Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal rats.
Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal rats.
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DOI：
10.1007/s11064-023-03865-4
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发表时间：
2023-06
影响因子：
4.4
通讯作者：
Zuo, Zhiyi
中科院分区：
文献类型：
--
作者：
Zhang, Hui;Sun, Xiaoru;Li, Jun;Shan, Weiran;Yang, Jianjun;Zuo, Zhiyi
新生儿手术和麻醉可能导致认知障碍或行为异常。研究表明，自噬在神经精神疾病中起着关键作用，而自噬在新生儿术后认知障碍中的作用尚不清楚。在这里，我们确定了这种作用和参与内质网（ER）应激调节脑细胞自噬手术后。7日龄新生大鼠（P7）在3%七氟烷麻醉下暴露右侧颈总动脉2 h。分别在P31 - 42和P42 - 44用巴恩斯迷宫（BM）和恐惧条件（FC）测试学习记忆能力。在另一个实验中，老鼠的大脑被收获用于生化研究。新生大鼠手术和麻醉后24 h，脑内微管相关蛋白1轻链3（LC 3）BII/I比值升高，多形核小体1（P62/SQSTM 1）水平降低。LC 3B的免疫荧光染色与神经元或小胶质细胞标记物共定位，但与手术大鼠中的星形胶质细胞标记物不共定位。当这些大鼠处于青春期时，它们在BM和FC测试中的表现比对照组大鼠差。预处理与自噬抑制剂，3-甲基腺嘌呤，衰减的表现不佳。手术和麻醉增加了78 kDa葡萄糖调节蛋白（BIP/GRP 78）的表达，这是ER应激的一个指标，手术和麻醉后6 h。ER应激激活剂衣霉素和抑制剂牛磺熊去氧胆酸分别增加对照大鼠的自噬标记物和减少手术大鼠的自噬标记物。我们的研究结果表明，新生大鼠的手术诱导ER应激，然后激活神经元和小胶质细胞自噬，这有助于在以后的生活中的学习和记忆障碍。
Surgery and anesthesia in neonates may lead to cognitive impairment or abnormal behaviors. It has been shown that autophagy plays a critical role in neuropsychiatric disorders, while the role of autophagy in postoperative cognitive impairment in neonates is not known. Here, we determined this role and the involvement of endoplasmic reticulum (ER) stress in regulating brain cell autophagy after surgery. Seven-day old neonatal rats (P7) had right common carotid artery exposure under anesthesia with 3% sevoflurane for 2 h. Learning and memory were tested using Barnes maze (BM) and fear conditioning (FC) on P31 – 42 and P42 – 44, respectively. In another experiment, rat brains were harvested for biochemical studies. The ratio of microtubule-associated protein 1 light chain 3 (LC3) BII/I was increased and sequestosome 1 (P62/SQSTM1) levels were decreased in the brain 24 h after surgery and anesthesia in neonatal rats. Immunofluorescent staining of LC3B was co-localized with a neuronal or a microglial marker but was not co-localized with a marker for astrocytes in rats with surgery. These rats had a poorer performance in the BM and FC tests than control rats when they were adolescent. Pretreatment with an autophagy inhibitor, 3-methyladenine, attenuated the poor performance. Surgery and anesthesia increased the expression of 78 kDa glucose-regulated protein (BIP/GRP78), an indicator of ER stress, 6 h after surgery and anesthesia. The ER stress activator tunicamycin and inhibitor tauroursodeoxycholic acid increased the markers for autophagy in control rats and decreased the autophagy markers in rats with surgery, respectively. Our results suggest that surgery in neonatal rats induces ER stress that then activates neuronal and microglial autophagy, which contributes to learning and memory impairment later in life.
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影响因子：
11
作者：
Lai Z;Shan W;Li J;Min J;Zeng X;Zuo Z
通讯作者：
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影响因子：
16.2
作者：
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作者：
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通讯作者：
Black SM
影响因子：
4.7
作者：
Gui, Lingli;Lei, Xi;Zuo, Zhiyi
通讯作者：
Zuo, Zhiyi
影响因子：
5.3
作者：
Carloni, Silvia;Albertini, Maria Cristina;Balduini, Walter
通讯作者：
Balduini, Walter