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 这项提案的总体目标是调查一种新的机制，突然意外死亡， 癫痫（SUDEP）。我们的实验室最近意外地发现， 过度活跃的压力电路表现出SUDEP的发病率增加，这一发现被证实是 在确诊或死亡的患者中观察到神经内分泌异常， 疑似SUDEP。考虑到压力和SUDEP都与中枢神经系统的破坏有关， 调节心肺功能，我们提出，夸大活动的中央应力电路上 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。下丘脑室旁核内的促肾上腺皮质激素释放激素神经元 (PVN)位于应力轴的顶点，并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 心肺反应的压力，使他们成为一个可能的驱动器心肺功能障碍有关， 中央应力轴过度兴奋，可能还有SUDEP。事实上，我们的初步数据表明， PVN-NTSCRH的化学发生活化增加SUDEP的发生率。当前应用程序将基于 Jamie Maguire和Carie Boychuk博士的专业知识，以检验HPA轴过度兴奋的假设， 慢性癫痫小鼠通过增加PVN-NTSCRH驱动增加SUDEP的风险， 心脏迷走神经输出在稳态挑战。我们将通过检查是否 存在与SUDEP风险相关的PVN-NTSCRH驱动增加，以及是否过度激活该 该途径足以增加SUDEP的发生率。我们将询问潜在的，新的病理生理学 机制介导过度活跃的压力电路对SUDEP风险的影响， 心迷走神经输出量最后，我们将调查是否与多动相关的环境因素， 应激回路，如慢性应激，可影响心脏迷走神经功能和SUDEP风险。此应用程序有 揭示导致SUDEP风险的新机制的可能性，这也可能与其他 突然死亡的形式。