睡眠剥夺介导神经元自噬抑制对小鼠抑郁样行为和认知功能的影响-东南大学学报医学版

睡眠剥夺介导神经元自噬抑制对小鼠抑郁样行为和认知功能的影响

单位：郴州市第一人民医院神经内科, 湖南郴州 423000

分类号：R-332;R749.4

出版年·卷·期（页码）：2021·40·第五期（657-665）

摘要：

目的：探讨睡眠剥夺对小鼠抑郁样行为和认知功能障碍的机制。方法：将36只小鼠随机分为对照组、睡眠剥夺组和雷帕霉素组，每组12只。雷帕霉素组小鼠以剂量20 mg·kg^-1雷帕霉素治疗。通过行为学测试判断小鼠抑郁样症状，使用Morris水迷宫以探究认知功能障碍，采用电子显微镜技术、HE染色、免疫荧光和免疫印迹探究小鼠海马组织中自噬相关蛋白表达。结果：睡眠剥夺造成小鼠糖水摄取率和开野穿格次数显著减少（P<0.05），悬尾和强迫游泳不动时间显著延长（P<0.05）。此外，睡眠剥夺造成小鼠逃避潜伏期显著延长（P<0.05），穿越平台象限次数显著减少（P<0.05）。然而，雷帕霉素干预明显改善了小鼠抑郁样行为相关指标，且提高了小鼠认知功能。睡眠剥夺小鼠海马组织中哺乳动物雷帕霉素靶蛋白（mTOR）表达增加（P<0.05），而自噬微管相关蛋白轻链3（LC3）-II/LC3-I、自噬效应蛋白（Beclin-1）表达却显著降低（P<0.05），且自噬囊泡减少而神经元凋亡却增加。与睡眠剥夺组相比，雷帕霉素组海马组织中mTOR表达下降（P<0.05），LC3-II/LC3-I和Beclin-1表达增加（P<0.05），增加神经元自噬的同时减少神经元凋亡。结论：长期睡眠剥夺通过上调mTOR表达，抑制LC3-II/LC3-I、Beclin-1表达，抑制神经元自噬并介导神经元凋亡，最终诱导小鼠出现抑郁样症状和认知功能障碍。

Objective: To explore the mechanism of sleep deprivation mediated depression-like behavior and cognitive dysfunction in mice. Methods: 36 mice were randomly divided into control group, sleep deprivation group, and rapamycin group, 12 mice in each group. The mice in sleep deprivation group and the rapamycin group were constructed for sleep deprivation model, and then the mice in rapamycin group were treated with 20 mg·kg^-1 rapamycin. Depression-like symptoms were tested through behavioral tests. Cognitive dysfunction was explored by Morris water maze experiment, The expressions of autophagy-related proteins in hippocampus were investigated based on electron microscopy, HE staining, immunofluorescence and immunoblotting. Results: Sleep deprivation leaded to a significant decrease in sucrose consumption and the scores in open fields in mice (P<0.05), and the immobility time in suspension and forced swimming tests increased significantly (P<0.05). In addition, sleep deprivation caused a significant increase in the escape latency in Morris water maze experiment (P<0.05), and the number of crossing platform quadrants decreased(P<0.05). However, treatment of rapamycin obviously improved depression-related behaviors and cognitive function in mice. At the same time, sleep deprivation increased expression of mTOR protein in hippocampus (P<0.05), while the expression of LC3-II/LC3-I and Beclin-1 were significantly downregulated (P<0.05). In addition, not only the decreasing autophagosomes but also the increasing neuronal apoptosis were found in mice administrated with sleep deprivation. However, when the mice treated with rapamycin, it significantly decreased the expression of mTOR protein (P<0.05), and increased LC3-II/LC3-I ratio and Beclin-1 expression(P<0.05), also it increased autophagosomes and decreased neuronal apoptosis. Conclusion: The depression-like symptoms and cognitive dysfunction induced by long-term sleep deprivation in mice are related to the increasing expression of mTOR, which leading to reduced neuronal autophagy and neuronal apoptosis.

