Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA189420 | ENA |
REPOSITORIES: ENA
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Project description:Neurodegenerative brain disorders become more common in the aged. Most of these disorders are associated with or caused by selective death of certain neuronal subpopulations. The mechanisms underlying the differential vulnerability of certain neuronal populations are still largely unexplored and few neuroprotective treatments are available to date. Elucidation of these mechanisms may lead to a greater understanding of the pathogenesis and treatment of neurodegenerative diseases. Moreover, preconditioning by a short seizure confers neuroprotection following a subsequent prolonged seizure. Our goal is to identify pathways that confer vulnerability and resistance to neurotoxic conditions by comparing the basal and preconditioned gene expression profiles of three differentially vulnerable hippocampal neuron populations. Hippocampal CA1 and CA3 pyramidal neurons are highly susceptible to seizures and ischemia, whereas dentate gyrus granule cells are relatively resistant. A brief preconditioning seizure confers protection to the pyramidal cells. We will first determine gene expression profiles of untreated rat CA1 and CA3 pyramidal cells, and dentate granule cells, using laser capture microscopy to obtain region-specific neuronal mRNA. We will then determine the effect of a brief preconditioning seizure, which is neuroprotective in CA1 and CA3, on these expression profiles. We hypothesize that common molecular mechanisms exist in neurons that determine their susceptibility to seizure-induced injury. Intrinsic differences in gene expression exist between hippocampal glutamatergic CA1 and CA3 pyramidal neurons, on the one hand, and dentate granule cells on the other, which contribute to the greater susceptibility of pyramidal neurons to degeneration in experimental stroke and epilepsy. We specifically hypothesize that differences in basal energy metabolism genes may confer differential susceptibility to neurodegeneration produced by seizures and ischemia. Anesthetized animals will be sacrificed by decapitation, and frozen 10 micron sections will be lightly stained with cresyl violet to identify cell layers in the hippocampus. Approximately 1000 neurons from each of the three cell layers will be isolated by LCM. Poly-A RNA will be amplified using a modified Eberwine protocol. The quality of our aRNA will be evaluated by quantitative RT-PCR of GluR6 and KA2 mRNA levels before we send the samples to the Center for labeling and hybridization to Affymetrix rat 230A arrays. We will provide a one-round amplification cDNA product to the center for labeling and hybridization. This protocol is identical to a previously approved study by Jim Greene in our laboratory.
2007-09-18 | E-GEOD-1994 | biostudies-arrayexpress
Project description:Neurodegenerative brain disorders become more common in the aged. Most of these disorders are associated with or caused by selective death of certain neuronal subpopulations. The mechanisms underlying the differential vulnerability of certain neuronal populations are still largely unexplored and few neuroprotective treatments are available to date. Elucidation of these mechanisms may lead to a greater understanding of the pathogenesis and treatment of neurodegenerative diseases. Moreover, preconditioning by a short seizure confers neuroprotection following a subsequent prolonged seizure. Our goal is to identify pathways that confer vulnerability and resistance to neurotoxic conditions by comparing the basal and preconditioned gene expression profiles of three differentially vulnerable hippocampal neuron populations. Hippocampal CA1 and CA3 pyramidal neurons are highly susceptible to seizures and ischemia, whereas dentate gyrus granule cells are relatively resistant. A brief preconditioning seizure confers protection to the pyramidal cells. We will first determine gene expression profiles of untreated rat CA1 and CA3 pyramidal cells, and dentate granule cells, using laser capture microscopy to obtain region-specific neuronal mRNA. We will then determine the effect of a brief preconditioning seizure, which is neuroprotective in CA1 and CA3, on these expression profiles. We hypothesize that common molecular mechanisms exist in neurons that determine their susceptibility to seizure-induced injury. Intrinsic differences in gene expression exist between hippocampal glutamatergic CA1 and CA3 pyramidal neurons, on the one hand, and dentate granule cells on the other, which contribute to the greater susceptibility of pyramidal neurons to degeneration in experimental stroke and epilepsy. We specifically hypothesize that differences in basal energy metabolism genes may confer differential susceptibility to neurodegeneration produced by seizures and ischemia. Anesthetized animals will be sacrificed by decapitation, and frozen 10 micron sections will be lightly stained with cresyl violet to identify cell layers in the hippocampus. Approximately 1000 neurons from each of the three cell layers will be isolated by LCM. Poly-A RNA will be amplified using a modified Eberwine protocol. The quality of our aRNA will be evaluated by quantitative RT-PCR of GluR6 and KA2 mRNA levels before we send the samples to the Center for labeling and hybridization to Affymetrix rat 230A arrays. We will provide a one-round amplification cDNA product to the center for labeling and hybridization. This protocol is identical to a previously approved study by Jim Greene in our laboratory. Keywords: other
2004-11-24 | GSE1994 | GEO
Project description:Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory epilepsy syndrome; kainic acid (KA) induced seizures have been studied as a MTLE model as limbic seizures produced by systemic injections of KA result in a distinctive pattern of neurodegeneration in the hippocampus that resembles human hippocampal sclerosis. In our "2-hit" seizure model, animals subjected to seizures during week 2 of life become more susceptible to seizures later in life and sustain extensive hippocampal neuronal injury after second KA seizures in adulthood. Using high-density oligonucleotide gene arrays, we began to elucidate the molecular basis of this priming effect of early-life seizures and of the age-specific neuroprotection against seizure-induced neuronal injury. We seek to identify target genes for epileptogenesis and cell death by selecting transcripts that are differentially regulated at various times in the P15 and P30 hippocampus. To screen for and identify candidate genes responsible for epileptogenesis and seizure-induced cell death. We hypothesize that active process of cell death signaling and long-term synaptic changes leading to chronic epilepsy is mediated by distinct transcriptional responses in mature brain that are different from those in immature brain. We will select for transcripts that are highly regulated at 1, 6, 24, 72 and 240 hours (h) after KA-induced seizures at P30 compared to P15. These differentially regulated genes will serve as potential target genes for therapeutic intervention. Highly regulated genes identified in our array analysis will then be confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Causative roles of select genes will be directly tested by gene silencing using RNA interference technology or by gene delivery using viral vectors.
