for further research on the origin of differences between two types of milk knot samples.

Dural Arteriovenous Fistula Complicated with Cerebral Venous Sinus Thrombosis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is always confused with dural arteriovenous fistula (DAVF) in clinical practice; however, both of them are very rare cerebral vascular diseases. In this report, we provide one case of DAVF combined with CVST. CASE DESCRIPTION: A 75-year-old woman complained of headache with nausea and vomiting for 4 days. Magnetic resonance venography revealed filling defect in the torcular, left transverse, and sigmoid sinus, which strongly suggested sinus thrombosis. The patient underwent anticoagulation treatment for 9 days. However, the manifestation was not alleviated, magnetic resonance imaging detected the lesion was enlarged, and the midline shifted to the left. Digital subtraction angiography examination detected that one fistula classified as Borden type IA was fed by the left superficial temporal artery and drained into the left transverse and sigmoid sinus. Endovascular embolization with ethylene vinyl alcohol was conducted. CONCLUSIONS: Follow-up at 6 months indicated that the patient recovered without any sequelae.

Rapid antidepressant actions of imipramine potentiated by zinc through PKA-dependented regulation of mTOR and CREB signaling.

The slow onset of traditional antidepressants has become an urgent clinical issue, researchers are constantly exploring new antidepressants with prompt action. Previous studies have found that zinc levels were decreased in serum and brain of depressed patients or animal models. Zinc treatment can improve depressive symptoms and enhance the antidepressant effects of monoamine antidepressants. However, its mechanism of action is still unclear. This present study aims to investigate whether the zinc can enhance the rapid action of traditional antidepressant imipramine and to explore the potential mechanisms of action through the rapid antidepressant targets CREB (cAMP-response element binding protein) and mTOR (mammalian target of the rapamycin). Drug treatment included intraperitoneal injection of imipramine or zinc alone and imipramine plus zinc. Zinc had a rapid enhanced antidepressive effect on the imipramine and achieved a rapid antidepressant effect similar to ketamine. Combination of zinc with imipramine rapidly enhanced the phosphorylation of mTOR Ser2448 and CREB Ser133, and increased the expression of mTOR and CREB, which were dependent on the activation of PKA. In conclusion, combination therapy with zinc and monoamine antidepressants may overcome the problem of slow-onset action of traditional antidepressants in clinical uses.

Overexpression of PRR11 promotes tumorigenic capability and is associated with progression in esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies of gastrointestinal tract in the world, and the long-term prognosis for ESCC patients still remains dismal due to the lack of effective early diagnosis biomarkers. MATERIALS AND METHODS: Western blot and immunochemistry were used to determine the expression of PRR11 in 201 clinicopathologically characterized ESCC specimens. The effects of PRR11 on stem cell-like traits and tumorigenicity were examined by tumor sphere formation assay and SP assays in vitro and by a tumorigenesis model in vivo. The mechanism by which PRR11 mediated Wnt/ß-catenin signaling was explored using luciferase reporter, immuno-chemistry, and real time-PCR (RT-PCR) assays. RESULTS: We found that PRR11 was markedly upregulated, at the level of both transcription and translation, in ESCC cell lines as compared with normal esophageal epithelial cells (NECCs). Immunohistochemical analysis showed that 69.2% paraffin-embedded archival ESCC specimens exhibited high levels of PRR11 expression, and multivariate analysis revealed that PRR11 upregulation might be an independent prognostic indicator for the survival of patients with ESCC. Furthermore, overexpression of PRR11 dramatically enhanced, whereas inhibition of PRR11 reduced the capability of cancer stem cell (CSC)-like phenotypes and tumorigenicity of ESCC cells both in vitro and in vivo. Mechanically, we demonstrated PRR11-enhanced tumorigenicity of ESCC cells via activating Wnt/ß-catenin signaling, and PRR11 expression is found to be significantly correlated with ß-catenin nuclear location in ESCC. CONCLUSION: Our findings suggest that the PRR11 might represent a novel and valuable prognostic marker for ESCC progression and play a role during the development and progression of this malignancy.

TRIM31 promotes glioma proliferation and invasion through activating NF-κB pathway.

