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

• 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
• 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

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.

项目摘要 该提议的总体目标是调查一种新的机制，以实现突然出乎意料的死亡的新机制 癫痫（SUDEP）。我们的实验室最近提出了一个意外发现，即小鼠为 多动应力电路表现出增加的SUDEP的发生率，这一发现已被证实为 死于确认或 怀疑的Sudep。鉴于压力和SUDEP与负责的中央电路的破坏联系在一起 心肺功能的调节，我们提出夸张的中央应力电路的活性 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。皮质激素释放激素（CRH）神经元在下丘脑的室室核中 （PVN）位于应力轴的顶点，直接投射到对自主神经调节至关重要的脑干区域， 包括孤立道的核（PVN-NTSCRH）。 PVN-NTSCRH在整合中具有完善的作用 心肺对压力的反应，使其成为与心脏呼吸功能障碍的驱动力相关的 中央应力轴过度刺激性，并可能是Sudep。实际上，我们的初步数据表明 PVN-NTSCRH的化学发生激活增加了SUDEP的发病率。当前的应用程序将建立在 博士的专业知识。杰米·马奎尔（Jamie Maguire）和卡里·博伊奇克（Carie Boychuk 长期癫痫小鼠通过增加的PVN-NTSCRH驱动器增加了SUDEP的风险，夸大了 在稳态挑战期间的心脏迷走神经输出。我们将通过研究是否是否 与SUDEP风险相关的PVN-NTSCRH驱动器增加以及是否过度激活 途径足以增加SUDEP的发生率。我们将询问潜力，新的病理生理学 通过检查对SUDEP风险的影响的机制，通过检查对SUDEP风险的影响 心迷走式输出。最后，我们将调查是否与多动性相关的环境因素 压力电路（例如慢性压力）会影响心迷走功能和SUDEP风险。该应用程序具有 发现有助于SUDEP风险的新型机制的潜力，这也可能与其他机制有关 突然死亡的形式。