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Seizure Engram

癫痫发作印迹

基本信息

批准号：
9979524
负责人：
ROBERT E GROSS
金额：
$ 42.9万
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979524
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/摘要癫痫发作的特征是整个大脑中神经元的协调和同步活动一段较长的时间。我们假设，与其他正常的大脑控制行为一样，癫痫发作不是由神经元的随机活动引起的，而是由特定的、有组织的大脑网络中的活动引起的。我们的首要目标是阐明大脑中这种癫痫特异的网络，并将基因神经调节专门针对这种癫痫发作产生网络，以进行量身定制的癫痫发作抑制。在我们的建议，我们首先确定构成急、慢性啮齿动物癫痫发作网络的所有关键脑细胞癫痫模型。然后，我们将操纵这样的网络来阻止癫痫的发生。我们将识别和可视化在整个大脑中导致癫痫发作的大脑结构和细胞通过利用复杂的基因表达技术用荧光蛋白标签标记这些细胞转基因小鼠(特定目标1)。当神经元表现出癫痫发作的特异性标记时，就会出现这种标记在癫痫发作期间，系统中存在化学物质时的广泛活动。这个贴标签的程序将重复检查相同的神经元群体是否在两个不同的发作中变得活跃癫痫发作。标记有荧光报告的细胞将在荧光显微镜下进行检查。两次癫痫发作之间神经元的重叠标记将支持我们的假设，即相同的子集神经元反复参与癫痫发作的发生。然后，我们将采用类似的策略，将遗传神经调节传递给癫痫发作产生网络 (具体目标2)。我们设计了一种病毒载体，它携带一种分子工具，当一种激活剂被注射到动物体内。这种病毒载体将被注射到负责我们将在癫痫的啮齿类动物模型中使用癫痫的产生。我们预计，这种操纵将抑制随后的癫痫发作。我们的假说将癫痫发作视为大脑中的一种网络功能。与强大的网络特异性抑制癫痫小鼠模型的发作，这将改变我们看待和治疗这种疾病。