小胶质细胞的炎症反应及其相关膜功能对应激诱导抑郁症的调控机制

批准号:
81471223
项目类别:
面上项目
资助金额:
70.0 万元
负责人:
宋采
依托单位:
学科分类:
H0907.神经系统免疫异常及相关疾病
结题年份:
2018
批准年份:
2014
项目状态:
已结题
项目参与者:
千忠吉、赵云涛、张永平、刘亚、邱德全、李鹏、邵海艳、戚亚伟
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中文摘要
作用于神经递质系统的抗抑郁剂只能治愈50%的患者, 为此抑郁症的炎症假说独辟蹊径。我们已证明炎症能够导致抑郁和神经退行性病变,如刺激HPA轴释放应激激素、减少神经递质合成、抑制神经营养因子(NTFs)功能和神经发生。反之,慢性应激能驱动胶质细胞的炎症反应而导致抑郁。我们也证明细胞膜成分Omega-3 fatty acids (FAs)能够治疗抑郁并改善认知和记忆,其机制为抗炎、抗氧化以及调节神经递质和NTFs的功能。 待解决的重要问题是:慢性应激如何改变1)胶质细胞活性从而将M1和M2表型转向炎症反应;2)细胞膜促炎和抗炎FAs浓度与细胞膜流动性和功能之间的关系;3)膜胆固醇的浓度及与炎症和HPA功能的关系;4)FAs敏感受体和离子通道的的功能;6)FAs治疗抑郁的膜机制。本研究以慢性应激诱导的大鼠模型为对象,用精神神经免疫学的理念,结合行为学、药理学和分子生物学方法,揭示以上关键的机制。
英文摘要
Classic hypotheses of depression or neurodegeneration, such as Alzheimer's disease (AD) were based on neurotransmitter deficits, dysfunction of hypothalamic-pituitary-adrenal (HPA) axis and neurotoxic deposition. Therefore, current treatments focus on neurotransmitter synthesis, uptake, metabolism and receptors, as well as on the antagonist of glucocorticoids or receptors. Due to most ineffective treatments with many side-effects, the exploration of new mechanisms and treatments are urgent. In the past 20 years, we have demonstrated that increased innate (non-specific) inflammatory response, neurotrophin dysfunction and omega (n)-3 unsaturated fatty acid (FA) deficits may play crucial roles in the onset and progress of depression and neurodegenerative diseases. In animal models, we showed that stress could trigger inflammatory response, while inflammation could stimulate stress hormone release. Furthermore, we revealed that n-3 FA exerted antidepressant and neuroprotective effects via anti-inflammation, anti-oxidants and normalizing neurotransmitter and neurotrophic systems. However, several important mechanisms are unknown: 1) whether and how chronic stress induces neuroinflammation through activating brain glial cells, which triggers specific microglia M1 and M2,then promote inflammatory response; 2) the relationship between chronic stress/inflammation and membrane functions, such as FA profile, membrane fluidity and raft function; 3) how stress/inflammation-induced changes cause the dysfunction of the HPA axis and neurotransmitter systems by distributing membrane FAs and cholesterols; 4) whether and how stress changes the function of "FA sensitive receptors", such as neuronal ion channel proteins, G-proteins and peroxisome proliferator-activated proteins. Thus, the present project aims to answer these questions. In chronic and multiple stressors induced rodent model and normal controls, the studies will step by step carry out from FA profile, membrane fluidity, cholesterol concentrations, then membrane associated changes in microglia-modulated neuroinflammation and astrocytes modulated neurotrophin functions, to the activity of the HPA axis and function of neurotransmitters, finally to depression and AD-like behavioural output. Upon the new discoveries, the membrane mechanism by which n-3 FA treat depression and AD will be explored. The study will reveal new mechanisms of these brain diseases and open a new direction for drug treatments.
