Stably maintained microtubules protect dopamine neurons and alleviate depression-like behavior after intracerebral hemorrhage.
Stably maintained microtubules protect dopamine neurons and alleviate depression-like behavior after intracerebral hemorrhage.
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稳定维持的微管可保护多巴胺神经元并减轻脑出血后的抑郁样行为
DOI：
10.1038/s41598-018-31056-7
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发表时间：
2018-08-23
影响因子：
4.6
通讯作者：
Tan L
中科院分区：
文献类型：
--
作者：
Yang Y;Zhang K;Zhong J;Wang J;Yu Z;Lei X;Chen X;Quan Y;Xian J;Chen Y;Liu X;Feng H;Tan L
中脑边缘多巴胺(DA)系统损害在抑郁症的病理生理学中起关键作用，我们先前的研究表明微管(MT)稳定性降低加重了脑出血(ICH)后黑质纹状体通路的损害。本研究旨在进一步探讨脑出血后抑郁行为的发生规律，以及维持MT的稳定是否能保护被盖腹侧区(VTA)的DA神经元，从而减轻脑出血后的抑郁行为。纹状体内注射20 μL自体血或MT解聚剂诺可达唑模拟小鼠脑出血模型的病理改变。检测脑出血后大鼠下丘脑室旁核DA含量、DA能神经元数量和α微管蛋白乙酰化水平，并进行抑郁相关行为测试。应用MT稳定剂EpoB(EpoB)，观察MT稳定剂对脑出血后DA神经元和抑郁行为的影响。结果表明，脑出血后7、14、28天出现明显的抑郁样行为(P<； 0.01)。这些时点与VTA内DA含量(P<； )和DA神经元数量(P<； )显著减少有关。此外，脑出血和一氧化氮注射后乙酰化α-微管蛋白表达的减少可能是延髓内DA神经元损伤的原因之一，而NOCO注射也加重了脑出血后抑郁行为和DA神经元的损伤。此外，EpoB可明显改善脑出血和一氧化氮合酶诱导的抑郁行为(P<； 0.05)，并通过增加乙酰化 -微管蛋白的水平增加多巴胺的浓度(P<； 0.05)和DA神经元的数量(P<；α0.05)。结果表明，EpoB可通过提高MT的稳定性来保护DA神经元，减轻脑出血后的抑郁行为。这种针对MT的治疗策略显示出作为治疗脑出血后抑郁的一种从长凳到床边的转换方法的前景。
Mesolimbic dopamine (DA) system lesion plays a key role in the pathophysiology of depression, and our previous study demonstrated that reduced microtubule (MT) stability aggravated nigrostriatal pathway impairment after intracerebral hemorrhage (ICH). This study aimed to further investigate the occurrence regularity of depression-like behavior after ICH and determine whether maintaining MT stabilization could protect DA neurons in ventral tegmental area (VTA) and alleviate depression-like behavior after ICH. An intrastriatal injection of 20 μl of autologous blood or MT depolymerization reagent nocodazole (Noco) was used to mimic the pathology of ICH model in mice. The concentration of DA, number of DA neurons and acetylated α-tubulin (a marker for stable MT) in VTA were checked, and depression-related behavior tests were performed after ICH. A MT-stabilizing agent, epothilone B (EpoB), was administered to explore the effects of MT stabilization on DA neurons and depression-like behavior after ICH. The results showed that obvious depression-like behavior occurred at 7, 14, and 28 days (P< 0.01) after ICH. These time-points were related to significant decreases in the concentration of DA (P< 0.01) and number of DA neurons (P< 0.01) in VTA. Moreover, The decrease of acetylated α-tubulin expression after ICH and Noco injection contributed to DA neurons’ impairment in VTA, and Noco injecton also aggravate ICH-induced depression-like behaviors and DA neurons’ injury. Furthermore, EpoB treatment significantly ameliorated ICH and Noco-induced depression-like behaviors (P< 0.05) and increased the concentration of DA (P< 0.05) and number of DA neurons (P< 0.05) in VTA by increasing the level of acetylated α-tubulin. The results indicate that EpoB can protect DA neurons by enhancing MT stability, and alleviate post-ICH depressive behaviors. This MT-targeted therapeutic strategy shows promise as a bench-to-bedside translational method for treating depression after ICH.
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