Determining the shared neuronal network mechanisms of focal epileptic discharges and impaired memory processing in temporal lobe epilepsy

确定颞叶癫痫局灶性癫痫放电和记忆处理受损的共享神经元网络机制

• 批准号: 10734254
• 负责人: Laura Ewell
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734254
• 关键词: Acute; Affect; Animals; Area; Behavioral; Benchmarking; Cells; Chronic; Coupled; Data; Disease; Electrophysiology (science); Epilepsy; Genetic; Genetic Techniques; Hippocampus; Hour; Intervention; Knowledge; Laboratories; Location; Memory; Memory impairment; Microelectrodes; Monitor; Mus; National Institute of Neurological Disorders and Stroke; Nature; Neurologic; Neurons; Patients; Pattern; Performance; Phase; Physiological; Population; Public Health; Research; Seizures; Short-Term Memory; Sleep; Source; Synapses; Temporal Lobe Epilepsy; Testing; Work; comorbidity; density; experience; improved; in vivo; insight; kainate; long term memory; memory process; mouse model; neuromechanism; place fields; recruit; shared memory

ABSTRACT Memory impairment is a common and devastating comorbidity of temporal lobe epilepsy. The network mechanisms underlying memory impairments are poorly understood. Micro-electrode recordings from temporal lobe epilepsy patients reveal frequent focal epileptic discharges (FEDs) that are only detectable with invasive recordings. Preliminary studies performed in our laboratory in a chronic epileptic mouse model revealed that mice experience frequent FEDs while they performed a spatial working memory task. Intriguingly, FEDs occurred robustly at specific locations on the maze, where healthy hippocampus normally generates population activity (sharp wave ripples, SWR) necessary for working memory. These data support the overall hypothesis that the cellular networks that normally partake in memory processes are hi-jacked by FEDs. We will test this hypothesis with three aims. For Aim 1 we will perform large scale tetrode recordings from freely moving mice to test the hypothesis that neurons active during FEDs overlap with neurons active during working memory SWR (wm-SWRs). For Aim 2 we will combine high-density linear probe recordings and chemogenetic inhibition to test the hypothesis that FEDs are generated in the CA3 region of the hippocampus. Finally, in the same animals as used in Aims 1 and 2, we will perform multi-day 24-hour recordings to test the hypothesis that FEDS occurring during working memory share cellular and network mechanisms with the early phase of behavioral seizures. The proposed research could help fill vital gaps in our knowledge about focal epileptic discharges – both in terms of their mechanisms and how they impact memory processing. We hope to elucidate which neurons participate in them, develop selective interventions to inhibit them, and determine how they impact behavioral seizures.

抽象的 记忆障碍是颞叶癫痫的一种常见且具有破坏性的合并症。 人们对记忆损伤背后的机制知之甚少。 叶性癫痫患者表现出频繁的局灶性癫痫放电 (FED)，只有通过侵入性检查才能检测到 我们实验室对慢性癫痫小鼠模型进行的初步研究表明： 小鼠在执行空间工作记忆任务时会经历频繁的 FED。 在迷宫的特定位置强烈发生，健康的海马体通常在那里产生种群 工作记忆所需的活动（尖波波纹，SWR）这些数据支持总体假设。 通常参与内存处理的蜂窝网络被 FED 劫持了，我们将对此进行测试。 具有三个目标的假设。对于目标 1，我们将对自由移动的小鼠进行大规模四极记录。 检验 FED 期间活跃的神经元与工作记忆 SWR 期间活跃的神经元重叠的假设 (wm-SWR) 对于目标 2，我们将结合高密度线性探针记录和化学遗传学抑制 最后，检验 FED 在海马 CA3 区域产生的假设。 对于目标 1 和 2 中使用的动物，我们将进行多天 24 小时记录来检验以下假设： 工作记忆期间发生的 FEDS 与早期阶段共享细胞和网络机制 拟议的研究可以帮助填补我们对局灶性癫痫的认识的重要空白。 放电——无论是在它们的机制还是它们如何影响记忆处理方面。 阐明哪些神经元参与其中，制定选择性干预措施来抑制它们，并确定如何 它们会影响行为癫痫发作。