|Alternative Title||The role of TNF-α in depressive-like behavior of rats|
|Place of Conferral||北京|
|Keyword||抑郁样行为 细胞因子 强迫游泳应激 LPS TNF-α 海马 infliximab|
|Abstract||抑郁症的细胞因子假说提出已有十几年，越来越得到学者们的认可。然而，不同实验室、不同动物模型的研究中，所报道的细胞因子的变化不尽相同。目前尚鲜有研究考察不同类型的抑郁症中是否存在共同的风险性细胞因子。本研究以此为出发点，采用两种不同类型的大鼠抑郁模型：慢性应激所致抑郁和慢性炎症所致抑郁，以大鼠的体重增长、糖精水偏爱、旷场行为和悬尾测试为观察的行为指标，RT-PCR 和western-blot 技术检测mRNA 水平和蛋白水平促炎性细胞因子在抑郁相关脑区的变化，考察慢性应激和慢性炎症所致抑郁中是否存在共同的风险性细胞因子，并考察其重要性。|
研究包括以下五个实验。实验一：强迫游泳应激和重复中枢LPS 注射诱发大鼠抑郁样行为，建立两种类型的大鼠抑郁模型，考察其中体重增长、糖精水偏爱、悬尾测试中不动时间和不动潜伏期的变化。实验二：强迫游泳应激和重复中枢LPS 注射对中枢抑郁相关脑区中促炎性细胞因子表达水平的影响，考察了两个模型下前额叶、海马和杏仁核中TNF-α、IL-1β 和IL-6 mRNA 水平的变化。实验三：中枢TNF-α 注射诱发大鼠抑郁样行为，考察中枢直接注射不同剂量的TNF-α 能否诱发大鼠出现抑郁样行为，分别考察其在2h 和24h 的行为变化。实验四：TNF-α 抑制剂infliximab 对强迫游泳应激和重复中枢LPS 注射诱发的大鼠抑郁样行为的影响，考察减少发挥功能的TNF-α 能否阻断抑郁样行为的发生。实验五：TNF-α 抑制剂infliximab 对强迫游泳应激和重复中枢LPS 注射诱发的中枢促炎性细胞因子变化的影响，考察在强迫游泳应激和重复中枢LPS 注射模型下，中枢注射TNF-α 抑制剂对前额叶、海马和杏仁核中TNF-α 和IL-1β 的蛋白表达水平的影响。
研究结果显示：（1）强迫游泳应激和重复中枢LPS 注射均诱发大鼠的体重增长减少，糖精水偏爱水平下降及悬尾测试中不动潜伏期的缩短或不动时间的延长，即诱发大鼠出现抑郁样行为。（2）在强迫游泳应激和重复中枢LPS 注射两个模型中，均发现中枢TNF-α mRNA 水平的升高，并且共同变化的脑区是海马。IL-1β mRNA 水平的增高仅发生在重复中枢LPS 注射模型下，IL-6 mRNA 水平在两个模型下均没有增加。（3）中枢TNF-α 注射剂量依赖性和时间依赖性的诱发了大鼠的糖精水偏爱水平的下降，开放臂停留时间的减少和不动时间的延长。（4）TNF-α 抑制剂infliximab 改善了强迫游泳应激诱发的大鼠糖精水偏爱水平的下降和悬尾测试中不动时间的延长，没有改善强迫游泳应激诱发的大鼠体重增长的下降；TNF-α 抑制剂infliximab 改善了重复中枢LPS 注射诱发的糖精水偏爱水平的下降和旷场测试中直立行为的减少，但没有改善重复中枢LPS 注射诱发的大鼠体重增长的下降，旷场测试中运动距离的减少及悬尾测试中不动时间的延长。（5）TNF-α 抑制剂infliximab 的注射显著降低了强迫游泳应激和重复中枢LPS 诱发的海马区域的TNF-α 含量的增多，在前额叶和杏仁核未发现显著差异，未显著影响前额叶、海马和杏仁核中IL-1β 的含量。
综上所述，中枢TNF-α 是慢性应激和慢性炎症所致大鼠抑郁样行为中重要的调控因子。慢性应激和慢性炎症诱发抑郁样行为的大鼠均显示增多的中枢TNF-α mRNA 表达，TNF-α 直接中枢注射可剂量依赖和时间依赖性的诱发大鼠出现抑郁样行为，TNF-α 抑制剂的注射又可以有效改善慢性应激和慢性炎症所致大鼠抑郁样行为。海马区可能是TNF-α 调控慢性应激和慢性炎症所致抑郁的重要脑区。
|Other Abstract||The cytokine hypothesis of depression has been proposed more than a decade, and is more and more widely accepted. Among multiple studies, the alteration of cytokines reported by different laboratory,or used different animal models was different. Till now, few investigations have searched for specific and common changes in cytokines. In the present study, two animal models of depression were compared: a chronic stress model using forced swim stress and an immune activation model using repeated central lipopolysaccharide (LPS) infusion. The depressive-like behaviors were assessed by the body weight gain, saccharin preference test, open field test, and tail suspension test. The alterations of cytokine mRNA and protein expression in depression-related brain regions were measured by RT-PCR and western-blot, respectively. The aim of the present study was to investigate whether specific and common cytokines existed among different models of depression, and what the role of those cytokines play.|
The following experiments were carried out in the investigation. In experiment 1, forced swim stress or repeated central LPS infusion was used to induce the depressive-like behaviors of rats, in order to establish these two different animal models of depression. The body weight gain, saccharin preference test, and the tail suspension test were used to assess the depressive-like behaviors of rats. In experiment 2, the mRNA expression alterations of proinflammatory cytokines (TNF-α, IL-1β and IL-6) in depression-related regions (prefrontal cortex, hippocampus, and amygdale) induced by forced swim