Seizure Engram

癫痫发作印迹

基本信息

批准号：
10304392
负责人：
ROBERT E GROSS
金额：
$ 3.9万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304392
关键词：
Acute Adverse effects Affect Animals Behavior Biological Brain Brain region Cells Chemicals Chimeric Proteins Chronic Control Animal Disease Electric Stimulation Engineering Enterobacteria phage P1 Cre recombinase Epilepsy Exhibits FOS gene Fire - disasters Fluorescence Fluorescence Microscopy Gene Expression Generalized seizures Generations Genes Genetic Genetic Recombination Goals Hippocampus (Brain)Histologic Immediate-Early Genes Injections Intervention Intractable Epilepsy Knowledge Label Light Luciferases Memory Molecular Mus Neurons Operative Surgical Procedures Opsin Patients Pentylenetetrazole Pharmaceutical Preparations Population Prevention Procedures Process Proteins Pump Reagent Reporter Rodent Rodent Model Seizures Stereotyping Structure System Tamoxifen Techniques Testing Time Transgenic Mice Viral Vector base brain cell cell type coelenterazine comparative efficacy dentate gyrus effective therapy granule cell innovation mouse model neuroregulation optogenetics prevent promoter success tool

项目摘要

PROJECT SUMMARY/ABSTRACT Epileptic seizures can be characterized as concerted and synchronized activity of neurons across the brain for an extended period of time. We hypothesize that, as for other normal brain-controlled behavior, epileptic seizures are not caused by random activity of neurons, but rather arise from activity in a specific, organized brain network. Our overarching goal is to elucidate such a seizure-specific network in the brain and to deliver genetic neuromodulation specifically to such a seizure-generating network for tailored seizure suppression. In our proposal, we first identify all the critical brain cells that make up that seizure network in acute and chronic rodent models of epilepsy. Then, we will manipulate such a network to stop seizure occurrence. We will identify and visualize brain structures and cells responsible for generation of seizures in the whole brain by labeling these cells with a fluorescent protein tag utilizing sophisticated gene expression techniques in genetically modified mice (Specific Aim 1). This seizure-specific labelling of neurons occurs when they exhibit extensive activity in the presence of a chemical in the system during a seizure episode. This labelling procedure will be repeated to examine if the same neuronal populations become active in two separate episodes of seizures. The cells labeled with the fluorescence reporter will be examined by fluorescence microscopy. Overlapped labelling of neurons between two seizure episodes will support our hypothesis that the same subset of neurons is repeatedly involved in generation of seizures. We will then employ a similar strategy to deliver genetic neuromodulation to a seizure-generating network (Specific Aim 2). We engineered a viral vector that carries a molecular tool that suppress neuronal activity when an activating drug is injected into the animal. This viral vector will be injected into a brain region responsible for generation of seizures in the rodent models of epilepsy we will use. We expect that such manipulation will suppress subsequent seizures. Our hypothesis views and treats epileptic seizures as a network function in the brain. Together with robust network-specific suppression of seizures in mouse models of epilepsy, this will change the way we view and treat this disease.

项目摘要/摘要癫痫发作可以表征为整个大脑神经元的协同和同步活性长时间。我们假设，对于其他正常的脑控制行为，癫痫发作不是由神经元的随机活性引起的，而是由特定有组织的大脑网络中的活动引起的。我们的总体目标是阐明大脑中的这种癫痫发作特定网络并提供遗传神经调节专门针对这种癫痫发作网络，用于定制癫痫发作。在我们的提案，我们首先确定构成急性和慢性啮齿动物癫痫发作网络的所有关键脑细胞癫痫的模型。然后，我们将操纵这样的网络以停止癫痫发作。我们将识别和可视化负责整个大脑癫痫发作的大脑结构和细胞通过使用利用复杂基因表达技术的荧光蛋白质标记这些细胞在转基因小鼠（特定目标1）。这种神经元的癫痫发作特异性标记发生时会发生在癫痫发作中，系统中有化学物质存在的广泛活动。此标签过程将重复检查是否在两个单独的情节中相同的神经元种群活跃癫痫发作。用荧光记者标记的细胞将通过荧光显微镜检查。两次癫痫发作之间神经元的重叠标记将支持我们的假设，即同一子集神经元反复参与发作的产生。然后，我们将采用类似的策略来将遗传神经调节提供给癫痫发作网络（特定目标2）。我们设计了一个病毒载体，该病毒载体携带一种分子工具，该工具抑制神经元活性激活药物被注入动物。该病毒载体将被注入负责的大脑区域我们将使用癫痫啮齿动物模型中的癫痫发作。我们希望这样的操纵会抑制随后的癫痫发作。我们的假设将癫痫发作视为大脑中的网络功能。与健壮的人一起网络特定于癫痫鼠标模型中癫痫发作的抑制，这将改变我们的查看方式和治疗这种疾病。