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，是液体和食物从肠道中移动所必需的

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.