Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems
Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems
复制标题
多不饱和脂肪酸补充剂通过保护脑血管和类淋巴系统来缓解抑郁症引起的认知功能障碍。
DOI：
10.1016/j.bbi.2020.07.022
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发表时间：
2020-10-01
影响因子：
15.1
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Liu, Xinghua;Hao, Jiahuan;Wang, Wei
前言：抑郁症是最常见的心境障碍，与脑血管疾病和认知功能下降有很高的共病率。然而，抑郁症及其共病的脑血管损害和认知功能障碍的细胞机制还知之甚少。在这里，我们测试了预测，慢性不可预测的轻度应激（CIMTS）小鼠模型将表现为胶质淋巴功能紊乱，膳食补充多不饱和脂肪酸（PUFA）可以改善这些缺陷，同时减轻抑郁相关的认知能力下降。方法：为了测试PUFA或Es对行为的治疗效果，我们应用悬尾、旷场和蔗糖偏好试验来评估抑郁症状，并应用Morris水迷宫测试评估对照组、慢性不可预测轻度应激（CHNS）组、PUFA组和艾司西酞普兰（Es）治疗组的认知能力。采用液相色谱-质谱联用法测定了前额叶皮层（PFC）微透析液中多巴胺（DA）、5-羟色胺（5-HT）和去甲肾上腺素（NA）的浓度。用免疫荧光法和免疫印迹法分别检测胶质细胞和炎症因子。我们在体内用双光子和激光散斑成像测试脑血管功能，并在体内用双光子成像和离体荧光示踪成像测量胶质淋巴系统功能，使用清醒和麻醉的小鼠。此外，我们还利用激光散斑成像系统监测了皮层扩散性抑制。结果：实验证实，AQP 4去极化可引起抑郁样和遗忘症状，并伴有PFC单胺类神经递质浓度降低和神经炎症标志物表达上调。此外，CUMS小鼠表现出大脑动脉搏动和顺应性减少，并表现出AQP 4的去极化表达，从而表明在清醒和麻醉状态下都存在胶质淋巴功能障碍。PUFA补充剂挽救了BOS小鼠的抑郁样行为，减少了神经炎症和脑血管功能障碍，最终改善了认知能力，所有这些都伴随着恢复胶质淋巴系统功能。相比之下，Es治疗缓解抑郁样的行为症状，而没有表现出对胶质淋巴功能和抑郁症事件的认知deficits.Conclusions的影响：ESTA抑郁症模型需要抑制胶质淋巴系统。PUFA补充剂通过恢复潜在的胶质淋巴系统破坏和保护脑血管功能，挽救了抑郁症的大多数行为体征和相关的认知功能障碍。
Introduction: Depression, the most prevalent mood disorder, has high comorbidity with cerebrovascular disease and cognitive decline. However, there is little understanding of the cellular mechanisms involved in depression and its comorbid cerebrovascular damage and cognition impairment. Here, we tested the prediction that the chronic unpredictable mild stress (CUMS) mouse model would manifest in disturbed glymphatic function and that dietary supplementation with polyunsaturated fatty acids (PUFA) could ameliorate these deficits while alleviating the depression-associated cognitive decline.Methods: To test the treatment effects of PUFA or Es on behaviours, we applied the tail suspension, open field, and sucrose preference tests to assess depressive symptoms, and applied the Morris water maze test to assess cognition in groups of control, chronic unpredictable mild stress (CUMS), PUFA, and escitalopram (Es) treatment. We measured the extracellular concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in microdialysates from prefrontal cortex (PFC) by liquid chromatography mass spectrometry. Glia cells and inflammatory factors were analysed with fluorescent immunochemistry and western blot, respectively. We tested brain vasomotor function with two-photon and laser speckle imaging in vivo, and measured glymphatic system function by two-photon imaging in vivo and fluorescence tracer imaging ex vivo, using awake and anesthetized mice. Besides, we monitored cortical spreading depression by laser speckle imaging system. AQP4 depolarization is analysed by fluorescent immunochemistry and western blot.Results: We confirmed that CUMS elicited depression-like and amnestic symptoms, accompanied by decreased monoamines neurotransmitter concentration in PFC and upregulated neuroinflammation markers. Moreover, CUMS mice showed reduced arterial pulsation and compliance in brain, and exhibited depolarized expression of AQP4, thus indicating glymphatic dysfunction both in awake and anesthetized states. PUFA supplementation rescued depression-like behaviours of CUMS mice, reduced neuroinflammation and cerebrovascular dysfunction, ultimately improved cognitive performance, all of which accompanied by restoring glymphatic system function. In contrast, Es treatment alleviated only the depression-like behavioural symptoms, while showing no effects on glymphatic function and depression-incident cognitive deficits.Conclusions: The CUMS depression model entails suppression of the glymphatic system. PUFA supplementation rescued most behavioural signs of depression and the associated cognitive dysfunction by restoring the underlying glymphatic system disruption and protecting cerebral vascular function.