BACKGROUND: Glioma is the most lethal primary brain tumor, the survival rate still isn't improved in the past decades. It's essential to study the regulatory mechanism of glioma progression, hoping to find new therapy targets or methods. The family of tripartite motif (TRIM) containing proteins are E3 ubiquitination ligases, which play critical role in various tumor progression. METHODS: Cell proliferation and invasion were analyzed by colony formation assay, soft agar growth assay, BrdU incorporation assay and transwell invasion assay. Luciferase reporter analysis was used to analyze NF-κB pathway activity. RESULTS: We found TRIM31 was upregulated in glioma cells and tissues, its overexpression significantly promoted glioma cell proliferation and invasion, while its knockdown significantly inhibited glioma cell proliferation and invasion. Mechanism analysis found TRIM31 promoted NF-κB pathway activity and increased its targets expression. NF-κB inhibition reversed the phenotype caused by TRIM31, confirming TRIM31 promoted glioma progression through activating NF-κB pathway. Using clinical specimens found TRIM31 expression was positively correlative with NF-κB activity. CONCLUSION: This study found TRIM31 promoted glioma proliferation and invasion through activating NF-κB activity.

Protein kinase A mediates scopolamine-induced mTOR activation and an antidepressant response.

BACKGROUND: Clinical reports have shown that scopolamine produces a rapid (3-4 d) and potent anti-depressive response without severe adverse effects. Animal experiments have proven that scopolamine induces mTOR pathway activation in an AMPAR dependent manner. The present study aimed to determine the role of PKA in scopolamine-induced potentiation of AMPAR, as well as in mTOR pathway activation and rapid antidepressant effects. METHODS: We utilized electrophysiological recording, Western blotting, and behavior tests to examine the effects of scopolamine, the selective M2 cholinergic receptor antagonist methoctramine, and H89, a PKA specific inhibitor on AMPAR potentiation, mTOR pathway activation, and behavioral responses in a rat depression model of learned helplessness. RESULTS: Scopolamine (1µM) rapidly increased AMPAR-fEPSP amplitudes and membrane GluA1 expression in CA1 region of hippocampal slices, both of which were abolished by H89. Moreover, scopolamine promoted AMPAR phosphorylation on GluA1 ser845, a PKA site involved in GluA1 membrane insertion. H89 disrupted both GluA1 ser845 phosphorylation and mTOR activation, as well as the antidepressant effects of scopolamine as determined via forced swim test. Additionally, methoctramine mimicked the effects of scopolamine on phosphorylation and counter-depressive action in a PKA-dependent manner. LIMITATIONS: Only one test was used to evaluate depressive behavior, and gene knock-out rats were not yet utilized to refine our hypotheses. CONCLUSION: Our findings revealed that PKA pathway is necessary for scopolamine-induced synaptic plasticity and mTOR pathway activation, and indicated that a potential M2-PKA mechanism underlies scopolamine's antidepressant effects. Such findings suggest that GluA1 ser845 phosphorylation may be a trigger event for scopolamine's actions, and that PKA may represent a novel target for the treatment of depressive symptoms.

Differential Mechanisms Underlying Antidepressant Responses of Ketamine and Imipramine.

BACKGROUND & OBJECTIVE: Ketamine, a noncompetitive NMDA receptor antagonist, exhibits rapid antidepressant actions, but the underlying mechanism remains obscure. AMPA receptor and cAMP response element-binding protein (CREB) are involved in the antidepressant actions of Ketamine and imipramine, a traditional tricyclic antidepressant. However, ketamine exerts its therapeutic actions much faster than imipramine. Understanding the discrepancy of antidepressant efficiency between ketamine and the traditional antidepressant is important for elucidating the mechanism underlying ketamine's fast-acting antidepressant responses as well as designing new rapid antidepressants. RESULTS: Here we show that the enhancement of the phosphorylation of CREB Ser133 and expression of CREB and glutamate receptor 1 (GluR1) are necessary for both ketamine's and imipramine's antidepressant actions, but the enhancements at early stage may account for the faster onset of ketamine's antidepressant action than imipramine. Notably, ketamine but not imipramine enhances CREBregulated transcription coactivator-1 (CRTC1) expression and induces potentiation of excitatory synaptic transmission at Schaffer collateral CA1 synapses, which indicates critical targets for unveiling ketamine's rapid antidepressant actions. CONCLUSION: Our study suggests that differential regulation of CRTC1 expression may contribute to the discrepancy of antidepressant efficacy between ketamine and imipramine, which may lead to a better understanding of ketamine's fast antidepressant responses.

