Project description:Neuropsychiatric consequences of poorly controlled seizures that begin in childhood can be devastating. School failure or behavioral difficulty in a child with epilepsy is common and can become the focus of concern for families. Current antiepileptic drugs compound problems with their CNS side effects; effective therapy is currently limited as little is known about the cellular and molecular changes caused by seizures in the developing brain. This study will investigate transcriptional regulation induced by early-life seizures and explore alternative nonpharmacological therapeutic strategies in reversing damages of early-life seizures. We will study the therapeutic efficacy of environmental enrichment in reducing seizure-induced neuronal injury and in modifying gene expression alterations. We will explore molecular mechanisms underlying the beneficial effects of enriched environment and examine how different genes act in concert to influence the outcome of seizure-induced damage. To test the effect of environmental enrichment in modifying KA seizure-induced alterations in gene expression. We hypothesize that environmental enrichment enhances plastic, homeostatic response of immature brain to excessive, dysregulating seizure activity and protect against maladaptive response of developing animals to seizures. After inducing seizures by systemic injection of KA (8 mg/kg) or PBS injections (control) at P20, we will randomly assign P21 male Long Evans rats to 4 groups: enrichment housing (control-enriched; SE-enriched) or to standard vivarium cages (control; SE). Sixteen animals (8 control-enriched; 8 SE-enriched) will be housed as a group in a plastic rectangular cage measuring 115cm x 80 cm containing a running wheel, tunnels, rubber balls, a maze, a mirror, and a clock with a cyclist pendulum. Control and KA will be housed individually in a standard cage. Four litters will be used for each run of experiment and the experiment will be repeated once to obtain 16 animals per group. At P30, 240 h after KA or PBS, animals will be deeply anesthetized with isoflurane, decapitated for total RNA preparation (half brain for each, n = 12 per group). Total RNA will be isolated from each hippocampus individually, and equal amounts of RNA from 4 hippocampi will be pooled for each Genechip. Three independent hybridizations will be performed per condition (total of 12 Genechip Rat Expression Set 230).

Project description:Neuropsychiatric consequences of poorly controlled seizures that begin in childhood can be devastating. School failure or behavioral difficulty in a child with epilepsy is common and can become the focus of concern for families. Current antiepileptic drugs compound problems with their CNS side effects; effective therapy is currently limited as little is known about the cellular and molecular changes caused by seizures in the developing brain. This study will investigate transcriptional regulation induced by early-life seizures and explore alternative nonpharmacological therapeutic strategies in reversing damages of early-life seizures. We will study the therapeutic efficacy of environmental enrichment in reducing seizure-induced neuronal injury and in modifying gene expression alterations. We will explore molecular mechanisms underlying the beneficial effects of enriched environment and examine how different genes act in concert to influence the outcome of seizure-induced damage. To test the effect of environmental enrichment in modifying KA seizure-induced alterations in gene expression. We hypothesize that environmental enrichment enhances plastic, homeostatic response of immature brain to excessive, dysregulating seizure activity and protect against maladaptive response of developing animals to seizures. After inducing seizures by systemic injection of KA (8 mg/kg) or PBS injections (control) at P20, we will randomly assign P21 male Long Evans rats to 4 groups: enrichment housing (control-enriched; SE-enriched) or to standard vivarium cages (control; SE). Sixteen animals (8 control-enriched; 8 SE-enriched) will be housed as a group in a plastic rectangular cage measuring 115cm x 80 cm containing a running wheel, tunnels, rubber balls, a maze, a mirror, and a clock with a cyclist pendulum. Control and KA will be housed individually in a standard cage. Four litters will be used for each run of experiment and the experiment will be repeated once to obtain 16 animals per group. At P30, 240 h after KA or PBS, animals will be deeply anesthetized with isoflurane, decapitated for total RNA preparation (half brain for each, n = 12 per group). Total RNA will be isolated from each hippocampus individually, and equal amounts of RNA from 4 hippocampi will be pooled for each Genechip. Three independent hybridizations will be performed per condition (total of 12 Genechip Rat Expression Set 230). Keywords: dose response

Project description:Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase, causing a toxic buildup of acetylcholine at muscarinic and nicotinic receptors. Current medical countermeasures to nerve agent intoxication increase survival if administered within a short period of time following exposure but may not fully prevent neurological damage. Therefore, there is a need to discover drug treatments that are effective when administered after the onset of seizures and secondary responses that lead to brain injury. Methods To determine potential therapeutic targets for such treatments, we analyzed gene expression changes in the rat piriform cortex following sarin (O-isopropyl methylphosphonofluoridate) exposure. Male Sprague-Dawley rats were challenged with 1.0 x LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride (2-PAM), and the anticonvulsant diazepam. Control animals received an equivalent volume of vehicle and drug treatments. The piriform cortex, a brain region particularly sensitive to neural damage from sarin-induced seizures, was extracted at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified sarin-induced seizure occurrence and time point following seizure onset as major sources of variability within the dataset. Based on these variables, the dataset was filtered and analysis of variance was used to determine genes significantly changed in seizing animals at each time point. The calculated p-value and geometric fold change for each probeset identifier were subsequently used for gene ontology analysis to identify canonical pathways, biological functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course. Results A multitude of biological functions and pathways were identified as being significantly altered following sarin-induced seizure. Inflammatory response and signaling pathways associated with inflammation were among the most significantly altered across the five time points examined. Conclusions This analysis of gene expression changes in the rat brain following sarin-induced seizure and the molecular pathways involved in sarin-induced neurodegeneration will allow a better identification of potential therapeutic targets for the development of effective neuroprotectants to treat nerve agent exposure. Three animals were used for each experimental group (naM-CM-/ve, sarin-exposed non-seizure, non-seizure control [saline], sarin-exposed seizure, and seizure control [saline]) at each time point (0.25, 1, 3, 6, 24 h), with the exception of 1 h seizure control, 3 h sarin-exposed seizure, 24 h sarin-exposed non-seizure, and 24 h sarin-exposed seizure (n=4).

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Transcription profiling of mouse hippocampus treated with a ketogenic diet

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