test and repeated central LPS infusion were tested. In experiment 3, to evaluate whether the direct infusion of TNF-α centrally could induce the depressive- like behaviors of rats, and whether it was dose-dependent or time-dependent, different doses of TNF-α were intracerebroventricular infused, and the behavior of rats were tested both at 2h and 24h after the last infusion. In experiment 4, infliximab, TNF-α receptor antagonist, was used to investigate whether the reduction of TNF-α could block the occurrence of depressive- like behaviors induced by forced swim stress or repeated central infusion of LPS . In experiment 5, the alterations of central proinflammatory cytokines in experiment 4 were tested using western-blot, in order to investigate the effect of TNF-α receptor antagonist on the expression of TNF-α and IL-1β in prefrontal cortex, hippocampus, and amygdale under these two models.
The results showed that: (1) both forced swim stress and repeated central LPS infusion induced the depressive- like behaviors of rats, including reduced body weight gain, decreased saccharin preference, and shortened latency of immobility or increased immobility time in tail suspension test. (2) An increase o f central TNF-α mRNA expression was found in both forced swim stress model and repeated central LPS infusion model, especially in hippocampus. An increase of central IL-1β mRNA expression was found only in the repeated central LPS infusion model, and no significant alteration of central IL-6 mRNA expression was found in either of the two models. (3) Central infusion of TNF-α induced the decrease of saccharin preference and the time in open arm in elevated plus maze, and the increase of immobility time in tail suspension test in a dose- and time-dependent course. (4) Infliximab ameliorated the reduction of saccharin preference, the increase of immobility time in tail suspension test, but not the reduced body weight gain induced in the forced swim stress induced model of depression; infliximab ameliorated the reduced saccharin preference and the number of rearing in open field test, but not the reduced body weight gain, decreased distance traveled in open field test and the increased immobility time in tail suspension test in the central LPS infusion induced model of depression. (5) Infliximab reduced the increase of TNF-α in hippocampus induced by either forced swim stress or repeated central LPS infusion, while no changes were found in prefrontal cortex and amygdale. The protein expression of IL-1β was found unchanged in prefrontal cortex, hippocampus and amygdale in both depression models.
In conclusion, central TNF-α is an important common mediator in both chronic stress and chronic immune activation induced depression models. Central infusion of TNF-α could induce depressive- like behaviors dose- and time-dependently. The infusion of TNF-α receptor antagonist could ameliorate some of the depressive- like behaviors of rats induced both by chronic stress and by chronic immune activation. Additionally, hippocampus may be a very important common region for the regulation of chronic stress and chronic immune activation induced depression by TNF-α.
|管西婷. 促炎性细胞因子TNF-α在大鼠抑郁样行为中的作用[D]. 北京. 中国科学院研究生院,2015.|
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