Differential regulation of GluA1 expression by ketamine and memantine.

Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine's psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses.

Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine.

Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant action that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. We showed that ketamine potentiated Schaffer collateral-CA1 cell excitatory synaptic transmission in hippocampal slice preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser845 of the AMPA-type glutamate receptor in the hippocampal area CA1. These effects persisted when γ-aminobutyric acid (GABA) receptors were pharmacologically blocked. Ketamine reduced behavioral despair in wild-type mice but had no effect in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramidal cell), deletion of N-methyl-d-aspartate (NMDA)-type glutamate receptors eliminated the ketamine-induced enhancement of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamine in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). Our results implicate presynaptic NMDA receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increase in glutamate release and postsynaptic glutamate receptor activity, as a mechanism of ketamine action. These data provide a mechanism for changes in synaptic activity that could explain the fast-acting antidepressant effects of this drug.

Sex Differences in Long-Term Potentiation at Temporoammonic-CA1 Synapses: Potential Implications for Memory Consolidation.

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory.

The essential role of hippocampal alpha6 subunit-containing GABAA receptors in maternal separation stress-induced adolescent depressive behaviors.

Exposure to early stressful adverse life events such as maternal separation severely impacts the development of the nervous system. Using immunohistochemistry, quantitative PCR and Western blot approaches, we found that alpha6 subunit-containing GABAA receptors (Gabra6-containing GABAA Rs) were expressed on hippocampal interneurons of adolescent rats. Maternal separation stress (MS) from postnatal day 2 to15 significantly reduced Gabra6 expression and provoked depressive behaviors such as anhedonia. Furosemide, the selective antagonist of Gabra6-containing GABAARs, strongly increased peak amplitude of evoked IPSCs at CA3-CA1 synapses and the frequency of miniature IPSPs recorded from CA1 pyramidal cells in naive control animals, and this effect was occluded in MS animals. Knockdown of Gabra6 expression in hippocampus mimicked furosemide's effect and was sufficient to produce similar depressive symptoms that were observed in MS animals. These results indicate that the Gabra6-containing GABAA R is a key modulator of hippocampal synaptic transmission and likely plays a crucial role in the pathophysiology of maternal separation-induced depression.

Icariin exerts estrogen-like activity in ameliorating EAE via mediating estrogen receptor ß, modulating HPA function and glucocorticoid receptor expression.

BACKGROUND: Estrogen exerts neuroprotective and anti-inflammatory effects in EAE and multiple sclerosis (MS), but its clinical application is hindered due to side effects and risk of tumor. Phytoestrogen structurally or functionally mimics estrogen with fewer side effects than endogenous estrogen. Icariin (ICA), an active component of Epimedium extracts, demonstrates estrogen-like neuroprotective effects. However, it is unclear whether ICA is effective in EAE and what are the underlying mechanisms. OBJECTIVE: To determine the therapeutic effects of ICA in EAE and explore the possible mechanisms. METHODS: C57BL/6 EAE mice were treated with Diethylstilbestrol, different dose of ICA and mid-dose ICA combined with ICI 182780. The clinical scores and serum Interleukin-17 (IL-17), Corticosterone (CORT) concentrations were then analyzed. Western blot were performed to investigate the expressions of glucocorticoid receptor (GR), estrogen receptor alpha (ERα) and ERß in the cerebral white matter of EAE mice. RESULTS: High dose ICA is equally effective in ameliorating neurological signs of EAE as estrogen. Estrogen and ICA has no effects on serum concentrations of IL-17 in EAE. While the CORT levels were decreased by ICA at mid or high doses, the expressions of GR, ERα and ERß were up-regulated by estrogen or different doses of ICA in a dosedependent manner. Estrogen induced the elevation of ERα more markedly than ICA. In contrast, ICA at mid and high doses promoted ERß more significantly than estrogen. CONCLUSION: ICA exerts estrogen-like activity in ameliorating EAE via mediating ERß, modulating HPA function and up-regulating the expression of GR in cerebral white matter. ICA may be a promising therapeutic option for MS.