2008-06-11 | E-GEOD-1834 | biostudies-arrayexpress
Project description:Injury of the CA1 subregion induced by a single injection of kainic acid (1M-CM-^WKA) is attenuated when juvenile animals (P20) have a history of two sustained neonatal seizures on P6 and P9. To identify gene candidates involved in the spatially protective effects produced by early life conditioning seizures, we profiled and compared the transcriptomes of CA1 subregions from control, 1M-CM-^WKA, and 3M-CM-^WKA treated animals. More genes were regulated following 3M-CM-^WKA (9.6%) than after 1M-CM-^WKA (7.1%). Following 1M-CM-^WKA, genes supporting oxidative stress, growth, development, inflammation, and neurotransmission were upregulated (e.g., Cacng1, Nadsyn1, Kcng1, Aven, S100a4, GFAP, Vim, Hrsp12, Grik1). After 3M-CM-^WKA, protective genes were differentially over-expressed (e.g., Cat, Gpx7, GAD1, Hspa12A, Foxn1, adenosine A1 receptor, Ca2+ adaptor and homeostatic proteins, Cacnb4, Atp2b2, anti-apoptotic Bcl-2 gene members, intracellular trafficking protein, Grasp, suppressor of cytokine signaling (Socs3)). Distinct anti-inflammatory interleukins not observed in adult tissues (e.g., IL6 transducer, IL23 and IL33 or their receptors (ILF2)) were also over-expressed. Several transcripts were validated by real-time polymerase chain reaction (QPCR) and immunohistochemistry. QPCR showed that casp 6 was increased after 1M-CM-^WKA but reduced after 3M-CM-^WKA; pro-inflammatory gene cox1 was either upregulated or unchanged after 1M-CM-^WKA but reduced by ~70% after 3M-CM-^WKA. Enhanced GFAP immunostaining following 1M-CM-^WKA was selectively attenuated in the CA1 subregion after 3M-CM-^WKA. The observed differential transcriptional responses may contribute to early life seizure-induced pre-conditioning and neuroprotection by reducing glutamate receptor-mediated Ca2+ permeability of the hippocampus and redirecting inflammatory and apoptotic pathways which could lead to new genetic therapies for epilepsy. The transcriptomes of the hippocampal CA1 region of Sprague Dawley 23-day-old male rats after 1 or 3 seizures induced by kainic acid injection were compared to the corresponding controls (injected with PBS) using Duke 27k oligonucleotide arrays.
