Optogenetic hub cell control for no seizures, no side-effects in temporal lobe ep

光遗传学枢纽细胞控制无癫痫发作，颞叶 ep 无副作用

• 批准号: 8129962
• 负责人: IVAN SOLTESZ
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129962
• 关键词: Acceleration; Accounting; Adult; Adverse effects; Affect; Animal Model; Animals; Antiepileptic Agents; Applications Grants; Area; Brain; Cells; Chronic; Computer Simulation; Critiques; Data; Dose; Drug resistance; Epilepsy; Evaluation; Event; Fostering; Frequencies; Funding; Funding Opportunities; Generations; Goals; Hippocampus (Brain); Human; In Vitro; Individual; Institutes; Instruction; Investigation; Knowledge; Lasers; Learning; Light; Limbic System; Maintenance; Medial; Medical; Memory; Methodology; Methods; Mission; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Optics; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Play; Population; Probability; Rattus; Recurrence; Research; Risk; Role; Science; Seizures; Slice; Specificity; Study Section; Synapses; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; United States National Institutes of Health; Update; Writing; base; dentate gyrus; design; entorhinal cortex; granule cell; in vivo; information processing; innovation; kainate; meetings; novel; novel strategies; novel therapeutic intervention; prevent; research study; social; therapy resistant

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugs often have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. The central idea behind the proposed research is that it may be possible to achieve seizure control by transiently inhibiting, only at critical moments, the activity of a low number of unique neurons that may be primarily responsible to triggering seizures in the limbic system. Our recent large-scale computational modeling studies have shown that rare, abnormal, super- connected, hub-like neurons may play a key role in seizure initiation. Subsequently, such hub cells have been demonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hub cells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use novel optogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortex of epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational and temporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneous recurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in a temporally selective manner, effective seizure control may be achieved with minimal effects on the normal information processing of the circuit. If successful, the proposed research will demonstrate a fundamentally novel approach to achieving the goal of "no seizures, no side-effects" for the treatment of epilepsy.

描述（由申请人提供）：颞叶癫痫是成人最常见的癫痫形式。目前可用的抗癫痫药物通常具有显着且使人衰弱的副作用，颞叶癫痫经常对药物治疗产生耐药性，从而带来巨大的社会和医学问题。这项研究背后的中心思想是，通过仅在关键时刻短暂抑制少量独特神经元的活动，可能会实现癫痫控制，而这些神经元可能主要负责触发边缘系统中的癫痫发作。我们最近的大规模计算模型研究表明，罕见的、异常的、超连接的中枢样神经元可能在癫痫发作的发生中发挥关键作用。随后，这种中枢细胞在健康发育的海马体中得到了证实，并且已经证明，对切片中的单个中枢细胞进行调节可以阻止整个网络的自发爆发活动。在这里，我们建议使用新颖的光遗传学方法选择性抑制体内癫痫成年小鼠的齿状回和内嗅皮质中的异常轮毂样细胞，以防止内嗅海马网络内的连合-关联和颞-氨通路过度激活，特别是在自发性复发性癫痫发作时。由于操作只会以时间选择性的方式影响整个边缘系统中的少数细胞，因此可以在对电路的正常信息处理影响最小的情况下实现有效的癫痫控制。如果成功，拟议的研究将展示一种全新的方法来实现癫痫治疗“无癫痫发作、无副作用”的目标。