Association between serum potassium and Parkinson's disease in the US (NHANES 2005-2020).

Background: Evaluating the correlation between serum potassium and Parkinson's disease (PD) in US adults. Methods: A cross-sectional study was conducted on 20,495 adults aged 40 years or older using NHANES data from 2005 to 2020. The study utilized one-way logistic regression and multifactorial logistic regression to examine the correlation between serum potassium levels and PD. Additionally, a smoothed curve fitting approach was employed to assess the concentration-response relationship between serum potassium and PD. Stratified analyses were carried out to investigate potential interactions between serum potassium levels and PD with variables such as age, sex, race, marital status, education, BMI, smoking and medical conditions like coronary, stroke, diabetes, hypertension, and hypercholesterolemia. Results: In this study, a total of 20,495 participants, comprising 403 PD and 20,092 non-PD individuals, were included. After adjusted for covariates, multivariable logistic regression revealed that high serum potassium level was an independent risk factor for PD (OR:1.86, 95% CI:1.45 ~ 2.39, p < 0.01).The linear association between serum potassium and PD was described using fitted smoothing curves. Age, sex, race, education, marital, BMI, coronary, stroke, diabetes, hypertension and hypercholesterolemia were not significantly correlated with this positive connection, according to subgroup analysis and interaction testing (P for interaction >0.05). Conclusion: Serum potassium levels are elevated in patients with Parkinson's disease compared to non-PD patients. Additional prospective studies are required to explore the significance of serum potassium levels in individuals with Parkinson's disease.

Dose-Incorporated Deep Ensemble Learning for Improving Brain Metastasis Stereotactic Radiosurgery Outcome Prediction.

PURPOSE: To develop a novel deep ensemble learning model for accurate prediction of brain metastasis (BM) local control outcomes after stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A total of 114 brain metastases (BMs) from 82 patients were evaluated, including 26 BMs that developed biopsy-confirmed local failure post-SRS. The SRS spatial dose distribution (Dmap) of each BM was registered to the planning contrast-enhanced T1 (T1-CE) magnetic resonance imaging (MRI). Axial slices of the Dmap, T1-CE, and planning target volume (PTV) segmentation (PTVseg) intersecting the BM center were extracted within a fixed field of view determined by the 60% isodose volume in Dmap. A spherical projection was implemented to transform planar image content onto a spherical surface using multiple projection centers, and the resultant T1-CE/Dmap/PTVseg projections were stacked as a 3-channel variable. Four Visual Geometry Group (VGG-19) deep encoders were used in an ensemble design, with each submodel using a different spherical projection formula as input for BM outcome prediction. In each submodel, clinical features after positional encoding were fused with VGG-19 deep features to generate logit results. The ensemble's outcome was synthesized from the 4 submodel results via logistic regression. In total, 10 model versions with random validation sample assignments were trained to study model robustness. Performance was compared with (1) a single VGG-19 encoder, (2) an ensemble with a T1-CE MRI as the sole image input after projections, and (3) an ensemble with the same image input design without clinical feature inclusion. RESULTS: The ensemble model achieved an excellent area under the receiver operating characteristic curve (AUCROC: 0.89 ± 0.02) with high sensitivity (0.82 ± 0.05), specificity (0.84 ± 0.11), and accuracy (0.84 ± 0.08) results. This outperformed the MRI-only VGG-19 encoder (sensitivity: 0.35 ± 0.01, AUCROC: 0.64 ± 0.08), the MRI-only deep ensemble (sensitivity: 0.60 ± 0.09, AUCROC: 0.68 ± 0.06), and the 3-channel ensemble without clinical feature fusion (sensitivity: 0.78 ± 0.08, AUCROC: 0.84 ± 0.03). CONCLUSIONS: Facilitated by the spherical image projection method, a deep ensemble model incorporating Dmap and clinical variables demonstrated excellent performance in predicting BM post-SRS local failure. Our novel approach could improve other radiation therapy outcome models and warrants further evaluation.

Cationic mesoporous silica nanoparticles alleviate osteoarthritis by targeting multiple inflammatory mediators.

