Role of brainstem cardiorespiratory neurons in SUDEP

脑干心肺神经元在 SUDEP 中的作用

• 批准号: 10439312
• 负责人: MANOJ K PATEL
• 金额: $ 39.9万
• 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/10439312
• 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; Lead; Monitor; Motor Seizures; Mus; 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.

癫痫突然意外死亡（SUDEP）被定义为突然、意外且无法解释的死亡 癫痫病人的死亡。SUDEP占所有癫痫相关死亡的8%至17%， 50%的患者目前的治疗是无效的。在所有神经系统疾病中， 只会导致中风越来越多的证据支持呼吸暂停（呼吸停止）， 癫痫发作后死亡的主要原因据报道，呼吸暂停和氧饱和度下降，在一个大的 在惊厥发作期间和之后的患者百分比，以及通过监测的9例SUDEP病例中， 死亡时癫痫监测单元（EMU）中的视频EEG，均涉及呼吸骤停发生 终末心搏停止前（MORTEMUS研究）。更好地理解涉及的关键过程， 呼吸功能障碍和随后的SUDEP将允许开发新的救援疗法。 SUDEP发生在许多癫痫人群中。其中一个弱势群体是患有 SCN 8A癫痫性脑病（EE），NaV1.6钠通道功能获得性突变。 我们的小鼠模型含有在患有SUDEP的患者中发现的Scn 8a突变，并产生许多 患者的临床症状，包括自发性全身强直阵挛发作、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枢假设， 发作后呼吸停止时发生，由于持续的紧张性吸气活动， 呼吸恢复失败是由于心肺平衡受损。目标1：我们将确定 Bötzinger复合体（BötC）和后斜方核（RTN）脑干神经元在协调 使用光遗传学技术研究呼吸暂停期间的吸气活动。目的2：处于风险中的癫痫患者 SUDEP患者的中枢化疗敏感性受损。我们发现我们的SCN 8A EE小鼠也有受损的 中枢化学敏感性我们建议评估体内CO2敏感性的发展时间点，导致 SUDEP，并确定是否抑制钠通道（INa）电流可以拯救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，内在兴奋性和INa电流。 最后，我们将使用shRNA敲低RTN中的NaV1.6，并评估其对体内CO2- 敏感性和SUDEP。目的3：心脏控制受损是SUDEP的一个促成因素，我们发现， 心动过缓发生在SUDEP之前。我们将在体内确定副交感神经心脏驱动 导致SUDEP并确定INa抑制的效果。我们会记录副交感神经 心迷走神经元，并确定NaV1.6敲低对心动过缓和SUDEP的影响。这些 这些研究将显著影响我们目前对心肺功能改变的理解， SUDEP和可以提供重要的洞察新的治疗靶点，以防止SUDEP。