2013-02-14 | E-GEOD-44031 | biostudies-arrayexpress
Project description:Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory epilepsy syndrome; kainic acid (KA) induced seizures have been studied as a MTLE model as limbic seizures produced by systemic injections of KA result in a distinctive pattern of neurodegeneration in the hippocampus that resembles human hippocampal sclerosis. In our "2-hit" seizure model, animals subjected to seizures during week 2 of life become more susceptible to seizures later in life and sustain extensive hippocampal neuronal injury after second KA seizures in adulthood. Using high-density oligonucleotide gene arrays, we began to elucidate the molecular basis of this priming effect of early-life seizures and of the age-specific neuroprotection against seizure-induced neuronal injury. We seek to identify target genes for epileptogenesis and cell death by selecting transcripts that are differentially regulated at various times in the P15 and P30 hippocampus. To screen for and identify candidate genes responsible for epileptogenesis and seizure-induced cell death. We hypothesize that active process of cell death signaling and long-term synaptic changes leading to chronic epilepsy is mediated by distinct transcriptional responses in mature brain that are different from those in immature brain. We will select for transcripts that are highly regulated at 1, 6, 24, 72 and 240 hours (h) after KA-induced seizures at P30 compared to P15. These differentially regulated genes will serve as potential target genes for therapeutic intervention. Highly regulated genes identified in our array analysis will then be confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Causative roles of select genes will be directly tested by gene silencing using RNA interference technology or by gene delivery using viral vectors. Keywords: time-course
2004-10-14 | GSE1834 | GEO
Project description:Analysis of biopsy hippocampal tissue of patients with pharmacoresistant temporal lobe epilepsy (TLE) undergoing neurosurgical removal of the epileptogenic focus for seizure control. Chronic TLE goes along with focal hyperexcitability. Results provide insight into molecular mechanisms that may play a role in seizure propensity 150 human hippocampus samples
2014-12-04 | E-GEOD-63808 | biostudies-arrayexpress
Project description:Analysis of biopsy hippocampal tissue of patients with pharmacoresistant temporal lobe epilepsy (TLE) undergoing neurosurgical removal of the epileptogenic focus for seizure control. Chronic TLE goes along with focal hyperexcitability. Results provide insight into molecular mechanisms that may play a role in seizure propensity
2014-12-04 | GSE63808 | GEO
Project description:Posttraumatic epilepsy (PTE) is a major public health concern and strongly contributes to human epilepsy cases worldwide. However, their effective treatment and prevention remains a matter of intense research. The present study provides new insights into the GABAA-receptor-stabilizing protein ubiquilin-1 (ubqln1) and its regulation in a mouse model of traumatic brain injury (TBI)- and in vitro epilepsy. We performed label-free quantification on isolated cortical GABAergic interneurons from GAD67-GFP mice that received unilateral TBI and discovered reduced expression of ubqln1 24 hours post-TBI. To investigate the link between this regulation and the development of epileptiform activity, we further studied the ubqln1 expression in hippocampal and cortical slices. Epileptiform events were evoked pharmacologically in acute brain slices by administration of picrotoxin (50 μM) and kainic acid (500 nM) and recorded in the hippocampal CA1 region using Multielectrode Arrays (MEA). Interestingly, quantitative Western blots revealed significant decreases in the ubqln1 expression 1-7 hours after seizure induction that could be restored by the application of the non-selective monoamine oxidase inhibitor nialamide (NM, 10 μM). In picrotoxin-dependent dose-response relationships, NM-administration alleviated frequency and peak amplitude of SLEs. These findings indicate a potential role of the monoamine transmitter systems in recovering excitatory-inhibitory (E/I) balance in posttraumatic epileptogenesis.
2022-07-14 | PXD031368 | JPOST Repository
Project description:Traumatic brain injury occasionally causes posttraumatic epilepsy. To elucidate the molecular events responsible for posttraumatic epilepsy, we established a rodent model that involved the injection of microliter quantities of FeCl3 solution into the amygdalar nuclear complex. We previously compared hippocampal gene expression profiles in the traumatic epilepsy model and normal rats at 5 days after brain injury (acute phase) and observed the role of inflammation. In this study, we focused on later stages of epileptogenesis. We compared gene expression profiles at 5, 15 (sub-chronic phase), and 30 days (chronic phase) after brain injury to identify temporal changes in molecular networks involved in epileptogenesis. A total of 81 genes was significantly (at least 2-fold) up- or downregulated over the course of disease progression. We found that genes related to lipid metabolism, namely, Apoa1, Gh, Mc4r, Oprk1, and Pdk4, were temporarily upregulated in the sub-chronic phase. Changes in lipid metabolism regulation might be related to seizure propagation during epileptogenesis. This temporal description of hippocampal gene expression profiles throughout epileptogenesis provides clues to potential markers of disease phases and new therapeutic targets.
2012-12-31 | GSE40490 | GEO
Project description:<h4><strong>INTRODUCTION: </strong>Approximately 1% of the world's population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet, a high-fat, low-carbohydrate diet. Despite the KD's success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal excitation.</h4><h4><strong>OBJECTIVES: </strong>The goal of this study was to explore changes in the lipidome in hippocampal and cortical tissue from Kv1.1-KO model of epilepsy.</h4><h4><strong>METHODS: </strong>FT-ICR/MS analysis was utilized to examine nonpolar metabolome of cortical and hippocampal tissue isolated from a Kv1.1 channel knockout mouse model of epilepsy (n = 5) and wild-type mice (n = 5).</h4><h4><strong>RESULTS: </strong>Distinct metabolic profiles were observed, significant (p < 0.05) features in hippocampus often being upregulated (FC ≥ 2) and the cortex being downregulated (FC ≤ 0.5). Pathway enrichment analysis shows lipid biosynthesis was affected. Partition ratio analysis revealed that the ratio of most metabolites tended to be increased in Kv1.1-/-. Metabolites in hippocampal tissue were commonly upregulated, suggesting seizure initiation in the hippocampus. Aberrant mitochondrial function is implicated by the upregulation of cardiolipin, a common component in the mitochondrial membrane.</h4><h4><strong>CONCLUSION: </strong>Generally, our study finds that the lipidome is changed in the hippocampus and cortex in response to Kv1.1-KO indicating changes in membrane structural integrity and synaptic transmission.</h4>
2022-01-06 | MTBLS1432 | MetaboLights