Osteoarthritis (OA) is a common and complex inflammatory disorder that is frequently compounded by cartilage degradation, synovial inflammation, and osteophyte formation. Damaged chondrocytes release multiple danger mediators that exacerbate synovial inflammation and accelerate the progression to OA. Conventional treatments targeting only a single mediator of OA have failed to achieve a strong therapeutic effect. Addressing the crucial role of multiple danger mediators in OA progression, we prepared polyethylenimine (PEI)-functionalized diselenide-bridged mesoporous silica nanoparticles (MSN-PEI) with cell-free DNA (cfDNA)-binding and anti-oxidative properties. In models of surgery-induced and collagenase-induced arthritis, we showed that these cationic nanoparticles attenuated cartilage degradation and provided strong chondroprotection against joint damage. Mechanistically, multiple target blockades alleviated oxidative stress and dampened cfDNA-induced inflammation by suppressing the M1 polarization of macrophages. This study suggests a beneficial direction for targeting multiple danger mediators in the treatment of intractable arthritis.

A radiomics-incorporated deep ensemble learning model for multi-parametric MRI-based glioma segmentation.

Objective.To develop a deep ensemble learning (DEL) model with radiomics spatial encoding execution for improved glioma segmentation accuracy using multi-parametric magnetic resonance imaging (mp-MRI).Approach.This model was developed using 369 glioma patients with a four-modality mp-MRI protocol: T1, contrast-enhanced T1 (T1-Ce), T2, and FLAIR. In each modality volume, a 3D sliding kernel was implemented across the brain to capture image heterogeneity: 56 radiomic features were extracted within the kernel, resulting in a fourth-order tensor. Each radiomic feature can then be encoded as a 3D image volume, namely a radiomic feature map (RFM). For each patient, all RFMs extracted from all four modalities were processed using principal component analysis for dimension reduction, and the first four principal components (PCs) were selected. Next, a DEL model comprised of four U-Net sub-models was trained for the segmentation of a region-of-interest: each sub-model utilizes the mp-MRI and one of the four PCs as a five-channel input for 2D execution. Last, four softmax probability results given by the DEL model were superimposed and binarized using Otsu's method as the segmentation results. Three DEL models were trained to segment the enhancing tumor (ET), tumor core (TC), and whole tumor (WT), respectively. The segmentation results given by the proposed ensemble were compared to the mp-MRI-only U-Net results.Main Results.All three radiomics-incorporated DEL models were successfully implemented: compared to the mp-MRI-only U-net results, the dice coefficients of ET (0.777 → 0.817), TC (0.742 → 0.757), and WT (0.823 → 0.854) demonstrated improvement. The accuracy, sensitivity, and specificity results demonstrated similar patterns.Significance.The adopted radiomics spatial encoding execution enriches the image heterogeneity information that leads to the successful demonstration of the proposed DEL model, which offers a new tool for mp-MRI-based medical image segmentation.

Predicting busulfan exposure in patients undergoing hematopoietic stem cell transplantation using machine learning techniques.

PURPOSE: This study aimed to establish an optimal model to predict the busulfan (BU) area under the curve at steady state (AUCss) by using machine learning (ML). PATIENTS AND METHODS: Seventy-nine adult patients (age ≥18 years) who received BU intravenously and underwent therapeutic drug monitoring from 2013 to 2021 at Fujian Medical University Union Hospital were enrolled in this retrospective study. The whole dataset was divided into a training group and test group at the ratio of 8:2. BU AUCss were considered as the target variable. Nine different ML algorithms and one population pharmacokinetic (pop PK) model were developed and validated, and their predictive performance was compared. RESULTS: All ML models were superior to the pop PK model (R2 = 0.751, MSE = 0.722, 14 and RMSE = 0.830) in model fitting and had better predictive accuracy. The ML model of BU AUCss established through support vector regression (SVR) and gradient boosted regression trees (GBRT) had the best predictive ability (R2 = 0.953 and 0.953, MSE = 0.323 and 0.326, and RMSE = 0.423 and 0.425). CONCLUSION: All the ML models can potentially be used to estimate BU AUCss with the aim of facilitating rational use of BU on the individualized level, especially models built by SVR and GBRT algorithms.

Depletion of gut microbiota resistance in 5×FAD mice enhances the therapeutic effect of mesenchymal stem cell-derived exosomes.

Mesenchymal stem cell-derived exosomes (MSCs-exo) can be used for treating Alzheimer's disease (AD) by promoting amyloid-ß (Aß) degradation, modulating immune responses, protecting neurology, promoting axonal growth, and improving cognitive impairment. Increasing evidence suggests that the alteration of gut microbiota is closely related to the occurrence and development of Alzheimer's disease. In this study, we hypothesized that dysbiosis of gut microbiota might limit the therapy of MSCs-exo, and the application of antibiotics would improve the therapy. METHODS: In this original research study, we used MSCs-exo to treat 5 ×FAD mice and fed them antibiotic cocktails for 1 week to detect cognitive ability and neuropathy. The mice's feces were collected to investigate alterations in the microbiota and metabolites. RESULTS: The results revealed that the AD gut microbiota eliminated the therapeutic effect of MSCs-exo, whereas antibiotic modulation of disordered gut microbiota and associated metabolites enhanced the therapeutic effect of MSCs-exo. CONCLUSIONS: These results encourage the research of novel therapeutics to enhance MSCs-exo treatment for AD, which could benefit a broader range of patients with AD.

