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

基本信息

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
项目类别：
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

项目摘要

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在因神经系统疾病导致的潜在寿命损失中，癫痫是仅次于中风的第二大疾病。已提出 SUDEP 的几种病因，包括心脏和疾病。另一个假设是癫痫发作会损害觉醒。与 SUDEP 特别相关的一种刺激是 CO2 在癫痫发作后升高。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相关。中枢性呼吸暂停和阻塞性呼吸暂停进一步恶化 CO2 的积累。唤醒被认为是另一种猝死实体（婴儿猝死）的病因学因素综合征，与 SUDEP 有许多相似之处，我们发现癫痫发作会损害 CO2 唤醒。癫痫发作的小鼠和那些死亡率没有特别高的小鼠是否属实。具有强 SUDEP 表型的小鼠模型尚不清楚，因此，我们本提案的目标是确定。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，我们将确定我们将重点关注毛果芸香碱-TLE 模型中 CO2 唤醒受损的程度。死于 SUDEP 的患者有 TLE 和 DS 模型，正如 DS 患者有我们还将确定这些人是否患有癫痫。在目标 2 中，我们将削弱 CO2 唤醒作为 SUDEP 风险的潜在、易于测量的生物标志物。确定通过纤维光度测定评估的唤醒系统组件的神经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在目标 3 中，我们将确定 CO2 唤醒的关键节点是否受到癫痫发作和癫痫的损害。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了直接的见解。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这些研究与 SUDEP 更加相关。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我们希望能够利用这些机制来识别高风险个体并减少死亡。远离这种毁灭性的疾病。