CRH dysregulation of brainstem autonomic circuits increases SUDEP risk

项目摘要 这项建议的首要目标是研究一种新的猝死机制。 癫痫(SUDEP)。我们的实验室最近有了一个意想不到的发现，通过基因工程改造的小鼠 过度活跃的应激回路显示出SUDEP的发生率增加，这一发现被证实是 确诊或死亡的患者中观察到的神经内分泌异常与翻译相关 疑似SUDEP。鉴于压力和SUDEP都与中央电路中断有关， 心肺功能的调节，我们认为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。下丘脑室旁核促肾上腺皮质激素释放激素(CRH)神经元 (PVN)位于应激轴的顶端，并直接投射到对自主神经调节至关重要的脑干区域， 包括孤束核(PVN-NTSCRH)。PVN-NTSCRH在整合 对压力的心肺反应，使它们可能是与以下相关的心肺功能障碍的驱动因素 中心应力轴过度兴奋，可能还有超感诱发电位。事实上，我们的初步数据表明， PVN-NTSCRH的化学激活增加了SUDEP的发生率。当前应用程序将构建在 Jamie Maguire博士和Carie Boychuk博士的专业知识，以检验HPA轴在 慢性癫痫小鼠通过PVN-NTSCRH驱动增加SUDEP的风险，夸大 稳态挑战时的心脏迷走神经输出量。我们将通过检验 存在与SUDEP风险相关的PVN-NTSCRH驱动器增加，以及这种过度激活 通路足以增加SUDEP的发生率。我们将询问潜在的，新的病理生理学 通过研究过度活跃应激回路对SUDEP风险的影响来调节其机制 心迷走神经输出量。最后，我们将调查环境因素是否与多动症有关。 应激回路，如慢性应激，会影响心脏迷走神经功能和SUDEP风险。此应用程序具有 发现导致SUDEP风险的新机制的可能性，这可能也与其他 各种形式的猝死。

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.