Regulation of swallow and the effects of high cervical spinal cord injury

摘要。吞咽是一种基本的、关键的行为，它是将液体和食物从胃中移走所必需的。 经食道进入胃。当吞咽异常（吞咽困难）时，液体和食物可能 进入喉和气管（吸入），引起随后的肺炎。虽然集体文献报道 吞咽困难的发生率差异很大，2017年的一项前瞻性研究显示， 76%的cSCI患者。我们的长期目标是了解cSCI后吞咽困难的机制， 并开发具有高度临床应用可能性的新疗法。我们的核心假设是， 脊髓回路对于吞咽的成功执行至关重要。具体来说，中央模式生成器 (CPG)在脑干中，控制这种重要的气道保护行为的神经元连接到颈动脉中的回路， 脊髓我们的初步数据表明，急性C2和C3半切抑制膈肌活动 这导致吞咽期间的正胸内压。这些病变也增加了上气道 肌肉募集相当大（~200-800%），在治疗期间顺序肌肉募集完全丧失。 吞咽的咽部阶段。此外，高剂量的5-HT 1A激动剂增加了膈肌活动， 吞咽，这伴随着上气道顺序激活的恢复。以强为导 初步数据我们的中心假设将测试以下目标：目标1：确定的影响， 颈脊髓中断对吞咽运动模式的影响;目的2：确定 8-OH-DPAT（5-HT 1A激动剂）对急性脊髓半切术后吞咽功能恢复的影响。我们将使用 电生理技术，以确定C2，C3和C4半切对吞咽执行的影响。 我们还将通过C2半切和内侧半切的联合方案来确定吞咽功能的变化。 脊髓切开术将在完整动物中测试8-OH-DPAT对吞咽功能的治疗有效性， 以及C2 C3和C4半切。确保治疗效果与5-HT 1A受体相关 激活后，还将用5-HT 1A拮抗剂WAY-100635进行一系列实验。这些 在动物模型中，研究将首次表明，颈脊髓通路的丧失具有有害的 对吞咽的影响此外，我们将提供临床前证据，证明可以使用5-HT 1A受体激动剂 来治疗吞咽障碍，这将是第一个治疗吞咽困难的方法。这些信息将教育 临床社区了解cSCI后吞咽困难的风险，并提供新型干预措施的选择。

ABSTRACT. Swallow is a basic, critical behavior necessary for the movement of liquids and food from the mouth, through the esophagus to the stomach. When swallow is abnormal (dysphagia), liquid and food may enter the larynx and trachea (aspiration) causing subsequent pneumonia. While the collective literature reports a large variance in the incidence of dysphagia, a 2017 prospective study shows disordered swallow production in 76% of cSCI patients. Our long-term goal is to understand the mechanism(s) of dysphagia following cSCI, and to develop novel therapies which have a high likelihood of clinical utility. Our central hypothesis is that spinal circuits are critical for the successful execution of swallow. Specifically, the central pattern generator (CPG) in the brainstem controlling this vital airway protective behavior is connected to circuitry in the cervical spinal cord. Our preliminary data demonstrates that acute C2 and C3 hemisections depress diaphragm activity which results in positive intra-thoracic pressure during swallow. These lesions also increased upper airway muscle recruitment considerably (~200-800%), with a total loss of sequential muscle recruitment during the pharyngeal phase of swallow. Additionally, a high dose of a 5-HT1A agonist increased diaphragm activity during swallow, which was accompanied by restoration of upper airway sequential activation. Guided by strong preliminary data our central hypothesis will be tested with the following aims: Aim 1: Identify the effects of cervical spinal cord disruption on the swallow motor pattern; and Aim 2: Determine the therapeutic efficacy of 8-OH-DPAT (5-HT1A agonist) on recovery of swallow function after acute spinal hemisection. We will use electrophysiology techniques to determine the effects of C2, C3 and C4 hemisection on execution of swallow. We will also determine changes in swallow function with a combined protocol of C2 hemisection and medial myelotomy. The therapeutic effectiveness of 8-OH-DPAT on swallow function will be tested in intact animals as well as with C2, C3 and C4 hemisections. To ensure the treatment effects are related to 5-HT1A receptor activation, a series of experiments will also be performed with the 5-HT1A antagonist WAY-100635. These studies will be the first to show, in an animal model, that loss of cervical spinal pathways has a deleterious effect on swallow. Additionally, we will provide pre-clinical evidence that a 5-HT1A receptor agonist can be used to treat swallow impairments, which will be the first of its kind for dysphagia. This information will educate the clinical community about risk of dysphagia after cSCI and provide options for novel interventions.