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.

摘要 记忆障碍是颞叶癫痫常见且严重的共病。网络 记忆损伤的潜在机制还知之甚少。来自时间的微电极记录 额叶癫痫患者表现出频繁的局灶性癫痫放电(FED)，只有侵入性的才能检测到。 录音。我们实验室在慢性癫痫小鼠模型上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。有趣的是，联邦调查局 发生在迷宫上的特定位置，健康的海马体通常在那里产生种群 工作记忆所必需的活动(尖锐的波纹，SWR)。这些数据支持总体假设 通常参与记忆过程的蜂窝网络被联邦调查局劫持。我们将对此进行测试 有三个目的的假设。对于目标1，我们将执行大规模四极管记录，从自由移动的小鼠到 检验FED中活跃的神经元与工作记忆SWR中活跃的神经元重叠的假设 (WM-SWRS)。对于目标2，我们将结合高密度线性探针记录和化学发生抑制来 测试在海马区CA3区产生FED的假设。最后，在相同的 在AIMS 1和AIMS 2中使用的动物，我们将进行多天24小时录音，以检验假设 在工作记忆过程中发生的FED与早期阶段的细胞和网络机制相同 行为性癫痫。这项拟议的研究可能有助于填补我们对局灶性癫痫知识的重大空白 放电--从它们的机制和它们如何影响记忆处理的角度来看。我们希望 阐明哪些神经元参与其中，开发选择性干预措施来抑制它们，并确定如何 它们会影响行为发作。