Synergistic treatment of osteosarcoma with biomimetic nanoparticles transporting doxorubicin and siRNA.

Introduction: Osteosarcoma tumors are the most common malignant bone tumors in children and adolescents. Their treatment usually requires surgical removal of all detectable cancerous tissue and multidrug chemotherapy; however, the prognosis for patients with unresectable or recurrent osteosarcoma is unfavorable. To make chemotherapy safer and more effective for osteosarcoma patients, biomimetic nanoparticles (NPs) camouflaged by mesenchymal stem cell membranes (MSCMs) were synthesized to induce osteosarcoma cell apoptosis by co-delivering the anticancer drug doxorubicin hydrochloride(DOX) and a small interfering RNA (siRNA). Importantly, these NPs have high biocompatibility and tumor-homing ability. This study aimed to improve the efficacy of osteosarcoma therapy by using the synergistic combination of DOX and an siRNA targeting the apoptosis suppressor gene survivin. Methods: Biomimetic NPs (DOX/siSUR-PLGA@MSCM NPs) were synthesized by coloading DOX and survivin siRNA (siSUR) into poly (lactide-co-glycolide acid) (PLGA) via a double-emulsion solvent evaporation method. The NPs were camouflaged by MSCMs to deliver both DOX and survivin-targeting siRNA and characterized and evaluated in terms of cellular uptake, in vitro release, in vitro and in vivo antitumor effects, and biosafety. Results: DOX/siSUR-PLGA@MSCM NPs had good tumor-homing ability due to the MSCMs modification. The drug-laden biomimetic NPs had good antitumor effects in homozygous MG63 tumor-bearing mice due to the synergistic effect of the drug combination. Conclusion: DOX/siSUR-PLGA@MSCM NPs can show improved therapeutic effects in osteosarcoma patients due to the combination of a chemotherapeutic drug and gene therapy based on their good tumor targeting and biosafety.

Antibodies to sclerostin or G-CSF receptor partially eliminate bone or marrow adipocyte loss, respectively, following vertical sleeve gastrectomy.

Vertical sleeve gastrectomy (VSG), the most utilized bariatric procedure in clinical practice, greatly reduces body weight and improves a variety of metabolic disorders. However, one of its long-term complications is bone loss and increased risk of fracture. Elevated circulating sclerostin (SOST) and granulocyte-colony stimulating factor (G-CSF) concentrations have been considered as potential contributors to VSG-associated bone loss. To test these possibilities, we administrated antibodies to SOST or G-CSF receptor and investigated alterations to bone and marrow niche following VSG. Neutralizing either SOST or G-CSF receptor did not alter beneficial effects of VSG on adiposity and hepatic steatosis, and anti-SOST treatment provided a further improvement to glucose tolerance. SOST antibodies partially reduced trabecular and cortical bone loss following VSG by increasing bone formation, whereas G-CSF receptor antibodies had no effects on bone mass. The expansion in myeloid cellularity and reductions in bone marrow adiposity seen with VSG were partially eliminated by treatment with Anti-G-CSF receptor. Taken together, these experiments demonstrate that antibodies to SOST or G-CSF receptor may act through independent mechanisms to partially block effects of VSG on bone loss or marrow niche cells, respectively.

Integrin-mediated cancer progression as a specific target in clinical therapy.

Integrins, a group of heterodimer receptors for cell-matrix and cell-cell adhesion, mediate various intracellular activities, including cell migration, polarity, survival, growth, and death. Multiple types of integrins are differentially expressed in various cancers during different stages of progression, which are involved in the regulation of cancer cell proliferation, invasion, migration, and angiogenesis. The crucial roles of integrins in tumor progression provide valuable clues for cancer diagnosis and targeted therapy. Numerous integrin inhibitors have been investigated in clinical trials to explore effective regimens and minimize side effects. Given the complexity of the integrin-mediated tumor-promoting effect, challenges and difficulties remain in the research and development of integrin inhibitors, which seriously restrict the efficacy and application of integrin-targeted therapy. Novel targeted therapy of integrins, however, is beneficial for patients as a potential avenue forward, which needs better pharmacological effect, valid experimental models, and in-depth understanding of integrins. This review provides the insight needed to elucidate the mechanisms underlying cancer progression and novel protocols for the clinical treatment of cancer.

