Administrative Supplement to Serotonergic circuit mechanisms in postictal recovery and arousal

发作后恢复和唤醒过程中血清素回路机制的行政补充

• 批准号: 10841319
• 负责人: Gordon Frank Buchanan
• 金额: $ 2.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10841319
• 关键词: Acute; Administrative Supplement; Animal Model; Animals; Apnea; Arousal; Biological Markers; Carbon Dioxide; Cardiac; Cause of Death; Cell Nucleus; Cessation of life; Confusion; Conscious; Data; Death Rate; Detection; Disease; Electrocardiogram; Electroencephalography; Epilepsy; Etiology; Fiber; Genetic; Goals; Impairment; Individual; Intervention; Intractable Epilepsy; Life; Link; Measurable; Measurement; Measures; Methods; Modeling; Morbidity - disease rate; Mus; Neurons; Outcome; Pathway interactions; Patients; Phenotype; Photometry; Pilocarpine; Public Health; Publishing; Recovery; Regulation; Research; Risk; Risk Marker; Role; Seizures; Serotonin; Sleep; Status Epilepticus; Stimulus; Stroke; Stupor; Sudden Death; Sudden infant death syndrome; Symptoms; System; Temporal Lobe Epilepsy; Testing; Therapeutic; Wakefulness; Work; chemical reduction; dorsal raphe nucleus; dravet syndrome; epileptic encephalopathies; experimental study; insight; mortality; mouse model; nervous system disorder; novel; optogenetics; parabrachial nucleus; prevent; preventive intervention; prophylactic; respiratory; response; risk stratification; societal costs; sudden unexpected death in epilepsy

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.

抽象的 癫痫猝死（SUDEP）是难治性癫痫患者死亡的主要原因 癫痫。在因神经系统疾病导致的潜在寿命损失中，SUDEP 仅次于中风，是一种 重大公共卫生问题。 SUDEP 的多种病因已被提出，包括心脏和 呼吸失调。另一个假设是觉醒受损。癫痫发作会损害觉醒。之中 与 SUDEP 特别相关的一种唤醒刺激是 CO2。癫痫发作后二氧化碳浓度升高 是癫痫发作停止机制的一部分。癫痫发作通常与发作期和发作后有关 中枢性呼吸暂停和阻塞性呼吸暂停。呼吸暂停进一步加剧二氧化碳的积累。 CO2-的损害 唤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。我们发现癫痫发作会损害 CO2 唤醒 未发生癫痫发作的小鼠和那些死亡率不是特别高的小鼠。这是否属实 具有强 SUDEP 表型的小鼠模型尚不清楚。因此，我们在本提案中的目标是确定 不同睡眠状态下的癫痫发作如何损害颞叶癫痫小鼠模型中的二氧化碳唤醒 (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。我们将重点关注毛果芸香碱-TLE 模型 死于 SUDEP 的患者有 TLE 和 DS 模型，正如 DS 患者有 SUDEP 风险过高。我们还将确定这些患者是否患有癫痫症 模型削弱了 CO2 唤醒作为 SUDEP 风险的潜在、易于测量的生物标志物。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 中缝背核和臂旁核，睡眠-觉醒调节的两个重要贡献者 和二氧化碳唤醒的关键节点，会因癫痫发作和癫痫而受损。在目标 3 中，我们将确定是否 在癫痫发作之前，使用一种新型小鼠模型对 DS 小鼠中的 DRN-PBN 回路进行光遗传学刺激 预防癫痫引起的死亡，为可能的治疗措施提供直接见解。自从 使用的模型已经知道死亡率，我们将能够比较死亡小鼠之间的结果 那些幸存下来的研究使得这些研究与 SUDEP 更加相关。将这些发现与我们的相结合 在之前的工作中，我们将有一个强大的、严格的、可翻译的方法来识别收敛和 癫痫中 CO2 唤醒受损如何导致 SUDEP 的不同模型存在不同机制 风险。我们希望能够利用这些机制来识别高危人群并减少死亡 远离这种毁灭性的疾病。