我们已证明免疫炎症反应能够导致抑郁和神经退行性病变,如刺激HPA 轴释放应激激素、减少神经递质合成、抑制神经营养因子(NTFs)功能和神经发生。反之,慢性应激,作为抑郁的扳机,能驱动胶质细胞的炎症反应而导致抑郁。我们也证明细胞膜成分Omega(n)-3 不饱和脂肪酸(fatty acids,FAs)能够治疗抑郁,并改善认知和记忆,其机制为抗炎、抗氧化以及调节神经递质和NTFs 的功能。本课题待解决的重要问题是:慢性不可预测温和应激(chronic unpredicatable mild stress, CUMS)如何改变1)小胶质细胞从M1(炎症)向M2 (抗炎)之间的转化;2)细胞膜促炎和抗炎FAs 浓度与细胞膜流动性和功能之间的关系;3)膜胆固醇的浓度及与炎症和HPA 功能的关系;4)FAs 敏感受体和离子通道的的功能;6)FAs 治疗抑郁的膜机制。.本项目以CUMS诱导的大小鼠模型为对象,进行了以下几个方面研究并证明:1)CUMS通过刺激 HPA 轴的功能诱导神经炎症,抑郁行为和神经免疫变化以及雌雄模型动物对应激的不同反应与人类男女抑郁症状的相关性;2)CUMS诱导的抑郁和焦虑样行为是促进M1,抑制M2亚型和星形细胞功能的结果,而小胶质细胞抑制剂米诺环素治疗逆转了M1反应,并使行为正常化;3)n-3FAs eicosapentaenoic acid (EPA)和docosahexaenoic acid (DHA)及不同比例混合对慢性应激抑郁大鼠的差异调节。 EPA具有较强的抗炎和抗氧化,而DHA具有较好的抗凋亡和神经营养因子调节作用, 并发现EPA:DHA超过单独FA的最佳组合;4)EPA、DHA及海参提取物可通过通过神经免疫调节改善斑马鱼CUMS模型的行为异常记忆机制;5)秀丽隐杆线虫Fat-1转基因的内源性n-3 FAs小鼠可通过抑制M1反应,促进M2表型表达,加强BDNF功能,改善炎症诱发的抑郁症;6)海洋药物海马可通过调节CUMS诱发的应激激素释放和神经递质的异常改善抑郁症状;7)海参酶解液对CUMS诱导小鼠抑郁样行为的改善作用与抗炎和抗氧化相关;8)内源性n-3不饱和脂肪酸对嗅球切除模型小鼠的抑郁样及记忆损伤行为的改善作用。. 本项目基本回答了以上4个关键问题,对于进一步揭示抑郁症的机制和研发具有新的作用机制的防治抑郁症药物具有重
期刊论文列表
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专利列表
Mifepristone attenuates depression-like changes induced by chronic central administration of interleukin-1β in rats
米非司酮减轻大鼠长期中枢注射白细胞介素-1β 引起的抑郁样变化
DOI:10.1016/j.bbr.2018.03.033
发表时间:2018-07
期刊:Behavioural Brain Research
影响因子:2.7
作者:张永平;宋采
通讯作者:宋采
Application of Chitosan, Chitooligosaccharide, and Their Derivatives in the Treatment of Alzheimer's Disease.
壳聚糖、壳寡糖及其衍生物在治疗阿尔茨海默病中的应用
DOI:10.3390/md15110322
发表时间:2017-11-07
期刊:Marine drugs
影响因子:5.4
作者:Ouyang QQ;Zhao S;Li SD;Song C
通讯作者:Song C
Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat
米诺环素可改善大鼠由慢性不可预测的轻度应激引起的抑郁行为和神经免疫功能障碍
DOI:10.1016/j.bbr.2018.07.001
发表时间:2019-01
期刊:Behavioural Brain Research
影响因子:2.7
作者:张才;宋采
通讯作者:宋采
DOI:--
发表时间:2016
期刊:徐州医学院学报
影响因子:--
作者:薛红莎;宋采
通讯作者:宋采
DOI:--
发表时间:2017
期刊:广东海洋大学学报
影响因子:--
作者:刘白平;李玉玉;张才;薛红莎;张永平;赵云涛;卢虹玉;宋采
通讯作者:宋采
探索抑郁症中淋巴细胞功能障碍-炎症-胶质细胞极化失衡的通路及角色
- 批准号:--
- 项目类别:省市级项目
- 资助金额:10.0万元
- 批准年份:2021
- 负责人:宋采
- 依托单位:
白细胞介素-1beta诱导神经退化性疾病和记忆损伤的机制
- 批准号:81171118
- 项目类别:面上项目
- 资助金额:59.0万元
- 批准年份:2011
- 负责人:宋采
- 依托单位:
国内基金
海外基金