Discovery of Raf Family Is a Milestone in Deciphering the Ras-Mediated Intracellular Signaling Pathway.

The Ras-Raf-MEK-ERK signaling pathway, the first well-established MAPK pathway, plays essential roles in cell proliferation, survival, differentiation and development. It is activated in over 40% of human cancers owing to mutations of Ras, membrane receptor tyrosine kinases and other oncogenes. The Raf family consists of three isoforms, A-Raf, B-Raf and C-Raf. Since the first discovery of a truncated mutant of C-Raf as a transforming oncogene carried by a murine retrovirus, forty years of extensive studies have provided a wealth of information on the mechanisms underlying the activation, regulation and biological functions of the Raf family. However, the mechanisms by which activation of A-Raf and C-Raf is accomplished are still not completely understood. In contrast, B-Raf can be easily activated by binding of Ras-GTP, followed by cis-autophosphorylation of the activation loop, which accounts for the fact that this isoform is frequently mutated in many cancers, especially melanoma. The identification of oncogenic B-Raf mutations has led to accelerated drug development that targets Raf signaling in cancer. However, the effort has not proved as effective as anticipated, inasmuch as the mechanism of Raf activation involves multiple steps, factors and phosphorylation of different sites, as well as complex interactions between Raf isoforms. In this review, we will focus on the physiological complexity of the regulation of Raf kinases and their connection to the ERK phosphorylation cascade and then discuss the role of Raf in tumorigenesis and the clinical application of Raf inhibitors in the treatment of cancer.

(20R)-Panaxadiol as a Natural Active Component with Anti-Obesity Effects on ob/ob Mice via Modulating the Gut Microbiota.

Obesity is an important cause of diseases such as type 2 diabetes, non-alcoholic fatty liver and atherosclerosis. The use of ingredients extracted from traditional Chinese medicine for weight loss is now receiving more and more attention. Ginseng has been recorded since ancient times for the treatment of diabetes. The (20R)-Panaxadiol (PD) belongs to the ginseng diol type compounds, which are moderately bioavailable and may remain in the intestinal tract for a longer period of time. This study investigated the potential positive effect of PD in ob/ob mice and evaluated its effect against obesity. The ob/ob mice were administered PD for ten weeks. Our study showed that PD could improve obesity, glucose tolerance disorder, as well as gut dysbiosis. Panaxadiol decreased ob/ob mice's Firmicutes/Bacteroidetes (F/B). Furthermore, 16S rRNA gene sequencing of the fecal microbiota suggested that PD changed the composition of the gut microbiota in ob/ob mice and modulated specific bacteria such as lactobacillus, prevotellace and so on. Moreover, PD improved the intestinal wall integrity. In conclusion, our results suggest that (20R)-Panaxadiol, as an active ingredient of the traditional Chinese medicinal herb ginseng, may improve obesity to some extent via improving gut microbiota.

Analysis of Serum Metabolomics in Rats with Osteoarthritis by Mass Spectrometry.

Osteoarthritis is a common multifactorial chronic disease that occurs in articular cartilage, subchondral bone, and periarticular tissue. The pathogenesis of OA is still unclear. To investigate the differences in serum metabolites between OA and the control group, liquid chromatography/mass spectrometry (LC/MS)-based metabolomics was used. To reveal the pathogenesis of OA, 12 SD male rats were randomly divided into control and OA groups using collagenase to induce OA for modeling, and serum was collected 7 days after modeling for testing. The OA group was distinguished from the control group by principal component analysis and orthogonal partial least squares-discriminant analysis, and six biomarkers were finally identified. These biomarkers were metabolized through tryptophan metabolism, glutamate metabolism, nitrogen metabolism, spermidine metabolism, and fatty acid metabolism pathways. The study identified metabolites that may be altered in OA, suggesting a role in OA through relevant metabolic pathways. Metabolomics, as an important tool for studying disease mechanisms, provides useful information for studying the metabolic mechanisms of OA.

Berberine inhibits chemotherapy-exacerbated ovarian cancer stem cell-like characteristics and metastasis through GLI1.

