Role of brainstem cardiorespiratory neurons in SUDEP

脑干心肺神经元在 SUDEP 中的作用

• 批准号: 10763928
• 负责人: MANOJ K PATEL
• 金额: $ 8.33万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10763928
• 关键词: Address; Apnea; Benchmarking; Bradycardia; Brain Stem; Breathing; Carbon Dioxide; Cardiac; Cause of Death; Cell Nucleus; Cessation of life; Clinical; Complex; Development; Electroencephalography; Electrophysiology (science); Epilepsy; Failure; Heart Arrest; Homeostasis; Impairment; Monitor; Motor Seizures; Mus; Muscle; Mutation; National Institute of Neurological Disorders and Stroke; Neurologic; Neurons; Oxygen; Pathology; Patients; Persons; Phase; Population; Prevention strategy; Process; Recovery; Refractory; Reporting; Research; Respiration Disorders; Respiratory Diaphragm; Risk; Risk Factors; Role; SCN8A gene; Seizures; Sodium Channel; Stroke; Symptoms; Techniques; Testing; Time; Tonic - clonic seizures; Viral; Vulnerable Populations; cardiac pacing; clinically relevant; epileptic encephalopathies; expiration; gain of function mutation; heart function; in vivo; ineffective therapies; insight; knock-down; mortality; mouse model; neural circuit; neuroregulation; new therapeutic target; novel; novel therapeutics; optogenetics; patient population; prevent; respiratory; small hairpin RNA; sudden unexpected death in epilepsy; ventilation; years of life lost

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected, and unexplained death of a person with epilepsy. SUDEP accounts for between 8 and 17% of all epilepsy-related deaths, rising to 50% in patients for which current therapies are ineffective. Amongst all neurological conditions, it is second only to stroke for number of life-years lost. Increasing evidence supports apnea (breathing cessation) as the primary cause of death following a seizure. Apnea and oxygen desaturation have been reported in a large percentage of patients during and after convulsive seizures, and of the 9 SUDEP cases that were monitored by video-EEG in epilepsy monitoring units (EMUs) at the time of death, all involved respiratory arrest occurring before terminal asystole (MORTEMUS study). A better understanding of the key processes involved in respiratory dysfunction and subsequent SUDEP would allow for the development of novel rescue therapies. SUDEP occurs across numerous epilepsy populations. One such vulnerable population are patients with SCN8A epileptic encephalopathy (EE), who have a gain of function mutation in the NaV1.6 sodium channel. Our mice models harbor Scn8a mutations identified in patients that suffered SUDEP, and produce many of the clinical symptoms of the patients, including spontaneous generalized tonic-clonic seizures, apnea, and SUDEP. Using these clinically relevant mice models we will test our CENTRAL HYPOTHESIS that SUDEP occurs when breathing ceases after a seizure, as a result of constant tonic inspiratory activity, and failure of breathing recovery is due to impaired cardiorespiratory homeostasis. AIM 1: We will determine the role of the Bötzinger complex (BötC) and retrotrapezoid nucleus (RTN) brainstem neurons on coordinating inspiratory activity during seizure-induced apnea using optogenetic techniques. AIM 2: Epilepsy patients at risk for SUDEP have impaired central chemosensitivity. We show that our SCN8A EE mice also have impaired central chemosensitivity. We propose to assess in vivo CO2-sensitivity at developmental time points leading up to SUDEP and determine if inhibition of sodium channel (INa) currents can rescue CO2-sensitivity. We will determine changes in RTN neurons to determine their CO2/H+-sensitivity, intrinsic excitability, and INa currents. Finally, we will use shRNA to knockdown NaV1.6 in the RTN and assess its contribution to in vivo CO2- sensitivity and SUDEP. AIM 3: Impaired cardiac control is a contributor of SUDEP, and we find that bradycardia occurs immediately prior to SUDEP. We will determine in vivo parasympathetic cardiac drive leading up to SUDEP and determine effects of INa inhibition. We will make recordings from parasympathetic cardiovagal neurons and determine the effects of NaV1.6 knockdown on bradycardia and SUDEP. These studies will significantly impact our current understanding of the cardiorespiratory alterations that lead to SUDEP and could provide important insight into novel therapeutic targets to prevent SUDEP.

癫痫（SUDEP）突然出乎意料的死亡被定义为突然，意外且未知的 患有癫痫的人的死亡。 SUDEP占所有与癫痫有关的死亡的8％至17％，增加 当前疗法无效的患者中，至50％。在所有神经系统状况中，这是第二 只能让生命年的数量损失。越来越多的证据支持呼吸暂停（呼吸停止） 癫痫发作后的主要死亡原因。呼吸暂停和氧气死亡已在一个大的 抽搐性癫痫发作期间和之后的患者百分比，以及由9例SUDEP案件监测 癫痫监测单元（EMU）的视频EEG在死亡时，所有均涉及呼吸道停滞 终末疗法之前（Metemus研究）。更好地了解涉及的关键过程 呼吸功能障碍和随后的SUDEP将允许开发新的救援疗法。 SUDEP发生在众多癫痫群体中。这样一个脆弱的人口是患者 SCN8A癫痫性脑病（EE），在NAV1.6钠通道中具有功能突变。 我们的小鼠模型携带SCN8A突变，这些突变在患有SUDEP的患者中，并产生许多 患者的临床症状，包括自发的普遍性强调癫痫发作，呼吸暂停和 Sudep。使用这些临床相关的小鼠模型，我们将测试我们的中心假设 当癫痫发作后呼吸停止，由于持续的强调灵感活动而停止时，就会发生 呼吸恢复的失败是由于心肺稳态受损而导致的。目标1：我们将确定 Bötzinger络合物（Bötc）和逆转录核核（RTN）脑干神经元在协调中的作用 使用光遗传技术在癫痫发作诱导的呼吸暂停期间的励志活性。 AIM 2：处于危险的癫痫患者 因为SUDEP损害了中央化学敏感性。我们证明我们的SCN8A EE小鼠也有障碍 中央化学敏感性。我们建议在发育时间点评估体内二氧化碳的敏感性 为了确定并确定抑制钠通道（INA）电流是否可以挽救CO2敏感性。我们将 确定RTN神经元的变化，以确定其CO2/H+ - 敏感性，内在的刺激性和INA电流的变化。 最后，我们将使用shRNA在RTN中敲除NAV1.6，并评估其对体内CO2-的贡献。 灵敏度和sudep。 AIM 3：心脏控制受损是SUDEP的贡献，我们发现 心动过缓发生在Sudep之前。我们将确定体内副交感神经心脏驱动 导致SUDEP并确定INA抑制作用。我们将从副交感神经中做录音 心脏神经元并确定NAV1.6敲低对心动过缓和SUDEP的影响。这些 研究将显着影响我们当前对导致心肺改变的理解 Sudep并可以为防止SUDEP的新型治疗靶标提供重要的见解。