小脑外侧核DBS对早期缺血性卒中大鼠吞咽障碍的治疗作用及机制研究

Deep brain stimulation (DBS) at its origin in the lateral cerebellar nucleus (LCN) has been shown to enhance motor recovery in a rodent model of cortical ischemia infarction. Whether DBS at its origin in the LCN promoted the dysphagia rehabilitation after ischemia stoke, and what is its frequency range and mechanisms of electric stimulation treatment? Until now, there have been no studies in the world regarding about it. Therefore, based on early works of constructing the dysphagia animal model, we plan to use behavioral methods, immunohistochemical methods, transmission electron microscope techniques, stereological methods and molecular biological methods, the methods of determinating gene and protein, to study the effects of DBS at the LCN on dysphagia function after ischemia infarction and determine its effective treatment frequency range, and the effects on the capillaries and myelinated fibers of white matter and the mechanisms of these effects. We will further study DBS at the LCN modulate endogous eNOS to control the balance of angiogenesis regulatory factors, thereby affecting the angiogenesis on white matter, and it modulate NMDA/PSD-95/nNOS complex uncoupling to affect the myelinated fibers on white matter. Reveal the results and mechanisms of DBS LCN through the endogenous eNOS and nNOS pathway to regulate neurovascular unit on white matter on dysphagia after ischemia infarction. Finally, we aim to provide a new strategy for preventing dysphagia after ischemia infarction.

小脑外侧核深部电刺激是促进脑卒中后肢体运动感觉障碍恢复的一种新的治疗手段。其是否能够改善缺血性卒中后吞咽障碍功能？以及有效治疗频率及作用机制如何？国内外未见研究报道。本课题拟运用电生理学、免疫组化学、电镜技术、体视学，分子生物学等技术，在成功构建缺血性卒中后吞咽障碍大鼠模型的前期基础上，研究小脑外侧核深部电刺激对吞咽障碍的作用和有效治疗频率，以及对大脑白质毛细血管和有髓神经纤维的作用。通过分别阻断eNOS以及NMDA/PSD-95/nNOS通路，研究小脑外侧核深部电刺激是否通过内源性eNOS通路和NMDA/PSD-95/nNOS解偶联作用来分别影响白质内毛细血管和有髓神经纤维的生成。最终揭示小脑外侧核深部电刺激通过eNOS及nNOS通路对卒中后吞咽障碍白质内血管神经纤维这一整体单元的重塑作用，进而缓解吞咽障碍的分子机制。该研究将为卒中后吞咽障碍的防治提供新的理论依据和治疗靶点。

小脑外侧核深部电刺激是促进脑卒中后肢体运动感觉障碍恢复的一种新的治疗手段，本课题运用电生理学、免疫组化学、电镜技术、体视学、分子生物学等技术，在成功构建缺血性卒中后吞咽障碍大鼠模型的前期基础上，研究小脑外侧核深部电刺激对吞咽障碍的作用和有效治疗频率，对大脑毛细血管和有髓神经纤维的作用，以及NMDA/PSD-95/nNOS和NMDA/PSD-95/nNOS在此过程中的调控作用。本课题研究发现在急性缺血性脑梗死大鼠模型中，运动皮层的趋化激活可促进MCAO后整体神经状态、协调性和耐力的恢复；通过体视学定量研究发现内源性一氧化氮调控皮质毛细血管重塑：内源性NO参与调控皮质毛细血管重塑，对大脑皮质毛细血管总长度，总体积，总表面积具有调控作用。内源性NO对大脑皮质血管生成具有明显调控作用，对大脑皮质内血管生成因子VEGF，FGF-2，血管生成抑制因子Angiostatin，Endostatin具有明显调控作用。这些研究结果为研究电刺激对急性缺血性脑梗死吞咽功能障碍的作用及机制提供了有力的科学依据。

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