Despite the remarkable clinical response in ovarian cancer therapy, the distinctively high metastasis rate is still a barrier to achieve satisfying prognosis. Our study aimed to decipher the role of berberine in inhibiting chemotherapy-exacerbated ovarian cancer metastasis. We found that chemotherapy exacerbated the migration and cancer stem cell (CSC)-like characteristics through transcriptional factor GLI1, which regulated the pluripotency-associated gene BMI1 and the epithelial-mesenchymal transition (EMT) markers Vimentin and Snail. Berberine could not only down-regulate CSC-like characteristics but also reverse EMT and migration through inhibiting chemotherapy-activated GLI1/BMI1 signaling pathway. Together, our study revealed the pivotal role of berberine in overcoming chemotherapy-exacerbated ovarian cancer metastasis, thereby provided a potential adjuvant therapeutic agent in combination with chemotherapeutics to prevent metastasis during ovarian cancer chemotherapy.

Roflumilast prevents lymphotoxin α (TNF-ß)-induced inflammation activation and degradation of type 2 collagen in chondrocytes.

BACKGROUND AND PURPOSE: Osteoarthritis (OA) is a chronic disease accompanied by severe inflammation. The inflammation activation in the chondrocytes and the degradation of the extracellular matrix were reported to be involved in the progress of OA. Roflumilast is a selective PDE4 inhibitor used for treating chronic obstructive pulmonary disease (COPD) and exerts significant anti-inflammation effects. The present study aims to investigate the effects of Roflumilast on tumor necrosis factor-ß (TNF-ß)-induced inflammation activation and degradation of type 2 collagen in chondrocytes. METHODS: TNF-ß was used to establish the in-vitro inflammation model on ATDC5 chondrocytes. Quantitative real-time polymerase chain reaction (QRT-PCR) and western blot were used to determine the expression level of tumor necrosis factor receptor 2 (TNFR2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase 3 (MMP-3), matrix metalloproteinase 13 (MMP-13), type 2 collagen and nuclear factor kappa B (NF-κB) p65. The release of prostaglandin E2 (PGE2), MMP-3, and MMP-13 were evaluated by ELISA. The production of NO was determined by DAF-FM DA staining and the function of the NF-κB promoter was evaluated by Luciferase activity assay. RESULTS: TNFR2 and COX-2 were upregulated and the release of PGE2 was promoted by TNF-ß stimulation, which were all inhibited by Roflumilast. Roflumilast suppressed the promoted iNOS expression and NO production induced by TNF-ß. MMP-3 and MMP-13 were up-regulated, and type 2 collagen was down-regulated by TNF-ß stimulation, which were all reversed by Roflumilast. Roflumilast inhibited the promoted releasing of Interleukin-8 (IL-8) and Interleukin-12 (IL-12), expression of up-regulated NF-κB, and activation of NF-κB transcriptional activity induced by TNF-ß. CONCLUSION: Roflumilast may prevent TNF-ß-induced inflammation activation and degradation of type 2 collagen in chondrocytes.

Doxorubicin Delivered Using Nanoparticles Camouflaged with Mesenchymal Stem Cell Membranes to Treat Colon Cancer.

PURPOSE: The primary goal of the present study was to design doxorubicin (DOX)-loaded superparamagnetic iron oxide (SPIO) nanoparticles (NPs) coated with mesenchymal stem cell (MSC) membranes and explore their effect on colon cancer in vitro and in vivo. METHODS: DOX-SPIO NPs were coated with MSC membranes using an extruder, and the morphological characteristics of MSC membrane-camouflaged nanodrug (DOX-SPIO@MSCs) evaluated by transmission electron microscopy (TEM) and NP-tracking analysis. Drug loading and pH response were assessed by UV spectrophotometry. Intracellular colocalization was analyzed using NP-treated MC38 cells stained with 3,3'-dioctadecyloxacarbocyanine perchlorate and Hoechst 33342. Cellular uptake was analyzed using an inverted fluorescence microscope and flow cytometry and cytotoxicity evaluated by cell counting kit-8 assay. Biological compatibility was assessed by hemolysis analysis, immunoactivation test and leukocyte uptake experiments. Furthermore, intravenous injection of chemotherapy drugs into MC38 tumor-bearing C57BL/6 mice was used to study anti-tumor effects. RESULTS: Typical core-shell NP structures were observed by TEM. Particle size remained stable in fetal bovine serum and phosphate-buffered saline (PBS). Compared with DOX-SPIO, DOX-SPIO@MSCs improved cellular uptake efficiency, enhanced anti-tumor effects, and reduced the immune system response. Animal experiments demonstrated that DOX-SPIO@MSCs enhanced tumor treatment efficacy while reducing systemic side effects. CONCLUSION: Our experimental results demonstrate that DOX-SPIO@MSCs are a promising targeted nanocarrier for application in treatment of colon cancer.

