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Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke.
ASN Neuro ( IF 3.9 ) Pub Date : 2020-09-23 , DOI: 10.1177/1759091420961612
Daniela F Goncalves 1, 2 , Monica S Guzman 1, 3 , Robert Gros 1, 3 , André R Massensini 2 , Robert Bartha 1, 4 , Vania F Prado 1, 3, 5 , Marco A M Prado 1, 3, 5
Affiliation  

Acetylcholine (ACh) has been suggested to facilitate plasticity and improve functional recovery after different types of brain lesions. Interestingly, numerous studies have shown that striatal cholinergic interneurons are relatively resistant to acute ischemic insults, but whether ACh released by these neurons enhances functional recovery after stroke is unknown. We investigated the role of endogenous striatal ACh in stroke lesion volume and functional outcomes following middle cerebral artery occlusion to induce focal ischemia in striatum-selective vesicular acetylcholine transporter-deficient mice (stVAChT-KO). As transporter expression is almost completely eliminated in the striatum of stVAChT-KO mice, ACh release is nearly abolished in this area. Conversely, in other brain areas, VAChT expression and ACh release are preserved. Our results demonstrate a larger infarct size after ischemic insult in stVAChT-KO mice, with more pronounced functional impairments and increased mortality than in littermate controls. These changes are associated with increased activation of GSK-3, decreased levels of β-catenin, and a higher permeability of the blood–brain barrier in mice with loss of VAChT in striatum neurons. These results support a framework in which endogenous ACh secretion originating from cholinergic interneurons in the striatum helps to protect brain tissue against ischemia-induced damage and facilitates brain recovery by supporting blood–brain barrier function.



中文翻译:

纹状体乙酰胆碱有助于保留中风小鼠模型的功能结果。

乙酰胆碱 (ACh) 已被建议在不同类型的脑损伤后促进可塑性和改善功能恢复。有趣的是,大量研究表明纹状体胆碱能中间神经元对急性缺血性损伤具有相对抵抗力,但这些神经元释放的乙酰胆碱是否能增强中风后的功能恢复尚不清楚。我们研究了内源性纹状体乙酰胆碱酯酶在大脑中动脉闭塞后在纹状体选择性囊泡乙酰胆碱转运蛋白缺陷小鼠 (stVAChT-KO) 中诱发局灶性缺血后中风病变体积和功能结果中的作用。由于转运蛋白表达在 stVAChT-KO 小鼠的纹状体中几乎完全消除,因此该区域的乙酰胆碱释放几乎完全消除。相反,在其他脑区,VAChT 表达和乙酰胆碱释放被保留。我们的结果表明 stVAChT-KO 小鼠缺血性损伤后梗死面积更大,与同窝对照相比,功能障碍更明显,死亡率增加。这些变化与 GSK-3 激活增加、β-连环蛋白水平降低以及纹状体神经元 VAChT 缺失小鼠血脑屏障通透性增加有关。这些结果支持一个框架,其中源自纹状体中胆碱能中间神经元的内源性乙酰胆碱分泌有助于保护脑组织免受缺血诱导的损伤,并通过支持血脑屏障功能促进大脑恢复。这些变化与 GSK-3 激活增加、β-连环蛋白水平降低以及纹状体神经元 VAChT 缺失小鼠血脑屏障通透性增加有关。这些结果支持一个框架,其中源自纹状体中胆碱能中间神经元的内源性乙酰胆碱分泌有助于保护脑组织免受缺血诱导的损伤,并通过支持血脑屏障功能促进大脑恢复。这些变化与 GSK-3 激活增加、β-连环蛋白水平降低以及纹状体神经元 VAChT 缺失小鼠血脑屏障通透性增加有关。这些结果支持一个框架,其中源自纹状体中胆碱能中间神经元的内源性乙酰胆碱分泌有助于保护脑组织免受缺血诱导的损伤,并通过支持血脑屏障功能促进大脑恢复。

更新日期:2020-09-24
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