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

基本信息

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
项目类别：
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

项目摘要

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目前，无法预测或预防 SUDEP，但 SUDEP 已发生在癫痫病中。监测环境的特点是在心功能不全之前出现通气不足和呼吸暂停，这意味着癫痫相关的呼吸功能障碍是一个关键因素。人类颅内数据表明杏仁核是一个关键因素。前脑结构可能对呼吸控制很重要，并参与癫痫相关的呼吸了解涉及杏仁核结构的神经回路机制。癫痫相关的呼吸功能障碍会导致通气不足和死亡，这对于推进 SUDEP 至关重要预防方案目前尚不存在，我们的长期目标是确定潜在的神经回路。癫痫相关的呼吸功能障碍是预测和预防猝死的主要目标。拟议的项目是描绘参与癫痫相关的脑干投射扩展杏仁核神经元 SUDEP 小鼠模型的初步数据显示，呼吸功能障碍和呼吸停止。杏仁核结构终纹床核 (BNST) 代表潜在的介质我们的假设是癫痫发作期间 BNST 激活会导致癫痫发作相关的呼吸功能障碍。癫痫相关的呼吸功能障碍、呼吸停止和通过下游激活而死亡脑桥臂旁核（PBN）将通过以下具体目标进行检验。 SUDEP 模型：(1) 描述 BNST 和 BNSTPBN 激活在呼吸功能障碍中的作用 (2)确定急性BNST抑制对癫痫引起的呼吸功能障碍的影响。在 SUDEP 模型中，我们将使用病毒方法来选择性识别和剖析 BNST 神经元。癫痫发作激活以及确定 BNST 激活与呼吸之间的关系在目标 2 中，我们将使用 BNST 的体内光遗传学失活来确定癫痫发作期间的功能障碍。呼吸抑制和潜在干预活动的关键时期。拟议的研究，预期结果是癫痫激活的 BNST 脑干的表征 BNST 激活与癫痫相关呼吸功能障碍的电路和时间关系确定在此效应中急性 BNST 激活的充分性和所需的时间点。研究在 SUDEP 病理生理学方面重点关注 BNST 电路，在概念上具有创新性通过使用尖端系统神经科学技术进行技术创新 SUDEP 包括纤维光度测定、病毒介导的活性群体靶向重组 (TRAP) 和这些结果预计将对我们目前对光遗传学的理解产生重大影响。前脑呼吸回路的改变导致 SUDEP 并将为未来提供坚实的基础开发用于预防 SUDEP 的神经调节治疗小说和临床靶点。