Mechanism of Suspended Kaolinite Particle Clogging in Porous Media During Managed Aquifer Recharge.

Managed aquifer recharge is an effective strategy for urban stormwater management. Chemical ions are normally retained in stormwater and groundwater and may accelerate clogging during the recharge process. However, the effect of water chemistry on physical clogging has not previously been investigated. In this study, we investigated the hydrogeochemical mechanism of saturated porous media clogging in a series of column experiments. The column was packed with river sand and added suspensions of kaolinite particles. Calcium chloride and sodium chloride are used as representative ions to study chemical effects. We found that an increase in ionic strength resulted in retention of kaolinite solids in the column, with a breakthrough peak of C/C0 value of 1 to 0.2. The corresponding hydraulic conductivity decreased with increased solids clogging. Divalent cations were also found to have a greater influence on kaolinite particle clogging than monovalent cations. The enhanced hydrochemical-related clogging was caused by kaolinite solids flocculating and increasing the deposition rate coefficient by 1 to 2 times in high ionic strength conditions. Three clogging mechanisms of kaolinite solids are proposed: surface filtration, inner blocking, and attachment. This study further deepens the understanding of the mechanisms of solids clogging during aquifer recharge and demonstrates the significance of ionic strength on recharge clogging risk assessments.

Corticotrophin-Releasing Factor Modulates Cerebellar Purkinje Cells Simple Spike Activity in Vivo in Mice.

Corticotropin-releasing factor (CRF) is a major neuromodulator that modulates cerebellar neuronal activity via CRF receptors during stress responses. In the cerebellar cortex, CRF dose-dependently increases the simple spike (SS) firing rate of Purkinje cells (PCs), while the synaptic mechanisms of this are still unclear. We here investigated the effect of CRF on the spontaneous SS activity of cerebellar PCs in urethane-anesthetized mice by in vivo electrophysiological recording and pharmacological methods. Cell-attached recordings from PCs showed that micro-application of CRF in cerebellar cortical molecular layer induced a dose-dependent increase in SS firing rate in the absence of GABAA receptor activity. The CRF-induced increase in SS firing rate was completely blocked by a nonselective CRF receptor antagonist, α-helical CRF-(9-14). Nevertheless, application of either a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM) or a selective CRF-R2 antagonist, antisauvagine-30 (200 nM) significantly attenuated, but failed to abolished the CRF-induced increase in PCs SS firing rate. In vivo whole-cell patch-clamp recordings from PCs showed that molecular layer application of CRF significantly increased the frequency, but not amplitude, of miniature postsynaptic currents (mEPSCs). The CRF-induced increase in the frequency of mEPSCs was abolished by a CRF-R2 antagonist, as well as protein kinase A (PKA) inhibitors. These results suggested that CRF acted on presynaptic CRF-R2 of cerebellar PCs resulting in an increase of glutamate release through PKA signaling pathway, which contributed to modulation of the cerebellar PCs outputs in Vivo in mice.

Roles of N-methyl-d-aspartate receptors during the sensory stimulation-evoked field potential responses in mouse cerebellar cortical molecular layer.

The functions of N-methyl-d-aspartate receptors (NMDARs) in cerebellar cortex have been widely studied under in vitro condition, but their roles during the sensory stimulation-evoked responses in the cerebellar cortical molecular layer in living animals are currently unclear. We here investigated the roles of NMDARs during the air-puff stimulation on ipsilateral whisker pad-evoked field potential responses in cerebellar cortical molecular layer in urethane-anesthetized mice by electrophysiological recording and pharmacological methods. Our results showed that cerebellar surface administration of NMDA induced a dose-dependent decrease in amplitude of the facial stimulation-evoked inhibitory responses (P1) in the molecular layer, accompanied with decreases in decay time, half-width and area under curve (AUC) of P1. The IC50 of NMDA induced inhibition in amplitude of P1 was 46.5µM. In addition, application of NMDA induced significant increases in the decay time, half-width and AUC values of the facial stimulation-evoked excitatory responses (N1) in the molecular layer. Application of an NMDAR blocker, D-APV (250µM) abolished the facial stimulation-evoked P1 in the molecular layer. These results suggested that NMDARs play a critical role during the sensory information processing in cerebellar cortical molecular layer in vivo in mice.