Project description:The present study performed a detailed analysis of behavior in a rat model of epilepsy using both established and novel methodologies to identify behavioral impairments that may differentiate between animals with a short versus long latency to spontaneous seizures and animals with a low versus high number of seizures. Temporal lobe epilepsy was induced by electrical stimulation of the amygdala. Rats were stimulated for 25 min with 100-ms trains of 1-ms biphasic square-wave pluses that were delivered every 0.5 s. Electroencephalographic recordings were performed to classify rats into groups with a short latency (< 20 days, n = 7) and long latency (> 20 days, n = 8) to the first spontaneous seizure and into groups with a low number of seizures (62 ± 64.5, n = 8) and high number of seizures (456 ± 185, n = 7). To examine behavioral impairments, we applied the following behavioral tests during early and late stages of epilepsy: behavioral hyperexcitability, open field, novel object exploration, elevated plus maze, and Morris water maze. No differences in stress levels (e.g., touch response in the behavioral hyperexcitability test), activity (e.g., number of entries into the open arms of the elevated plus maze), or learning (e.g., latency to find the platform in the Morris water maze test during training days) were observed between animals with a short versus long latency to develop spontaneous seizures or between animals with a low versus high number of seizures. However, we found a higher motor activity measured by higher number of entries into the closed arms of the elevated plus maze at week 26 post-stimulation in animals with a high number of seizures compared with animals with a low number of seizures. The analysis of the Morris water maze data categorized the strategies that the animals used to locate the platform showing that the intensity of epilepsy and duration of epileptogenesis influenced swimming strategies. These findings indicate that behavioral impairments were relatively mild in the present model, but some learning strategies may be useful biomarkers in preclinical studies.

Project description:Neither the molecular basis of the pathologic tendency of neuronal circuits to generate spontaneous seizures (epileptogenicity) nor anti-epileptogenic mechanisms that maintain a seizure-free state are well understood. Here, we performed transcriptomic analysis in the intrahippocampal kainate model of temporal lobe epilepsy in rats using both Agilent and Codelink microarray platforms to characterize the epileptic processes. The experimental design allowed subtraction of the confounding effects of the lesion, identification of expression changes associated with epileptogenicity, and genes upregulated by seizures with potential homeostatic anti-epileptogenic effects. Using differential expression analysis, we identified several hundred expression changes in chronic epilepsy, including candidate genes associated with epileptogenicity such as Bdnf and Kcnj13. To analyze these data from a systems perspective, we applied weighted gene co-expression network analysis (WGCNA) to identify groups of co-expressed genes (modules) and their central (hub) genes. One such module contained genes upregulated in the epileptogenic region, including multiple epileptogenicity candidate genes, and was found to be involved the protection of glial cells against oxidative stress, implicating glial oxidative stress in epileptogenicity. Another distinct module corresponded to the effects of chronic seizures and represented changes in neuronal synaptic vesicle trafficking. We found that the network structure and connectivity of one hub gene, Sv2a, showed significant changes between normal and epileptogenic tissue, becoming more highly connected in epileptic brain. Since Sv2a is a target of the antiepileptic levetiracetam, this module may be important in controlling seizure activity. Bioinformatic analysis of this module also revealed a potential mechanism for the observed transcriptional changes via generation of longer alternatively polyadenlyated transcripts through the upregulation of the RNA binding protein HuD. In summary, combining conventional statistical methods and network analysis allowed us to interpret the differentially regulated genes from a systems perspective, yielding new insight into several biological pathways underlying homeostatic anti-epileptogenic effects and epileptogenicity.

