CAREER: Bridging epileptogenic molecular level changes to neuronal network synchrony to reveal basic mechanisms of epilepsy

职业：将致癫痫分子水平的变化与神经元网络同步联系起来，揭示癫痫的基本机制

• 批准号: 0954797
• 负责人: Theoden Netoff
• 金额: $ 42.27万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0954797&HistoricalAwards=false
• 关键词: CAREER; Bridging; epileptogenic; molecular; level

PI: Netoff, Theoden I.Proposal Number: 0954797 The etiologies of pathological behaviors that emerge in networks are especially difficult to diagnose. The causes are usually subtle changes in the dynamics of the nodes that lead to changes in population behavior. These multi-scale problems are very general. Epilepsy is an example of disease where molecular level changes in neurons caused by genetic mutations lead to pathological neuronal activity generating seizures. While there are many hypotheses, very little is known about how and why these mutations cause seizures, which prevents us from developing better treatments. Understanding how synchrony in networks are affected by known epileptogenic mutations and antiepileptic drugs with known molecular effects will provide a model system in which multiple scales may be bridged. A synergistic approach using numerical simulations electrophysiology experiments and computational simulations will be used. Computational models of neurons will be used to predict how epileptogenic mutations and antiepileptic drugs change the phase response curve (PRC) of a neuron. The PRC is a measure of a neuron?s sensitivity to synaptic inputs. From the PRC it is possible to infer how changes caused by epileptogenic mutations and antiepileptic drugs would alter synchrony in a network of neurons. Predictions from the modeling will be tested using dynamic clamp experiments, where a computer running a real-time interface is interfaced to a neuron through a patch clamp amplifier and electrode. Dynamic clamp experiments will be used to measure the effects of epileptogenic mutations (introduced thorough electrical knock-in) and bath applied antiepileptic drugs on the phase response curve of the neuron. Hybrid networks will then be created using the dynamic clamp to simulate synaptic connections between two patch clamped neurons in which effects of epileptogenic mutations and antiepileptic drugs on synchrony will be measured directly. Physiological experiments will be used to provide parameters to run large scale simulations where synchrony will be measured. Preliminary data is presented from simulations and electrophsiological experiments that epileptogenic mutations in voltage gated sodium channels decrease synchrony and antiepileptic drugs increase synchrony. These findings are in contrast to the popular view of epilepsy that epilepsy is caused by hypersynchrony. By developing our understanding of how these mutations and drugs actually work, we may develop new and better approaches to treating this disease. The goal of this proposed research is to test the hypotheses that changes in the dynamics of neurons caused by epileptogenic mutations increase network synchrony, and that the modulation of neurons by drugs that prevent seizures decrease network synchrony. By proving, or disproving these hypotheses, we will understand if developing new drugs or deep brain stimulation to prevent seizures should be optimized to decrease network synchrony. To test this hypothesis we propose the following specific aims: 1) use single cell modeling to identify effects of epileptogenic mutations and antiepileptic drugs on cell dynamics, 2) network modeling to assess the effect of epileptogenic mutations and antiepileptic drugs on network synchrony, and 3) characterize changes in cell dynamics caused by mutation of SCN1A channel using hybrid experiments with real neurons and virtual ion channels. Intellectual Merit: The research proposed here will help elucidate how changes in neuronal dynamics and topology of network connectivity result in pathological neuronal activity such as seizures. How neuron dynamics are affected by epileptogenic mutations and antiepileptic drugs will be discovered to help develop better models of seizures. Effects of known epileptogenic ion channel mutations and antiepileptic drugs on network synchrony will be used to probe the role of neuronal population synchrony in epilepsy. With this knowledge we will develop more rational approaches to treating epilepsy. Broader impact: Electrophysiolgy data acquired will be cataloged in a database available to any scientist interested in analyzing the data. To complete the electrophysiolgical experiment, we will generate many modules for the dynamicclamp which will be made available to the community using the RTXI dynamic clamp. Code developed to run network simulations using CUDA enabled machines for supercomputer performance on a desktop will be made available to the public. Outreach plan includes collaborations with the Bakken museum, the Epilepsy Foundation, the University of Minnesota?s ?Brain U?, its summer high school program ?Exploring Careers in Engineering and Physical Science?, and it?s North Star Alliance Program.

