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

抽象的。吞咽是一种基本的、关键的行为，是液体和食物从 嘴巴，通过食道进入胃。当吞咽异常(吞咽困难)时，液体和食物可能 进入喉部和气管(吸入)，引起随后的肺炎。而集体文学报道 吞咽困难的发生率有很大差异，2017年的一项前瞻性研究显示吞咽生产紊乱 在76%的CSCI患者中。我们的长期目标是了解脊髓损伤后吞咽困难的机制(S)， 并开发具有很高临床实用可能性的新疗法。我们的中心假设是 脊椎回路是燕子手术成功的关键。具体地说，中央图案生成器 (Cpg)在控制这一重要的呼吸道保护行为的脑干中，连接到颈部的回路。 脊髓。我们的初步数据显示，急性的C2和C3半切抑制了横隔膜的活动 导致吞咽时胸腔内压力为正。这些病变也增加了上呼吸道。 相当大的肌肉招募(~200-800%)，在 吞咽的咽相。此外，大剂量的5-HT1a激动剂增加了横隔膜的活动 吞咽，伴随着上呼吸道序贯活动的恢复。以Strong为指导 初步数据我们的中心假设将通过以下目标进行检验：目标1：确定 目的2：确定颈髓损伤对吞咽运动模式的影响。 8-OH-DPAT(5-HT1A激动剂)对急性脊髓半横断后吞咽功能恢复的影响我们将使用 电生理学技术确定C2、C3和C4半横断对燕子执行的影响。 我们还将通过C2半切和内侧联合方案来确定吞咽功能的变化 脊髓切开术。8-羟基-DPAT对吞咽功能的治疗效果将在完整动物身上进行测试，如 C2、C3和C4半切面也是如此。确保治疗效果与5-HT1a受体有关 此外，还将用5-HT1a拮抗剂Way-100635进行一系列实验。这些 研究将首次在动物模型中表明，颈椎通路的丧失有有害的 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-HT1a受体激动剂。 治疗吞咽障碍，这将是吞咽困难的第一个此类治疗。这一信息将教育 临床社区对CSCI后吞咽困难风险的了解，并为新的干预措施提供选择。

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.