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

PI：Pedersen R21 - 2020年6月 项目总结/摘要 仅在美国，癫痫就影响了300多万人，大多数人报告与癫痫有关。 癫痫发作和睡眠-觉醒模式，大约一百万人患有睡眠障碍。此外，许多 癫痫的合并症，如情绪障碍、注意力和执行困难、记忆功能障碍，以及 精神病，因睡眠中断而恶化。尽管这种长期受到赞赏和强大的关系， 睡眠-觉醒和癫痫，很少有人知道这种相互作用的潜在机制。长期 这项工作的目的是更好地了解关键的大规模大脑回路，即那些控制睡眠-觉醒的回路 以及它们如何影响癫痫发作的频率和严重程度。总的假设是， 睡眠-觉醒回路的组成细胞群可用于治疗癫痫和癫痫发作，可能包括 癫痫的一些合并症。我们假设，也是基于初步的发现，杏仁核内 在小鼠中的内侧颞叶癫痫的红藻氨酸模型将显示与那些类似的睡眠中断 癫痫患者的情况。我们进一步假设，基于电路的睡眠-觉醒控制电路的操作 将对癫痫发作产生可预测的影响，增加睡眠减少癫痫发作，进一步减少睡眠 癫痫恶化我们在两个特定目标中使用一种新型的专用头板来检验这些假设 其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。的 第一个目的研究小鼠杏仁核内海人酸对睡眠-觉醒和癫痫发作的相互影响 颞叶癫痫模型初步数据显示，癫痫发作小鼠的睡眠受到严重干扰 癫痫发作与慢波睡眠有关，在快速眼动睡眠中很少发生。第二个目的 包括两个实验：一个是通过激活抑制性细胞因子， 脑干面旁区的神经元;另一个激活下丘脑唤醒的重要组成部分 网络，乳头体上核，驱动清醒而无睡眠反弹。我们预计， 睡眠时间的增加会降低睡眠质量，而长时间的清醒会使睡眠质量恶化。这项工作旨在提供 一项针对其他睡眠-觉醒核的新研究，一条癫痫研究的新途径， 大规模的调制电路，并汇集了睡眠-觉醒和癫痫研究。我们希望这项工作 将提高我们对大脑功能的理解，并有助于开发治疗癫痫的新方法。 1

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