Surgery, Anesthesia and Intensive Care Environment Induce Delirium-Like Behaviors and Impairment of Synaptic Function-Related Gene Expression in Aged Mice.
Surgery, Anesthesia and Intensive Care Environment Induce Delirium-Like Behaviors and Impairment of Synaptic Function-Related Gene Expression in Aged Mice.
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DOI：
10.3389/fnagi.2020.542421
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发表时间：
2020
影响因子：
4.8
通讯作者：
Lunardi N
中科院分区：
文献类型：
--
作者：
Illendula M;Osuru HP;Ferrarese B;Atluri N;Dulko E;Zuo Z;Lunardi N
建立临床相关的围手术期谵妄小鼠模型。老年 C57BL/6J 小鼠在 Y 迷宫新颖手臂偏好、埋藏食物、注意力转移测试的简单辨别任务和旷场测试中进行基线测试。随后他们被随机分为损伤组（麻醉、手术和重症监护室环境）或对照组。遭受侮辱的小鼠在七氟烷麻醉、异丙酚镇静以及间歇性灯光、声音和笼子摇动下接受剖腹手术。对照组没有接受麻醉、手术或重症监护环境。所有小鼠均在重症监护环境结束时（0 小时）以及每 6 小时至 24 小时进行 Y 迷宫新型手臂偏好、埋藏食物、注意力和开放场地测试。 24小时收集小鼠海马用于基因表达分析。手术、麻醉和重症监护环境减少了 Y 迷宫新臂中 0 小时（P = 0.001）、6 小时（P < 0.001）、18 小时（P = 0.002）和 24 小时（P = 0.029）的条目。侮辱暴露增加了在 18 小时（P = 0.035）和 24 小时（P = 0.027）时找到埋藏谷物奖励的潜伏期，并增加了注意力测试的反向复合辨别（P = 0.013）和超维度转移（P < 0.001）任务中标准的试验。 A/S/I 小鼠谵妄的总体发生率为 72%。损伤暴露后 24 小时，小鼠海马中突触核蛋白 α（相对于对照变化为−3.785 倍）、神经营养受体酪氨酸激酶 1（−2.267）和突触蛋白 1a（−1.498）的信使 RNA 水平降低。突触蛋白 1a (P = 0.012)、神经营养性受体酪氨酸激酶 1 (P = 0.039)、突触核蛋白 α (P = 0.017)、磷酸化突触核蛋白 α (P = 0.008)、突触素 (P = 0.002)、突触后密度蛋白 95 (P = 0.003) 和相对于对照组，微管相关蛋白 2 (P = 0.013) 也有所减少。手术、麻醉和重症监护环境损害了小鼠依赖注意力、记忆和思维组织的行为。这些变化发生时剧烈且随时间波动。患有谵妄的小鼠表现出关键突触功能相关基因的表达下降。麻醉、手术和重症监护环境引起的老年小鼠行为变化与人类谵妄的临床特征一致，支持该动物模型用于未来围手术期谵妄的机制研究。
To establish a clinically relevant mouse model of perioperative delirium. Aged C57BL/6J mice were tested at baseline in the Y-maze novel arm preference, buried food, simple discrimination task of the attentional set-shifting test, and open field tests. They were subsequently randomized to insult (anesthesia, surgery, and Intensive Care Unit environment) or control group. Insult-exposed mice received laparotomy under sevoflurane anesthesia, propofol sedation and exposure to intermittent lights, sounds and cage shaking. Controls did not receive anesthesia, surgery, or intensive care environment. All mice were tested in the Y-maze novel arm preference, buried food, attentional, and open field tests at the end of intensive care environment (0 h) and every 6 h up to 24 h. Mouse hippocampi were collected at 24 h for gene expression analyses. Surgery, anesthesia and Intensive Care environment decreased the entries in the Y-maze novel arm at 0 h (P = 0.001), 6 h (P < 0.001), 18 h (P = 0.002), and 24 h (P = 0.029). Insult exposure increased the latency to find a buried cereal reward at 18 h (P = 0.035) and 24 h (P = 0.027), and increased the trials to criterion in the reverse compound discrimination (P = 0.013) and extradimensional shift (P < 0.001) tasks of the attentional test. The overall incidence of delirium was 72% in A/S/I mice. Messenger RNA levels of synuclein alpha (−3.785 fold change relative to controls), Neurotrophic Receptor Tyrosine Kinase1 (−2.267), and syntaxin1a (−1.498) were decreased in the hippocampus of mice 24 h after insult exposure. Protein levels of syntaxin 1a (P = 0.012), Neurotrophic Receptor Tyrosine Kinase1 (P = 0.039), synuclein alpha (P = 0.017), phosphorylated synuclein alpha (P = 0.008), synaptophysin (P = 0.002), postsynaptic density protein 95 (P = 0.003), and microtubule-associated protein 2 (P = 0.013) were also decreased, relative to controls. Surgery, anesthesia and Intensive Care environment impaired mouse behaviors that depend on attention, memory, and thought organization. The changes were acute in onset and fluctuating in time. Mice with delirium exhibited decreased expression of key synaptic function-related genes. The behavioral changes induced by anesthesia, surgery, and Intensive Care environment in aged mice are consistent with the clinical features of human delirium, and support the use of this animal model for future mechanistic studies of perioperative delirium.
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DOI：
10.1073/pnas.241503698
发表时间：
2001-11-20
影响因子：
11.1
作者：
Akwa, Y;Ladurelle, N;Baulieu, EE
通讯作者：
Baulieu, EE
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T
DOI：
10.1523/jneurosci.4673-11.2012
发表时间：
2012-05-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Field RH;Gossen A;Cunningham C
通讯作者：
Cunningham C
影响因子：
3.6
作者：
Aboulkassim, Tahar;Tong, Xin-Kang;Saragovi, H. Uri
通讯作者：
Saragovi, H. Uri
影响因子：
1.2
作者：
Heisler, Jillian M.;Morales, Juan;O'Connor, Jason C.
通讯作者：
O'Connor, Jason C.