参考文献：

[1] UHER R,PAYNE J L,PAVLOVA B,et al.Major depressive disorder in DSM-5:implications for clinical practice and research of changes from DSM-IV[J].Depress Anxiety,2014,31(6):459-471.
[2] BOLAND E M,RAO H,DINGERS D F,et al.Meta analysis of the antidepressant effects of acute sleep deprivation[J].J Clin Psychiatry,2017,78(8):e1020-e1034.
[3] ZHEN W,LU C,LING Z,et al.Paradoxical sleep deprivation modulates depressive-like behaviors by regulating the MAOA levels in the amygdala and hippocampus[J].Brain Res,2017,1664:1724.
[4] PIBER D,EISENBERGER N I,OLMSTEAD R,et al.Sleep deprivation,inflammation and facial emotion recognition in older adults[J].Brain Behav Immun,2019,76:e12.
[5] DAL P,GUSTAVO C,JRIO M,et al.Effects of lithium and valproate on behavioral parameters and neurotrophic factor levels in an animal model of mania induced by paradoxical sleep deprivation[J].J Psychiatr Res,2019,119:76-83.
[6] POILLET-PEREZ L,XIE X,ZHAN L,et al.Autophagy maintains tumour growth through circulating arginine[J].Nature,2018,563(7732):569-573.
[7] WANG P,SHAO B Z,DENG Z Q,et al.Autophagy in ischemic stroke[J].Prog Neurobiol,2018,163-164:98-117.
[8] MA W N,WANG H R,SHI F Y,et al.Chronic paradoxical sleep deprivation-induced depressionlike behavior,energy metabolism and microbial changes in rats[J].Life Sci,2019,225:88-97.
[9] MELO M C A,ABRE R L C,LINHARES NETO V B,et al.Chronotype and circadian rhythm in bipolar disorder:a systematic review[J].Sleep Med Rev,2017,34:46-58.
[10] LIPPMAN S,GARDENER H,RUNDEK A T,et al.Short sleep is associated with more depressive symptoms in a multi-ethnic cohort of older adults[J].Sleep Med,2017,40:58-62.
[11] 曾龙快,胡珍玉,梅曦,等.睡眠剥夺治疗抑郁症的最新研究[J].现代实用医学,2019,31(3):423-425.
[12] LI Y C,ZHENG X X,XIA S Z,et al.Paeoniflorin ameliorates depressive-like behavior in prenatally stressed offspring by restoring the HPA axis-and glucocorticoid receptor-associated dysfunction[J].J Affect Disord,2020,274:471-481.
[13] JIA J,LE W D.Molecular network of neuronal autophagy in the pathophysiology and treatment of depression[J].Neurosci Bull,2015,31(4):427-434.
[14] 吴婷,张静思,向军,等.自噬在抑郁症发生发展中作用的研究进展[J].复旦学报,2018,45(4):573-576.
[15] KARA N,TOKER L,AGAM G,et al.Trehalose induced antidepressant-like effects and autophagy enhancement in mice[J].Psychopharmacology,2013,229(2):367.
[16] ANDERSON C,FRANCIS L P,JULIA M R,et al.Augmentation effect of ketamine by guanosine in the novelty-suppressed feeding test is dependent on mTOR signaling pathway[J].J Psychiatr Res,2019,115:103-112.
[17] NAKATSU Y K,KOTAKE Y C,TAKAI N,et al.Involvement of autophagy via mammalian target of rapamycin (mTOR) inhibition in tributyltin-induced neuronal cell death[J].J Toxicol Sci,2010,35(2):245-251.
[18] MENG Y C,LOU X L,YANG L Y,et al.Role of the autophagy-related marker LC3 expression in hepatocellular carcinoma:a meta-analysis[J].J Cancer Res Clin Oncol,2020,146(5):1103-1113.
[19] LI Q,HAN Y,DU J,et al.Alterations of apoptosis and autophagy in developing brain of rats with epilepsy:changes in LC3,P62,Beclin-1 and Bcl-2 levels[J].Neurosci Res,2018,130:47-55.
[20] HUNG S Y,HUANG W P,LIOU H C,et al.Autophagy protects neuron from abeta-induced cytotoxicity[J].Autophagy,2009,5(4):502-510.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录