PI：Netoff，Theoden I. proposal编号：0954797网络中出现的病理行为的病因特别困难。 原因通常是导致人口行为变化的节点动力学的细微变化。这些多尺度问题非常普遍。癫痫是疾病的一个例子，其中由遗传突变引起的神经元的分子水平变化导致病理神经元活性产生癫痫发作。尽管有许多假设，但对于这些突变如何以及为什么引起癫痫发作的原因很少，这阻止了我们开发更好的治疗方法。了解网络中的同步如何受到已知的具有已知分子效应的已知癫痫发生突变和抗癫痫药的影响，将提供一个模型系统，其中可能会桥接多个尺度。使用数值模拟电生理实验和计算模拟的协同方法。 神经元的计算模型将用于预测癫痫发生突变和抗癫痫药如何改变神经元的相反应曲线（PRC）。中国是对突触输入的神经元敏感性的量度。从中国，可以推断出由癫痫发生突变和抗癫痫药引起的变化如何改变神经元网络中的同步。将使用动态夹具实验对建模的预测进行测试，其中运行实时接口的计算机通过斑块夹放大器和电极连接到神经元。动态夹具实验将用于测量癫痫发生突变（引入彻底的电敲门）和在神经元的相反应曲线上施用的抗癫痫药。然后，将使用动态夹具创建混合网络，以模拟两个贴片夹神经元之间的突触连接，在两个贴片夹神经元之间，将直接测量癫痫发生突变和抗癫痫药对同步的影响。生理实验将用于提供参数，以运行将测量同步的大规模模拟。初步数据是通过模拟和电生物学实验提供的，即电压门控钠通道中的癫痫发生突变减少同步和抗癫痫药增加了同步性。这些发现与癫痫的流行观点形成鲜明对比：癫痫是由超同步引起的。通过我们对这些突变和药物如何实际发挥作用的理解，我们可能会开发出一种新的，更好的方法来治疗这种疾病。 这项拟议的研究的目的是测试由癫痫突变引起的神经元动力学变化的假设增加网络同步，并通过预防癫痫发作的药物调节神经元降低网络同步。通过证明或反驳这些假设，我们将理解是否应优化开发新药或深脑刺激以防止癫痫发作以减少网络同步。为了检验该假设，我们提出以下特定目的：1）使用单细胞建模来鉴定癫痫发生突变和抗癫痫药对细胞动力学的影响，2）网络建模，评估通过SCNCHRONY引起的细胞动力学在SCN1A中引起的细胞动力学的变化，以评估癫痫发生突变和抗活毒的癫痫病的影响。频道。 智力优点：这里提出的研究将有助于阐明神经元动力学的变化和网络连通性的拓扑如何导致病理神经元活动（例如癫痫发作）。将发现神经元动力学如何受到癫痫发生突变和抗癫痫药的影响，以帮助开发更好的癫痫发作模型。已知的癫痫离子通道突变和抗癫痫药对网络同步的影响将用于探测神经元种群同步在癫痫中的作用。有了这些知识，我们将开发更多理性的方法来治疗癫痫。 更广泛的影响：所获得的电生理数据将在任何有兴趣分析数据的科学家可用的数据库中分类。为了完成电生理学实验，我们将生成许多动态插槽的模块，这些模块将使用RTXI动态夹提供给社区。开发用于使用启用CUDA的机器运行网络模拟的代码将向桌面上的超级计算机性能提供给公众。外展计划包括与Bakken博物馆，癫痫基金会，明尼苏达大学的Brain U？的合作，其夏季高中计划？探索工程和物理科学领域的职业？以及它的北星联盟计划。