The role of brainstem projecting extended amygdala neurons in sudden unexpected death in epilepsy

脑干投射扩展杏仁核神经元在癫痫猝死中的作用

• 批准号: 10718024
• 负责人: William Paul Nobis
• 金额: $ 51.24万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718024
• 关键词: Acute; Amygdaloid structure; Apnea; Arousal; Brain Stem; Breathing; Cause of Death; Cell Nucleus; Central Sleep Apnea; Cessation of life; Chronic; Clinical; DBA/1 Mouse; Data; Development; Disease; Electric Stimulation; Electrocardiogram; Electrocorticogram; Electroencephalography; Electrophysiology (science); Epilepsy; Evaluation; FOS gene; Fiber; Foundations; Functional disorder; Future; Genetic; Genetic Recombination; Goals; Human; Hypoventilation; Impairment; Intervention; Intractable Epilepsy; Light; Maps; Medial; Mediating; Mediator; Mission; Modeling; Monitor; Mus; Myocardial dysfunction; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neurons; Neurosciences; Opioid; Opsin; Outcome; Outcome Study; Output; Patients; Pharmacologic Substance; Photometry; Physiologic Monitoring; Physiologic pulse; Pontine structure; Population; Pre-Clinical Model; Prosencephalon; Public Health; Research; Respiration Disorders; Risk; Role; Seizures; Structure; Structure of terminal stria nuclei of preoptic region; Sudden Death; Synapses; System; Techniques; Testing; Time; Translating; Ventilatory Depression; Viral; Whole Body Plethysmography; Work; audiogenic seizure; clinical translation; critical period; high risk; improved; in vivo; innovation; mortality; mouse model; nervous system disorder; neural circuit; neurophysiology; neuroregulation; novel; novel therapeutics; optogenetics; parabrachial nucleus; patch clamp; prevent; preventable epilepsy; respiratory; risk stratification; selective expression; sudden unexpected death in epilepsy; tool

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Currently, it is impossible to predict or prevent SUDEP. However, SUDEPs that have occurred in monitored settings were characterized by hypoventilation and apnea prior to cardiac dysfunction, implicating seizure-related respiratory dysfunction as a critical factor. Human intracranial data suggests the amygdala as a forebrain structure that may be important for respiratory control and involved in seizure-related respiratory dysfunction. Understanding the neural circuit mechanisms involving amygdalar structures that underlies seizure-related respiratory dysfunction that leads to hypoventilation and death is critical to advancing SUDEP prevention options, which currently do not exist. Our long-term goal is to identify the neural circuits underlying seizure-related respiratory dysfunction to predict and prevent sudden death. The main objective of the proposed project is to delineate brainstem projecting extended amygdalar neurons involved in seizure-related respiratory dysfunction and arrest. Preliminary data in a mouse model of SUDEP show that the extended amygdalar structure the bed nucleus of the stria terminalis (BNST) represents a potential mediator underlying seizure-related respiratory dysfunction. Our hypothesis is that BNST activation during seizures contributes to seizure-related respiratory dysfunction, respiratory arrest, and death via downstream activation in the parabrachial nucleus (PBN) of the pons. This hypothesis will be tested via the following specific aims in a model of SUDEP: (1) Characterize the role of BNST and BNSTPBN activation in respiratory dysfunction in a model of SUDEP. (2) Determine the effect of acute BNST inhibition on seizure-induced respiratory dysfunction in a model of SUDEP. In Aim 1, we will use a viral approach to selectively identify and dissect BNST neurons activated by seizures as well as determine the relationship between BNST activation and respiratory dysfunction during seizures. In Aim 2, we will use in vivo optogenetic inactivation of the BNST to determine the critical period of activity for respiratory depression and potential intervention. At the successful completion of the proposed research, the expected outcomes are characterization of seizure-activated BNST-brainstem circuitry and the temporal relationship of BNST activation to seizure-related respiratory dysfunction to determine sufficiency and the timepoint necessary for acute BNST activation in this effect. The proposed research is conceptually innovative through its focus on BNST circuitry in terms of SUDEP pathophysiology and technically innovative through the use of cutting-edge systems neuroscience techniques applied to SUDEP including fiber photometry, virally-mediated Targeted Recombination in Active Populations (TRAP) and in vivo optogenetics. These results are expected to have a significant impact on our current understanding of alterations of forebrain respiratory circuits that lead to SUDEP and will provide a strong basis for future development of novel therapeutics and clinical targets for neuromodulation to prevent SUDEP.

癫痫猝死(SUDEP)是难治性癫痫患者最常见的死亡原因 癫痫。目前，预测或预防SUDEP是不可能的。然而，已经发生的SUDEP 被监测的环境的特征是在心功能障碍之前出现低通气量和呼吸暂停，这表明 癫痫相关的呼吸功能障碍是一个关键因素。人类的颅内数据表明杏仁核是一种 可能对呼吸控制和癫痫相关呼吸起重要作用的前脑结构 功能障碍。了解杏仁核结构的神经回路机制 导致低通气量和死亡的癫痫相关呼吸功能障碍是SUDEP进展的关键 目前尚不存在的预防办法。我们的长期目标是确定潜在的神经回路 癫痫相关呼吸功能障碍预测和预防猝死。该计划的主要目标是 拟议的项目是描绘脑干投射延伸的杏仁核神经元，涉及癫痫相关 呼吸功能障碍和呼吸骤停。在SUDEP小鼠模型中的初步数据显示，扩展的 杏仁核终纹床核(BNST)是一种潜在的 癫痫相关的呼吸功能障碍。我们的假设是，癫痫发作期间BNST的激活有助于 癫痫相关的呼吸功能障碍、呼吸骤停和通过下游激活导致的死亡 桥臂旁核(PBN)。这一假设将通过以下具体目标在 SUDEP模型：(1)BNST和BNSTPBN激活在老年呼吸功能障碍中的作用 SUDEP的模型。(2)确定急性BNST抑制对癫痫所致呼吸功能障碍的影响 在SUDEP的模型中。在目标1中，我们将使用病毒方法选择性地识别和解剖BNST神经元 以及确定BNST激活与呼吸之间的关系 癫痫发作时的功能障碍。在目标2中，我们将使用体内BNST的光遗传失活来确定 呼吸抑制的活动关键期及可能的干预措施。在成功完成 建议的研究，预期的结果是癫痫激活的BNST-脑干的特征 BNST激活与癫痫相关呼吸功能障碍的回路和时间关系 确定BNST在这种作用下激活的充分性和所需时间点。建议数 这项研究在概念上是创新的，其重点是在SUDEP病理生理学方面的BNST回路 并通过使用尖端系统神经科学技术进行技术创新 SUDEP包括纤维光度法、病毒介导的活性种群中的靶向重组(TRAP)和 活体光遗传学。预计这些结果将对我们目前对 导致SUDEP的前脑呼吸回路的改变将为未来的研究提供强有力的基础 神经调节预防SUDEP的新疗法和临床靶点的开发。