Sleep-Wake and Epilepsy Interactions in a Mouse Model of Temporal Lobe Epileps

颞叶癫痫小鼠模型中的睡眠-觉醒和癫痫相互作用

• 批准号: 10196519
• 负责人: Nigel Paul Pedersen
• 金额: $ 43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196519
• 关键词: Affect; Amygdaloid structure; Anatomy; Animal Model; Area; Arousal; Attention; Bilateral; Brain; Brain Stem; Cannulas; Cell Nucleus; Cells; Cellular Structures; Circadian Rhythms; Clinical; Data; Development; Electrodes; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Epilepsy; Epileptogenesis; Excessive Daytime Sleepiness; Foundations; Frequencies; Future; Glutamates; Goals; Head; Hippocampus (Brain); Histology; Human; Hypothalamic structure; Implant; Incidence; Juvenile Myoclonic Epilepsy; Kainic Acid; Lead; Ligands; Link; Medial; Mediating; Memory impairment; Microelectrodes; Microinjections; Modeling; Mood Disorders; Mus; Muscarinic Acetylcholine Receptor; Neurons; Operative Surgical Procedures; Pattern; Perfusion; Population; Pre-Clinical Model; Psychoses; Publishing; REM Sleep; Reporting; Research; Seizures; Severities; Skeletal muscle structure of neck; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Targeted Research; Temporal Lobe; Temporal Lobe Epilepsy; Time; Wakefulness; Work; base; cell type; circadian; comorbidity; experience; experimental study; frontal lobe; implantation; improved; inhibitory neuron; mouse model; neural circuit; novel; novel strategies; postoperative recovery; sleep abnormalities; sleep epilepsy; sleep regulation; sudden unexpected death in epilepsy; vector

PI: Pedersen R21 – June, 2020 PROJECT SUMMARY/ABSTRACT Epilepsy affects more than three million people in the US alone, with most reporting a relationship between seizures and sleep-wake patterns, and about one million having sleep disorders. Furthermore, many of the comorbidities of epilepsy, such as mood disorder, attentional and executive difficulties, memory dysfunction, and psychosis, are worsened by disrupted sleep. Despite this long-appreciated and robust relationship between sleep-wake and epilepsy, little is known about the underlying mechanisms of this interaction. The long-term objective of this work is to understand better key large-scale brain circuits, namely those that control sleep-wake and how they influence seizure frequency and severity. The overall hypothesis is that careful manipulations of component cell groups of sleep-wake circuits can be used to treat epilepsy and seizures, potentially including some comorbidities of epilepsy. We hypothesize, also based on preliminary findings, that the intra-amygdala kainic acid model of medial temporal lobe epilepsy in mice will show sleep disruptions that are similar to those of people with epilepsy. We further hypothesize that circuit-based manipulations of sleep-wake control circuits will have predictable effects on seizures, with increases in sleep reducing seizures and decreased sleep further worsening epilepsy. We examine these hypotheses in two Specific Aims using a novel purpose-build head plate that permits rapid implantation of microinjection cannula, screw, neck muscle, and depth electrodes in mice. The first Aim examines the mutual influence of sleep-wake and seizures in the mouse intra-amygdala kainic acid model of temporal lobe epilepsy. Preliminary data shows dramatic sleep disruption of sleep in mice with seizures and that seizures are associated with slow-wave sleep and rare in rapid eye movement sleep. The second Aim includes two experiments: One examines the effect of chemogenetically increasing sleep, by activating inhibitory neurons of the parafacial zone of the brainstem; the other activates a vital component of the hypothalamic arousal network, the supramammillary nucleus, that drives wake without sleep rebound. We anticipate that seizures will be reduced by increased sleep and worsened by prolonged wakefulness, respectively. This work Aims to provide a new line of research targeting other sleep-wake nuclei, a new avenue for epilepsy research that focuses on large-scale modulatory circuits and brings together sleep-wake and epilepsy research. We hope that this work will improve our understanding of brain function and help develop novel approaches to the treatment of epilepsy. 1

PI：Pedersen R21 - 2020年6月 项目摘要/摘要 仅在美国，癫痫就会影响超过300万人，大多数报告 癫痫发作和睡眠效果模式，大约有100万个患有睡眠障碍。此外，许多 癫痫的合并症，例如情绪障碍，注意力和执行困难，记忆功能障碍以及 精神病被破坏的睡眠遗忘。尽管存在这种长期以来的良好和牢固的关系 睡眠醒和癫痫病，对这种相互作用的基本机制知之甚少。长期 这项工作的目的是了解更好的关键大型大型脑电路，即控制睡眠效果的那些 以及它们如何影响癫痫发作的频率和严重程度。总体假设是对 睡眠觉醒电路的组成细胞组可用于治疗癫痫和癫痫发作，可能包括 癫痫的一些合并症。我们还基于初步发现，假设杏仁核内 小鼠内侧临时叶癫痫的海藻酸模型将显示与那些相似的睡眠干扰 有癫痫的人。我们进一步假设基于电路的睡眠效果控制电路的操作 会对癫痫发作产生可预测的影响，随着睡眠减少的癫痫发作和进一步的睡眠减少 恶化癫痫病。我们使用新颖的目的构建头板在两个特定的目标中检查了这些假设 这允许在小鼠中快速植入显微注射套管，螺钉，颈部肌肉和深度电极。这 首先要检查小鼠杏仁核内酸内酸的睡眠效果和癫痫发作的相互影响 临时叶癫痫的模型。初步数据显示，癫痫发作的小鼠睡眠急剧破坏 癫痫发作与慢波睡眠有关，在快速眼动睡眠中很少见。第二个目标 包括两个实验：一项检查通过激活抑制性化学上增加睡眠的影响 脑干瘫痪区的神经元；另一个激活下丘脑唤醒的重要组成部分 网络是超木核，它可以驱动唤醒而没有睡眠反弹。我们预计癫痫发作会 通过增加睡眠，分别通过长时间的清醒恶化来减少。这项工作旨在提供 针对其他睡眠核核的一系列新研究，这是一种癫痫研究的新途径，重点是 大规模调节电路，并将睡眠觉醒和癫痫研究融合在一起。我们希望这项工作 将提高我们对大脑功能的理解，并帮助开发新的癫痫治疗方法。 1

项目成果

Interfering with sleep apnea.

• DOI: 10.1186/s42234-023-00139-w
• 发表时间: 2024-01-24
• 期刊: Bioelectronic medicine
• 作者: Pedersen, Nigel Paul;Astorga, Raul Castillo
• 通讯作者: Astorga, Raul Castillo

Opening a conceptual space for metamemory experience.

为元记忆体验打开一个概念空间。

• DOI: 10.1016/j.newideapsych.2022.100995
• 发表时间: 2023
• 期刊: New ideas in psychology
• 影响因子: 2.6
• 作者: Neisser,Joseph;Abreu,George;Drane,DanielL;Pedersen,NigelP;Parsons,ThomasD;Cleary,AnneM
• 通讯作者: Cleary,AnneM