Minocycline inhibits sleep deprivation-induced aberrant microglial activation and Keap1-Nrf2 expression in mouse hippocampus
Minocycline inhibits sleep deprivation-induced aberrant microglial activation and Keap1-Nrf2 expression in mouse hippocampus
复制标题
米诺环素抑制睡眠剥夺诱导的小鼠海马异常小胶质细胞激活和 Keap1-Nrf2 表达
DOI：
10.1016/j.brainresbull.2021.05.028
复制
发表时间：
2021-06-04
影响因子：
3.8
通讯作者：
Long, Cheng
中科院分区：
文献类型：
--
作者：
Ahmed, Adeel;Misrani, Afzal;Long, Cheng
睡眠剥夺（SD）是现代社会的一个标志，与许多神经精神疾病有关，包括抑郁和焦虑。然而，SD相关抑郁和焦虑的细胞和分子机制仍然难以捉摸。神经炎症是否在介导SD效应中发挥作用？在这项研究中，我们调查了SD诱导的海马细胞和分子的变化，并询问是否与抗炎药，米诺环素治疗，可以减弱这些变化。我们发现，SD动物表现出激活的小胶质细胞和海马中Keap 1和Nrf 2（抗氧化剂和抗氧化因子）的水平降低。在体内的局部场电位记录显示减少的θ和β振荡，但增加高γ振荡，作为SD的结果。行为学分析显示，在强迫游泳和悬尾试验中，SD小鼠的不动时间增加，蔗糖摄入量减少，所有这些都表明抑郁样行为。此外，旷场实验和高架十字迷宫实验结果表明，SD增加焦虑样行为。有趣的是，用小胶质细胞调节剂米诺环素治疗阻止了SD诱导的小胶质细胞活化，恢复了Keap 1和Nrf 2水平，使神经元振荡正常化，并减轻了抑郁样和焦虑样行为。目前的研究表明，小胶质细胞激活和Keap 1-Nrf 2信号在SD诱导的行为改变中起着至关重要的作用，米诺环素治疗对这些改变具有保护作用。
Sleep deprivation (SD) is a hallmark of modern society and associated with many neuropsychiatric disorders, including depression and anxiety. However, the cellular and molecular mechanisms underlying SD-associated depression and anxiety remain elusive. Does the neuroinflammation play a role in mediating the effects of SD? In this study, we investigated SD-induced cellular and molecular alterations in the hippocampus and asked whether treatment with an anti-inflammatory drug, minocycline, could attenuate these alterations. We found that SD animals exhibit activated microglia and decreased levels of Keap1 and Nrf2 (antioxidant and antiinflammatory factors) in the hippocampus. In vivo local field potential recordings show decreased theta and beta oscillations, but increased high gamma oscillations, as a result of SD. Behavioral analysis revealed increased immobility time in the forced swim and tail suspension tests, and decreased sucrose intake in SD mice, all indicative of depressive-like behavior. Moreover, open field test and elevated plus maze test results indicated that SD increases anxiety-like behavior. Interestingly, treatment with the microglial modulator minocycline prevented SD-induced microglial activation, restored Keap1 and Nrf2 levels, normalized neuronal oscillations, and alleviated depressive-like and anxiety-like behavior. The present study reveals that microglial activation and Keap1-Nrf2 signaling play a crucial role in SD-induced behavioral alteration, and that minocycline treatment has a protective effect on these alterations.