Mechanisms of Lingual Motor Plasticity of Post-Stroke Dysphagia in an Animal Model

项目摘要 中风后，高达50%的人有吞咽困难，称为吞咽困难。中风后吞咽困难是一种 与不良结局相关的严重问题，包括营养不良、吸入性肺炎、长期护理， 与死临床护理往往限于补偿策略，因为缺乏证据证明任何 特别治疗最有益。中风后肢体功能的恢复，运动是首要的 康复的方法和大量的关于皮质脊髓可塑性的方面，有助于 恢复功能。运动方法，如舌头运动，也用于治疗中风后 吞咽困难然而，尽管舌运动对中风后吞咽困难产生了积极的效果， 对支配颅肌的皮质延髓束的中风后可塑性知之甚少。颅 肌肉运动核位于脑干中，并且通常比脑干接受更多的双侧神经支配。 四肢肌肉因此，有助于吞咽功能恢复的可塑性机制可能不同 基本上来自肢体，并且必须理解为改善中风后吞咽困难的临床治疗。 拟议中的研究将通过使用中风后吞咽困难的大鼠模型来解决这一知识缺口， 最近由Cullins博士验证，以建立舌皮质，脑干和肌肉的可塑性变化， 发生在中风后，以及年龄和基于临床的舌运动干预对这些 机制等K99阶段将重点关注年轻人中风后的舌神经肌肉可塑性， 老鼠会目的1：量化大鼠中风后影响舌运动功能的神经可塑性变化， 测试以下假设：（A）完整运动皮层中的舌表征将增加;（B）BDNF，a 与可塑性相关的神经营养因子，将在舌下神经脑干运动核中上调， 支配舌头，以及（C）这些塑性变化将与舌强度和吞咽相关 功能目的2：量化年龄对神经肌肉可塑性和吞咽功能恢复的影响 在大鼠中风模型中。K99阶段的培训和研究将使Cullins博士开始建立 在独立R 00期卒中后吞咽困难的治疗干预机制， 确定与舌头运动相关的肌肉、神经和功能变化。目标1：量化 肌肉可塑性对舌运动对舌强度和吞咽功能影响的贡献。 目的2：确定舌头运动对神经可塑性的影响以及年龄和运动之间的相互作用。 这项拟议的研究将产生关于中风后皮质延髓可塑性的基础知识，包括 与吞咽困难相关的皮质、脑干和肌肉变化以及年龄和舌运动的影响。 动物研究可以通过缩小潜在治疗的巨大可变空间来告知临床研究 范例包括诸如时机、剂量和组合治疗的因素。这项基础工作将使 未来的研究，以优化干预措施，并指导临床研究的长期目标，以改善临床 中风后吞咽困难的治疗。

Project Summary After stroke, up to 50% of people have difficulty swallowing, known as dysphagia. Post stroke dysphagia is a serious problem associated with poor outcomes including malnutrition, aspiration pneumonia, long-term care, and death. Clinical care is often limited to compensatory strategies due to a lack of evidence establishing any particular treatment as most beneficial. For recovering limb function after stroke, exercises are the primary rehabilitative approach and a great deal is known about aspects of corticospinal plasticity that contribute to recovery of function. Exercise approaches, such as tongue exercise, are also used in therapy for poststroke dysphagia. However, although tongue exercises have yielded positive results for post stroke dysphagia, much less is known about post stroke plasticity of the corticobulbar tract innervating the cranial muscles. Cranial muscle motor nuclei are located in the brainstem and generally receive much more bilateral innervation than limb muscles. Thus, the plastic mechanisms contributing to the recovery of swallowing function may differ substantially from limbs and must be understood to improve the clinical treatment of post stroke dysphagia. The proposed research will address this gap in knowledge by using a rat model of post stroke dysphagia, recently validated by Dr. Cullins, to establish plastic changes to the lingual cortex, brainstem, and muscles that occur after stroke and the impact of age and clinically based tongue exercise intervention on these mechanisms. The K99 phase will focus on lingual neuromuscular plasticity after stroke in young adult and aged rats. Aim 1: Quantify neuroplastic changes that impact lingual motor function after stroke in the rat by testing the hypotheses that: (A) tongue representation in the intact motor cortex will increase; (B) BDNF, a neurotrophin associated with plasticity, will be upregulated in the hypoglossal brainstem motor nuclei that innervate the tongue, and (C) and these plastic changes will correlate with lingual strength and swallowing function. Aim 2: Quantify the impact of age on neuromuscular plasticity and the recovery of swallowing function in a rat model of stroke. The training and research in the K99 phase will allow Dr. Cullins to begin to establish mechanisms of therapeutic interventions for post stroke dysphagia in the independent R00 phase, by determining the muscular, neural, and functional changes associated with tongue exercise. Aim 1: Quantify the contribution of muscular plasticity to the impact of tongue exercise on lingual strength and swallowing function. Aim 2: Determine the impact of tongue exercise on neuroplasticity and interactions between age and exercise. The proposed study will generate fundamental knowledge about corticobulbar plasticity after stroke including cortical, brainstem, and muscular changes related to dysphagia and the impact of age and tongue exercise. Animal studies can inform clinical research by narrowing the vast variable space of potential treatment paradigms including factors such as timing, dose, and combined treatments. This foundational work will allow future studies to optimize interventions and guide clinical research with a long-term goal to improve the clinical treatment of post stroke dysphagia.