The neural circuitry of seizure-induced apnea and SUDEP

癫痫发作引起的呼吸暂停和 SUDEP 的神经回路

基本信息

  • 批准号:
    10719519
  • 负责人:
  • 金额:
    $ 40.38万
  • 依托单位:
  • 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:
    2023-06-01 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

Sudden Unexpected Death in Epilepsy (SUDEP) accounts for up to 17% of all epilepsy-related deaths, and 50% for those refractory to treatment. There is increasing evidence that apnea (respiratory arrest) is the primary cause of death from SUDEP. We have shown in a number of mouse models - including PTZ injection, rapid kindling (prelim. data), and mouse models harboring Scn8a mutations identified from SUDEP patients - that sudden death is due to seizure-induced apnea (SIA) that occurs during tonic seizures, minutes prior to terminal asystole. As it pertains to this proposal, we have also made four other important observations: 1) artificial ventilation can prevent death and suppressed cardiac activity does not increase likelihood of fatality; 2) tonic contraction of breathing muscles represents a likely mechanism of SIA; 3) inhibition of cortical seizure activity does not impact SIA; and 4) inhibition of the inspiratory oscillator does not reduce apnea (prelim. data), suggesting seizure spread bypasses homeostatic elements of respiratory control circuitry. CENTRAL HYPOTHESIS: [AIM 1] Increased midbrain and pontine excitability is both necessary and sufficient to produce SIA, [AIM 2] the parabrachial/kölliker fuse (PB/KF) nucleus in the pons represents a key nodal point for SIA generation, and [AIM 3] that brainstem nuclei, like the PB/KF and PAG are recruited specifically during SIA, which we will explore using electrophysiology and genetic mapping. AIM 1: We have previously used chemogenetics to demonstrate that cortical ictal activity is not required for SIA and we now propose that hyperexcitability of the pons and midbrain drive SIA and SUDEP. We will use chemogenetics to inhibit different parts of the brainstem of Scn8a mutant mice to test their necessity for SIA and SUDEP. Additionally, we will test sufficiency of these regions by selectively expressing an Scn8a mutation that increases neuronal excitability. Using the rapid kindling model, we will also perform patch clamp recordings to test whether increased neuronal excitability in these regions occurs concurrently with the development of SIA. AIM 2: The parabrachial/kölliker fuse nucleus PB/KF in the Pons is a key nodal point for descending forebrain input and projects past the inspiratory oscillator, and is modulated by the vagus nerve. In this aim, we will photoinhibit the Foxp2-positive PB/KF neurons to regain normal breathing pattern during SIA, photostimulate P2ry1-positive vagal afferent nerve fibers to interrupt inspiration during SIA, and determine if PB/KF and Npy2r-positive vagal neuron photostimulation rescues postictal breathing in our PTZ SUDEP mouse model. AIM 3: We have demonstrated that tonic seizures with SIA and clonic seizures without SIA can occur in the very same mouse, both in Scn8a mutant and rapid kindling models (prelim. data) and that certain mid- and hindbrain structures are activated during SIA. We will determine the neuronal circuitry activated specifically during SIA and SUDEP using in vivo electrophysiology and TRAP2 identification of activated neurons.
癫痫猝死 (SUDEP) 占所有癫痫相关死亡的 17%,并且 对于那些难治性治疗的患者,50%。越来越多的证据表明呼吸暂停(呼吸停止)是 SUDEP 死亡的主要原因。我们已经在许多小鼠模型中展示了 - 包括 PTZ 注射, 快速点燃(初步数据),以及从 SUDEP 患者中鉴定出的含有 Scn8a 突变的小鼠模型 - 猝死是由于强直性癫痫发作期间发生的癫痫发作引起的呼吸暂停(SIA)造成的,几分钟前 至心搏停止末期。就该提案而言,我们还提出了其他四项重要意见: 1) 人工通气可以预防死亡,抑制心脏活动不会增加死亡的可能性; 2) 呼吸肌的强直收缩是 SIA 的一种可能机制; 3)抑制皮质癫痫发作 活动不会影响 SIA; 4) 抑制吸气振荡器不会减少呼吸暂停(初步数据), 表明癫痫发作绕过了呼吸控制回路的稳态元件。中央 假设:[目标 1] 中脑和脑桥兴奋性的增加对于 产生 SIA,[AIM 2] 脑桥中的臂旁/kölliker 融合 (PB/KF) 核代表关键节点 SIA 生成点,以及招募脑干核团(如 PB/KF 和 PAG)的 [AIM 3] 特别是在 SIA 期间,我们将利用电生理学和基因图谱进行探索。目标 1:我们 之前已经使用化学遗传学证明 SIA 不需要皮质发作活动,现在我们 提出脑桥和中脑的过度兴奋驱动 SIA 和 SUDEP。我们将利用化学遗传学 抑制Scn8a突变小鼠脑干的不同部位,以测试其对SIA和SUDEP的必要性。 此外,我们将通过选择性表达 Scn8a 突变来测试这些区域的充分性,该突变会增加 神经元的兴奋性。使用快速点燃模型,我们还将进行膜片钳记录以测试是否 这些区域的神经元兴奋性增加与 SIA 的发展同时发生。目标 2: 脑桥中的臂旁/科利克融合核 PB/KF 是前脑下降输入和 投射经过吸气振荡器,并受到迷走神经的调节。为了这个目标,我们将光抑制 Foxp2 阳性 PB/KF 神经元在 SIA 期间恢复正常呼吸模式,光刺激 P2ry1 阳性 迷走神经传入神经纤维在 SIA 期间中断吸气,并确定 PB/KF 和 Npy2r 阳性迷走神经是否 神经元光刺激可挽救我们的 PTZ SUDEP 小鼠模型的发作后呼吸。目标 3:我们有 证明伴有 SIA 的强直性癫痫发作和不伴有 SIA 的阵挛性癫痫发作可以发生在同一只小鼠身上, 在 Scn8a 突变体和快速点燃模型(初步数据)中,某些中脑和后脑结构是 在 SIA 期间激活。我们将使用以下方法确定在 SIA 和 SUDEP 期间特别激活的神经元回路 激活神经元的体内电生理学和 TRAP2 鉴定。

项目成果

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Ian Christopher Wenker其他文献

Ian Christopher Wenker的其他文献

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{{ truncateString('Ian Christopher Wenker', 18)}}的其他基金

Role of carboxyl-terminal modulator protein in autophagy and senescence of human induced pluripotent stem cells
羧基末端调节蛋白在人诱导多能干细胞自噬和衰老中的作用
  • 批准号:
    10756824
  • 财政年份:
    2019
  • 资助金额:
    $ 40.38万
  • 项目类别:
Carboxyl-terminal modulator protein, Aβ and brain aging
羧基末端调节蛋白、Aβ 和大脑衰老
  • 批准号:
    9816648
  • 财政年份:
    2019
  • 资助金额:
    $ 40.38万
  • 项目类别:
Brainstem control of blood pressure in conscious rodents
脑干对清醒啮齿动物血压的控制
  • 批准号:
    8907534
  • 财政年份:
    2015
  • 资助金额:
    $ 40.38万
  • 项目类别:
Brainstem control of blood pressure in conscious rodents
脑干对清醒啮齿动物血压的控制
  • 批准号:
    9127736
  • 财政年份:
    2015
  • 资助金额:
    $ 40.38万
  • 项目类别:

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