CRH dysregulation of brainstem autonomic circuits increases SUDEP risk

脑干自主回路的 CRH 失调会增加 SUDEP 风险

基本信息

批准号：
10607623
负责人：
Jamie Lynn Maguire
金额：
$ 62.03万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607623
关键词：
Apical Apnea Autonomic Dysfunction Behavioral Biological Markers Brain Stem Cardiac Cardiovascular system Chronic Chronic stress Corticotropin-Releasing Hormone Data Electrophysiology (science)Environmental Risk Factor Epilepsy Exhibits Functional disorder Genetic Genetically Engineered Mouse Heart Arrest Heart Rate Hyperactivity Hypothalamic structure Impairment Incidence Injections Laboratories Link Lung Mediating Methods Modeling Motor Motor output Mus Neurons Neurosecretory Systems Nucleus solitarius Output Pathway interactions Patients Physiology Radio Reflex action Regulation Risk Role Seizures Sensory Stress Sudden Death Tachycardia Telemetry Testing Therapeutic Whole Body Plethysmography comorbidity genetic approach hypothalamic-pituitary-adrenal axis innovation novel paraventricular nucleus pharmacologic respiratory response sudden unexpected death in epilepsy

项目摘要

Project Summary The overarching objective of this proposal is to investigate a novel mechanism for sudden unexpected death in epilepsy (SUDEP). Our laboratory recently made the unexpected discovery that mice genetically engineered for hyperactive stress circuits exhibit an increased incidence of SUDEP, a finding that was verified to be translationally relevant from observed neuroendocrine abnormalities in patients that died of confirmed or suspected SUDEP. Given that both stress and SUDEP link to disruption of central circuits responsible for the regulation of cardiorespiratory function, we propose that exaggerated activity of central stress circuits on downstream brainstem autonomic control centers represents a novel mechanism contributing to increased SUDEP risk. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are at the apex of the stress axis and project directly to brainstem regions critical for autonomic regulation, including the nucleus of the solitary tract (PVN-NTSCRH). PVN-NTSCRH has a well-established role in integrating cardiorespiratory responses to stress, making them a likely driver of cardiorespiratory dysfunction related to central stress axis hyperexcitability and, potentially, SUDEP. In fact, our preliminary data demonstrate that chemogenetic activation of PVN-NTSCRH increases SUDEP incidence. The current application will build on the expertise of, Drs. Jamie Maguire and Carie Boychuk, to test the hypothesis that HPA axis hyperexcitability in chronically epileptic mice increases the risk for SUDEP through increased PVN-NTSCRH drive, exaggerating cardiac vagal output during homeostatic challenges. We will investigate this hypothesis by examining whether there is increased PVN-NTSCRH drive associated with SUDEP risk and whether excessive activation of this pathway is sufficient to increase SUDEP incidence. We will interrogate potential, novel pathophysiological mechanisms mediating the impact of hyperactive stress circuits on SUDEP risk by examining the impact on cardiac vagal output. Finally, we will investigate whether environmental factors associated with hyperactive stress circuits, such as chronic stress, can impact cardiac vagal function and SUDEP risk. This application has the potential to uncover a novel mechanism contributing to SUDEP risk, which may also be relevant to other forms of sudden death.

项目概要该提案的首要目标是研究一种导致意外死亡的新机制癫痫（SUDEP）。我们的实验室最近有了一个意想不到的发现，小鼠经过基因改造过度活跃的应激回路表现出 SUDEP 发生率增加，这一发现已被证实在死于确诊或死亡的患者中观察到的神经内分泌异常具有转化相关性怀疑是SUDEP。鉴于压力和 SUDEP 都与负责心肺功能的调节，我们建议中枢应激回路的过度活动下游脑干自主控制中心代表了一种新的机制，有助于增加 SUDEP 风险。下丘脑室旁核中的促肾上腺皮质激素释放激素 (CRH) 神经元 (PVN) 位于压力轴的顶点，直接投射到对自主调节至关重要的脑干区域，包括孤束核（PVN-NTSCRH）。 PVN-NTSCRH 在整合方面具有明确的作用心肺对压力的反应，使它们成为与以下相关的心肺功能障碍的可能驱动因素中枢应力轴过度兴奋，以及潜在的 SUDEP。事实上，我们的初步数据表明 PVN-NTSCRH 的化学遗传学激活会增加 SUDEP 的发生率。当前的应用程序将建立在博士的专业知识。 Jamie Maguire 和 Carie Boychuk，检验 HPA 轴过度兴奋的假设慢性癫痫小鼠通过增加 PVN-NTSCRH 驱动来增加 SUDEP 的风险，夸大稳态挑战期间的心脏迷走神经输出。我们将通过检验是否与 SUDEP 风险相关的 PVN-NTSCRH 驱动增加，以及该驱动是否过度激活途径足以增加 SUDEP 的发生率。我们将探究潜在的、新颖的病理生理学通过检查对 SUDEP 风险的影响来调节过度活跃的应激回路对 SUDEP 风险影响的机制心脏迷走神经输出。最后，我们将研究环境因素是否与多动有关压力回路，例如慢性压力，会影响心脏迷走神经功能和 SUDEP 风险。这个应用程序有有可能发现导致 SUDEP 风险的新机制，这也可能与其他相关猝死的形式。