Dissecting the Developmental and Epileptic Components of Encephalopathy in DEE

项目摘要/摘要 发育性和癫痫性脑病(DEE)、早期生活癫痫和智力障碍患者 残疾常常伴随着唤醒/睡眠、交流/社会互惠、 摄食和/或感觉整合。这些神经行为合并症被假设为反映了一种协同作用 两个相互独立但相互交织的过程：(I)能够自我改变的煽动性损害(遗传或结构) 神经发育轨迹，以及(2)频繁发作的时期，特别是在生命早期，这进一步 加剧发育迟缓。在许多患者中，行为恶化可能在癫痫发作之前就开始了。 尽管完全控制了癫痫发作(或自发缓解)，但仍可持续。通过对整个外显子组进行测序， 我们现在认识到，遗传死因的名单正在迅速扩大，这些基因死因为获得遗传信息的小鼠提供了便利 关键时刻准备开发急需的精确疗法的模型，这种疗法超越了癫痫发作 控制力。今天的模型正在积极地揭示对分子和电路级别的病理的新的机械洞察力。 生理学，由于基因组操作和组学测量的最新进展，功能 连通性和钙成像，以及啮齿类动物电-电子系统的持续人体工学改进。 脑电图术。相比之下，在临床前阶段，很少有技术和概念创新 神经行为损害的分析，使该领域依赖于可能被混淆的行为电池 由睡眠/觉醒、癫痫复发、运动缺陷和人类嗅觉干扰引起的原发障碍。在……里面 在这一应用中，我们应用了归位仪器和自动视频跟踪方面的最新进展 定义在免实验者条件下衍生的DeE相关神经行为障碍的终点 条件(远程行为遥测)。我们描述了一种早期生活癫痫发作的DeE小鼠模型 表现出以多动和失眠为核心特征的强健的多方面行为综合征。使用这个 模型系统，这一建议检验了遗传死亡的中心假设，即神经行为后果 致因性遗传损害的一部分可以与反复发作的早期生命癫痫的行为后遗症相分离。 在目标1中，我们检测了一种转录因子，这种转录因子在海马区被癫痫发作激活，这是已知的 塑造一系列的情感和认知行为。在目标2中，我们通过以下方式测试早期生命癫痫发作的重要性 比较早期和晚期基因消融的行为和癫痫后果。在《目标3》中，我们将 在我们的突变小鼠中，多动和失眠对原发干扰的5h超常活动节律，并进行了测试 无论是药物干预还是行为干预，以恢复超常节律，都能发挥治疗作用。在……里面 短期内，这些实验将建立分子和电路级别的洞察力，同时提供一系列新颖的 促进DIE模型中药物发现的神经行为终点。从长远来看，这项工作发展了 数字神经精神病学的临床前基础，其中行为健康的主观测量是 补充了连续的、可在现场穿戴的衍生终端，为临床试验和患者护理提供信息。

Project Summary/Abstract In patients with developmental and epileptic encephalopathies (DEEs), early life seizures and intellectual disability are frequently accompanied by disturbances in arousal/sleep, communication/social reciprocity, feeding and/or sensory integration. These neurobehavioral comorbidities are hypothesized to reflect a synergy of two independent but intertwined processes: (i) an inciting lesion (genetic or structural) capable of itself altering neurodevelopmental trajectories, and (ii) periods of frequent seizures, particularly early in life, that further exacerbate developmental delays. In many patients, behavioral deterioration may begin prior to seizure onset and may persist despite complete seizure control (or spontaneous remission). With whole exome sequencing, we now recognize a rapidly expanding list of genetic DEEs, which have lent to genetically informed mouse models that are critically poised to develop the urgently needed precision therapies that extend beyond seizure control. Today’s models are actively revealing novel mechanistic insights into molecular and circuit-level patho- physiology, thanks to the latest advances in genome manipulation and measurements of omics, functional connectivity and calcium imaging, as well as continued ergonomic improvements in rodent electro- encephalography. In contrast, there have been few technical and conceptual innovations within preclinical assays for neurobehavioral impairment, leaving the field reliant on behavioral batteries that may be confounded by primary disturbances in sleep/arousal, seizure recency, motor deficits and human olfactory interference. In this application, we apply the latest advances in homecage instrumentation and automated videotracking to define endpoints for DEE-related neurobehavioral impairment that are derived under experimenter-free conditions (remote behavioral telemetry). We describe a mouse model of DEE with early life seizures that displays a robust multifaceted behavioral syndrome with core features of hyperactivity and insomnia. Using this model system, this proposal tests the central hypothesis of genetic DEE, that the neurobehavioral consequences of the causative genetic lesion can be dissociated from the behavioral aftereffects of recurrent early life seizures. In Aim 1, we examine a transcription factor that is activated by seizures in the hippocampus, and which is known to shape a range of emotional and cognitive behaviors. In Aim 2, we test the importance of early life seizures by comparing behavioral and epileptic consequences of an early versus late genetic ablation. In Aim 3, we connect hyperactivity and insomnia in our mutant mice to primary disruptions in 5h ultradian rhythms of activity, and test whether pharmacological or behavioral interventions to restore ultradian rhythms exert therapeutic benefits. In the short term, these experiments will build molecular and circuit-level insights while delivering a set of novel neurobehavioral endpoints to facilitate drug discovery in DEE models. In the long term, this work develops the preclinical foundation for digital neuropsychiatry, where subjective measures of behavioral wellbeing are supplemented with continuous, in situ wearable-derived endpoints that inform clinical trials and patient care.