Mechanisms underlying continuous spike-waves during slow-wave sleep in a mouse model of focal cortical dysplasia

 描述(由申请人提供)：该研究项目的长期目标是了解睡眠、远程感觉运动回路和癫痫回路之间与局灶性皮质发育不良(FCD)小鼠模型相关的更广泛的关系。FCD和相关的皮质发育畸形(MCDs)与儿童癫痫综合征和认知障碍高度相关。MCD是医学上难治性癫痫的一个日益公认的原因。更有效的治疗方法的开发将得益于对动物模型癫痫发生的病理生理学和机制的深入了解。我们将研究S1(SFFLS1R)治疗小鼠的单侧单一局灶性新生冰冻损伤的远程感觉运动回路特性。在目标1中，我们将获得SFFLS1R小鼠的24小时脑电数据，以验证我们的初步发现，即这些动物在慢波睡眠(CSWS)癫痫样放电过程中出现连续的棘波。CSWS是一种人类癫痫综合征，与慢波睡眠期间癫痫持续状态(ESES)的脑电模式有关。然后，我们将检验在发作前状态(即潜伏期)，异常发作前放电(APD)先于CSWS活动，并是同一动物CSWS癫痫发作严重程度的生物标志物的观点。在目标2中，我们将检验这一假设，即除了局部回路外，还需要大规模重组远程感觉运动和皮质丘脑回路，以支持SFFLS1R动物的全身性APDS和CSW。我们将结合小鼠遗传学和ChR2辅助电路映射(CRACM)方法来表征畸形S1中远程与局部抑制性皮质回路的非适应性重组。在目标3中，我们将进一步使用补充方法来测试SFFLS1R小鼠的阵发性癫痫样放电是由作用于其体内畸形S1靶点的长程回路介导的这一想法。我们将首先使用光学和化学遗传学工具来操纵体内的电路组件，以演示CSWS癫痫发作是否以及在多大程度上受到某些电路组件的激活/失活的调节。然后，我们将利用修改后的丰富环境来确定潜伏期内感觉经验是否以及在多大程度上调节了CSWS癫痫发作。在这个项目成功完成后，我们可以在小鼠模型中将慢性自发性CSWS/ESES癫痫发作与FCD联系起来。本项目成功完成后，我们可以将长程回路的动态变化与细胞发生联系起来，这将指导我们理解丘脑皮质回路在病理状态下存在动态双稳态的原因。了解正常睡眠和感觉运动回路转化为癫痫回路的机制将有助于开发与CSWS/ESES和FCDS/MCDs相关的基于回路的治疗策略。慢性FCD动物模型可能被用于开发基于行为的治疗方法，并为与ESES、MCD癫痫相关的新疗法筛选药物靶点。

 DESCRIPTION (provided by applicant): The long-term goal of this research project is to gain an understanding of the broader relationship between sleep, long-range sensorimotor circuits, and epilepsy circuits associated with a mouse model of focal cortical dysplasia (FCD). FCD and related malformations of cortical development (MCDs) are highly correlated with childhood seizure syndromes and cognitive disabilities. MCDs represent an increasingly recognized cause of medically intractable epilepsy. The development of more effective therapies will benefit from a deeper understanding of the pathophysiology and mechanisms of epileptogenesis in animal models. We will study long-range sensorimotor circuit properties in a unilateral single focal neonatal freeze lesion in S1 (SFFLS1R) treated mice. In Aim 1, we will obtain 24-hour EEG data from SFFLS1R mice to validate our preliminary finding that these animals developed continuous spike-waves during slow-wave sleep (CSWS) epileptiform discharges. CSWS is a human epileptic syndrome that is associated with the EEG pattern of electrical status epilepticus during slow wave sleep (ESES). We will then examine the idea that during the pre-ictal state (i.e. latent period), abnormal pre-ictal discharges (APDs) precede CSWS activity and are a biomarker for the severity of CSWS seizures in the same animals. In Aim 2, we will examine the hypothesis that large scale reorganization of long-range sensorimotor and corticothalamic circuits, in addition to local circuits, is required to support generalized APDs and CSWS in SFFLS1R animals. We will combine mouse genetics and the ChR2-assistant circuit mapping (CRACM) approach to characterize the maladaptive reorganization of long- range vs. local inhibitory cortical circuits in the malformed S1. In Aim 3, we will further use complementary approaches to test the idea that paroxysmal epileptiform discharges in SFFLS1R mice are mediated by long- range circuits acting on their targets in the malformed S1 in vivo. We will first use opto- and chemo-genetics tools to manipulate circuit components in vivo to demonstrate whether and to what extent CSWS seizures are modulated by activation/inactivation of certain circuit components. We will then take advantage of the modified enriched environment to determine whether and to what extent CSWS seizures are modulated by sensory experiences during the latent period. Upon successful completion of this project, we can associate chronic spontaneous CSWS/ESES seizures with FCD in a mouse model. Upon successful completion of this project, we can link dynamic changes of long-range circuits with ictogenesis, which will guide our understanding of why dynamic bistability exists in thalamocortical circuits in the pathological state. Understanding the mechanisms by which normal sleeping and sensorimotor circuits are transformed into epileptic circuits will help develop circuit-based treatment strategies for intractable epilepsy associated with CSWS/ESES and FCDs/MCDs. The chronic FCD animal model can potentially be used to develop behavior- based therapies and screen drug targets for novel therapies related to ESES, MCD epilepsy.