Administrative Supplement to Serotonergic circuit mechanisms in postictal recovery and arousal

摘要 癫痫猝死（SUDEP）是难治性癫痫患者死亡的主要原因。 癫痫SUDEP是仅次于中风的神经系统疾病潜在寿命损失年数， 重大公共卫生问题。已提出SUDEP的几种病因，包括心脏和 呼吸失调另一个假设是唤醒受损。癫痫发作会削弱性唤起。之间 唤醒刺激，可能与SUDEP特别相关的是CO2。缉获后二氧化碳上升， 是癫痫停止机制的一部分癫痫发作通常与发作期和发作后 中枢性和阻塞性呼吸暂停。呼吸暂停进一步加剧了二氧化碳的积累。CO2减值- 觉醒被认为是另一种猝死实体婴儿猝死的病因 综合征，与SUDEP有许多相似之处。我们发现癫痫发作损害了 癫痫初治小鼠和那些没有特别严重死亡率的小鼠。无论这是真的， 具有强SUDEP表型的小鼠模型是未知的。因此，我们在本提案中的目标是确定 不同睡眠状态下癫痫发作如何损害颞叶癫痫小鼠模型的CO2-觉醒 (TLE)和遗传性癫痫性脑病Dravet综合征（DS）。在目标1中，我们将确定 癫痫模型中CO2唤醒受损的程度。我们将重点研究匹罗卡品-TLE模型 许多死于SUDEP的患者患有TLE，而DS模型，DS患者有 不成比例的高SUDEP风险。我们还将确定是否只是癫痫在这些 模型削弱了CO2觉醒作为SUDEP风险的潜在易测量生物标志物。在目标2中， 确定是否神经元功能，通过纤维光度测定法评估，唤醒系统组件， 中缝背核和臂旁核，两个重要的贡献者的睡眠-觉醒调节 和二氧化碳唤醒的关键节点，被癫痫发作和癫痫损害。在目标3中，我们将确定 在癫痫发作之前，使用新型小鼠模型光遗传学刺激DS小鼠中的DRN-PBN回路 防止因中毒而导致的死亡，从而为可能的治疗措施提供直接见解。以来 使用的模型有已知的死亡率，我们将能够比较死亡小鼠之间的发现， 而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，可翻译的方法来确定收敛， 癫痫中CO2唤醒受损如何导致SUDEP的不同模型机制 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。

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.