Serotonergic circuit mechanisms in postictal recovery and arousal

摘要 癫痫猝死(SUDEP)是难治性癫痫患者的主要死亡原因 癫痫。在因神经系统疾病而失去的潜在寿命中，SUDEP仅次于中风，是一种 重大的公共卫生问题。SUDEP的几种病因已被提出，包括心脏病和 呼吸失调。另一种假设是唤醒功能受损。癫痫发作会损害觉醒。其中 唤醒刺激，可能与SUDEP特别相关的是二氧化碳。癫痫发作后二氧化碳上升 是癫痫停止机制的一部分。癫痫发作常常与发作期和发作后有关。 中枢性和阻塞性呼吸暂停。呼吸暂停会进一步加剧二氧化碳的积累。二氧化碳的损害- 唤醒被认为是另一种猝死的病因，即婴儿猝死。 综合症，它与SUDEP有许多相似之处。我们发现癫痫发作会损害大脑中的二氧化碳觉醒。 癫痫发作幼稚的老鼠和那些没有特别严重死亡率的老鼠。这在中国是否属实 具有强烈SUDEP表型的小鼠模型尚不清楚。因此，我们在这项提案中的目标是确定 不同睡眠状态下癫痫发作对小鼠颞叶癫痫模型二氧化碳觉醒的影响 (TLE)和遗传性癫痫脑病，Drave氏综合征(DS)。在目标1中，我们将确定 癫痫模型中二氧化碳唤醒受损的程度。我们将重点介绍匹罗卡品-TLE模型 由于许多死于SUDEP的患者有TLE，而DS模型，因为DS患者有一个 超高的SUDEP风险。我们还将确定这些患者是否患有简单的癫痫 模型损害了二氧化碳唤醒作为潜在的、容易测量的SUDEP风险的生物标志物。在《目标2》中我们将 确定通过纤维光度法评估的唤醒系统组件的神经元功能是否在 中缝背核和臂旁核是睡眠-觉醒调节的两个重要组成部分 以及二氧化碳唤醒中的关键节点，会因癫痫发作和癫痫而受损。在目标3中，我们将确定 在癫痫发作前，使用一种新的小鼠模型，在DS小鼠中采用光遗传刺激DRN-PBN回路 预防癫痫导致的死亡为可能的治疗措施提供了直接的见解。自.以来 使用的模型已经知道死亡率，我们将能够比较死亡的小鼠之间的结果 以及那些幸存下来的人，使这些研究与SUDEP更相关。将这些发现与我们的 以前的工作，我们将有一个强大的，严格的，可翻译的方法来识别收敛和 癫痫患者二氧化碳觉醒受损对SUDEP影响的不同模型间的机制差异 风险。我们希望能够利用这些机制来识别高危个体并减少死亡 从这种毁灭性的疾病中。

ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP is second only to stroke in years of potential life lost to neurological disease and is a major public health problem. Several etiologies have been proposed for SUDEP including cardiac and respiratory dysregulation. Another that is postulated is impaired arousal. Seizures impair arousal. Among arousal stimuli, one that may be particularly relevant to SUDEP is CO2. CO2 rises following seizures and is part of the seizure cessation mechanism. Seizures are frequently associated with ictal and post-ictal central and obstructive apneas. Apnea further exacerbates the accumulation of CO2. Impairment of CO2- arousal is proposed as an etiological factor in another sudden death entity, sudden infant death syndrome, which has many parallels with SUDEP. We discovered that seizures impaired CO2-arousal in seizure naïve mice and those that do not have a particularly profound death rate. Whether this is true in mouse models with strong SUDEP phenotypes is unknown. Thus, our goal in this proposal is to determine how seizures in different sleep states impair CO2-arousal in mouse models of temporal lobe epilepsy (TLE) and the genetic epileptic encephalopathy, Dravet Syndrome (DS). In Aim 1 we will determine the extent to which CO2-arousal is impaired in epilepsy models. We will focus on the pilocarpine-TLE model as many patients that die of SUDEP have TLE, and the DS model, as patients with DS have a disproportionately high SUDEP risk. We will also determine whether simply having epilepsy in these models impairs CO2-arousal as a potential easily measurable biomarker for SUDEP risk. In Aim 2 we will determine whether neuronal function, assessed via fiber photometry, of arousal system components in the dorsal raphe nucleus and parabrachial nucleus, two important contributors to sleep-wake regulation and key nodes in CO2-arousal, is impaired by seizures and epilepsy. In Aim 3 we will determine whether optogenetically stimulating a DRN-PBN circuit in DS mice, using a novel mouse model, prior to seizures prevents seizure-induced death lending direct insights into possible therapeutic measures. Since the models employed have known death rates, we will be able to compare findings between mice that die and those that survive making these studies more relevant to SUDEP. Combining these findings with our previous work, we will have a powerful, rigorous, translatable approach to identify convergent and divergent mechanisms across models for how impaired CO2-arousal in epilepsy contributes to SUDEP risk. We expect to be able to leverage these mechanisms to identify at-risk individuals and reduce death from this devastating disease.