Project description:Glioma is the most common type of primary brain cancer, and the prognosis of most patients with glioma, and particularly that of patients with glioblastoma, is poor. Tumor immunity serves an important role in the development of glioma. However, immunotherapy for glioma has not been completely successful, and thus, comprehensive examination of the immune-related genes (IRGs) of glioma is required. In the present study, differentially expressed genes (DEGs) and differentially expressed IRGs (DEIRGs) were identified using the edgeR package. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used for functional enrichment analysis of DEIRGs. Survival-associated IRGs were selected via univariate Cox regression analysis. A The Cancer Genome Atlas prognostic model and GSE43378 validation model were established using lasso-penalized Cox regression analysis. Based on the median risk score value, patients were divided into high-risk and low-risk groups for clinical analysis. Receiver operating characteristic curve and nomogram analyses were used to assess the accuracy of the models. Reverse transcription-quantitative PCR was performed to measure the expression levels of relevant genes, such as cyclin-dependent kinase 4 (CDK4), interleukin 24 (IL24), NADPH oxidase 4 (NOX4), bone morphogenetic protein 2 (BMP2) and baculoviral IAP repeat containing 5 (BIRC5). A total of 3,238 DEGs, including 1,950 upregulated and 1,288 downregulated DEGs, and 97 DEIRGs, including 60 upregulated and 37 downregulated DEIRGs, were identified. 'Neuroactive ligand-receptor interaction' and 'Cytokine-cytokine receptor interaction' were the most significantly enriched pathways according to KEGG pathway analysis. A prognostic model and a validation prognostic model were created for glioma, including 15 survival-associated IRGs (FCER1G, NOX4, TRIM5, SOCS1, APOBEC3C, BIRC5, VIM, TNC, BMP2, CMTM3, IL24, JAG1, CALCRL, HNF4G and CDK4). Furthermore, multivariate Cox regression analysis results suggested that age, high WHO Grade by histopathology, wild type isocitrate dehydrogenase 1 and high risk score were independently associated with poor overall survival. The infiltration of B cells, CD8+ T cells, dendritic cells, macrophages and neutrophils was positively associated with the prognostic risk score. In the present study, several clinically significant survival-associated IRGs were identified, and a prognosis evaluation model of glioma was established.

Project description:IntroductionGenetic Absence Epilepsy Rats from Strasbourg (GAERS) represent a model of genetic generalized epilepsy. The present longitudinal study in GAERS and age-matched non-epileptic controls (NEC) aimed to characterize the epileptic brain network using two functional measures, resting state-functional magnetic resonance imaging (rs-fMRI) and manganese-enhanced MRI (MEMRI) combined with morphometry, and to investigate potential brain network alterations, following long-term seizure activity.MethodsRepeated rs-fMRI measurements at 9.4 T between 3 and 8 months of age were combined with MEMRI at the final time point of the study. We used graph theory analysis to infer community structure and global and local network parameters from rs-fMRI data and compared them to brain region-wise manganese accumulation patterns and deformation-based morphometry (DBM).ResultsFunctional connectivity (FC) was generally higher in GAERS when compared to NEC. Global network parameters and community structure were similar in NEC and GAERS, suggesting efficiently functioning networks in both strains. No progressive FC changes were observed in epileptic animals. Network-based statistics (NBS) revealed stronger FC within the cortical community, including regions of association and sensorimotor cortex, and with basal ganglia and limbic regions in GAERS, irrespective of age. Higher manganese accumulation in GAERS than in NEC was observed at 8 months of age, consistent with higher overall rs-FC, particularly in sensorimotor cortex and association cortex regions. Functional measures showed less similarity in subcortical regions. Whole brain volumes of 8 months-old GAERS were higher when compared to age-matched NEC, and DBM revealed increased volumes of several association and sensorimotor cortex regions and of the thalamus.Discussionrs-fMRI, MEMRI, and volumetric data collectively suggest the significance of cortical networks in GAERS, which correlates with an increased fronto-central connectivity in childhood absence epilepsy (CAE). Our findings also verify involvement of basal ganglia and limbic regions. Epilepsy-related network alterations are already present in juvenile animals. Consequently, this early condition seems to play a greater role in dynamic brain function than chronic absence seizures.

Dataset Information

Development of a Rat Model for Glioma-Related Epilepsy.

Publications

Development of a Rat Model for Glioma-Related Epilepsy.

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