条件反射性免疫抑制及其脑机制的c-fos研究

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	条件反射性免疫抑制及其脑机制的c-fos研究
	郑丽
	2000
摘要	为探讨条件反射性免疫调节的神经机制，本研究采用经典的味觉厌恶学习模式，以糖精水为条件刺激(CS)，腹腔注射免疫抑制剂环磷酰胺(CY)为非条件刺激(UCS)，在Wistar大鼠上建立条件反射性体液免疫和细胞免疫抑制的动物模型。用c-fos免疫组织化学手段观察在条件反射性免疫抑制(CIS)形成、表达和消退过程中全脑内神经元活动的变化，并分析CS和UCS在脑内的信息传导和整合的可能机制。主要结果如下： 1．一次CS-UCS结合训练后，第5天单独CS就可导致外周血抗卵消蛋白(OVA)IgG抗体水平的进一步降低。两次CS-UCS结合训练并多次给予 CS 不仅诱导出对原发性体液免疫反应的抑制，而且使外周血淋巴细胞和白细胞数量都显著降低。说明 CS 可诱导出对免疫功能广泛的抑制作用，并且随着强化水平的增加，条件性免疫抑制效应增强。2．连续两次CS-UCS结合训练后第5天，再次接受CS的动物脾淋巴细胞对ConA、PHA和PWM的转化反应以及外周血淋巴细胞和白细胞数量均显著降低；训练后第15天CS仅仅对脾淋巴细胞PHA转化反应有明显抑制作刚；训练后30天再次给予CS，上述各种免疫指标都未出现明显变化。提示对细胞免疫功能的条件性抑制作川只能保持5-15天，30天后完全消退。3．不论一次还是两次 CS-UCS 结合训练，均使动物建立起对糖精水强烈的味觉厌恶反应，这种味觉厌恶性条件反射(CTA)非常稳定，在训练后30天内一直保持很好。表明CIS与CTA并不同步，它们形成和保持的机制可能有所不同。4．CS-UCS结合训练以及训练后单独给予CS在脑内诱导出广泛分布的FOS表达，表明许多脑结构参与了CIS。一些脑区如孤束核(Sol)、外侧臂旁核(LPB)和岛皮质等同时对CS和UCS发生反应，在训练过程中有大量c-fos表达，它们可能参与了 CS 和 UCS 信号在中枢的传导和整合。下丘脑室旁核(PVN)与视上核(SO)、穹隆下器(SFO)和最后区(AP)等核团在第一次训练后几乎见不到FOS阳性反应，在两次训练后以及训练后第 5 天单独给予 CS时有大量FOS表达，但在 CIS 消退后(训练后第30天)FOS表达显著降低甚至消失，表明它们可能在CIS表达过程中具有重要作用，也可能参与脑对CY免疫抑制作用的反应。扣带皮质(Cg)、杏仁中央核(Ce)、隔外侧核中间部(LSI)以及腹外侧臂旁核(VLPB)等结构在训练过程中呈现密集的FOS免疫阳性反应。在训练后第5天给予CS后也有明显的FOS表达，第30天给予CS时FOS表达很少或检测不到，说明它们与CIS特异相关，可能是CIS形成和表达的关键性结构。而额皮质(Fr)、眶腹侧皮质(VO)、岛颗粒皮质(GI)、嗅周皮质(PRh)以及孤束内侧核(SolM)等，在条件反射训练以及训练后第5天和第30天再次给予CS时均表现出较强的FOS表达，提示它们主要与CTA的获得和l保持有关。
其他摘要	To explore the neural mechanisms underlying conditioned immunomodulation, this study employed the classical taste aversion (CTA) behavioral paradigm to establish the conditioned humoral and cellular immunosuppression (CIS) in Wistar rats, by paring saccharin (CS) with intraperitoneal (i.p.) injection of an immunosuppressive drug cyclophophamide (UCS). C-fos immunohistochemistry method was used to observe the changes of the neuronal activities in the rat brain during the acquisition, expression and extinction of the conditioned immunosuppression (CIS). The followings are the main results: 1. Five days after one trial of CS-UCS paring, reexposure to CS alone significantly decreased the level of the anti-ovalbumin (OVA) IgG in the peripheral serum. Two trials of CS-UCS paring and three reexposures to CS not only resulted in further suppression of the primary immune response, but also reduced the numbers of peripheral lymphocytes and white blood cells. This finding indicates that CS can induce suppression of the immune function, and the magnitude of the effects is dependent on the intensity of training. 2. On day 5 following two trials of CS-UCS pairing, CS suppressed the spleen lymphocytes responsiveness to mitogens ConA, PHA and PWM, and decreased the numbers of peripheral lymphocytes and white blood cells. On day 15, only PHA induced lymphocyte proliferation was suppressed by CS. On day 30, presentation of CS did not have any effect on these immune parameters. These results suggest that the conditioned suppression of the cellular immune function can retain 5-15 days, and extinct after 30 days. 3. CTA was easily induced by one or two CS-UCS parings, and remained robust even after 30 days. These data demonstrate that CIS can be dissociated from CTA, and they may be mediated by different neural mechanisms. 4. Immunohistochemistry assays revealed a broad pattern of c-fos expression throughout the rat brain following the CS-UCS pairing and reexposure to CS, suggesting that many brain regions are involved in CIS. Some brain areas including the solitary tract nucleus (Sol), lateral parabrachial nucleus (LPB) and insular cortex (IC), showed high level c-fos expressions in response to both CS and UCS, suggesting that they may be involved in the transmission and integration of the CS and UCS signals in the brain. There were dense c-FOS positive neurons in the paraverntricular nucleus (PVN) and supraoptic nucleus (SO) of hypothalamus, subfornical organ (SFO) and area postrema (AP) etc. after two trials of CS-UCS paring and after the reexposure to CS 5 days later, but not in the first training and after the extinction of CIS (30 days later). The results reflect that these nuclei may have an important role in CIS expression, and may also response to the immunosuppression of UCS. The conditioned training and reexposure to CS 5 days later induced high level c-fos expression in the cingulate cortex (Cg), central amygdaloid nucleus (Ce), intermediate part of lateral septal nucleus (LSI) and ventrolateral parabrachial nucleus (VLPB) etc. But c-fos induction was not apparent when presenting CS 30 days later. These brain regions are mainly involved in CIS, and may be critical structures in the acquisition and expression of CIS. Some brain regions, including the frontal cortex (Fr), ventral orbital cortex (VO), IC, perirhinal cortex (PRh), LPB and the medial part of solitary nucleus (SolM), showed robust c-FOS expression following the conditioning training and reexposure to CS both on day 5 and day 30, suggesting that they are critically involved in CTA.
关键词	条件反射性免疫抑制脑区味觉厌恶性条件反射环磷酰胺
学位类型	博士
语种	中文
学位专业	生物心理学
学位授予单位	中国科学院心理研究所
学位授予地点	中国科学院心理研究所
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/4898
专题	中国科学院心理研究所回溯数据库(1956-2010)
推荐引用方式 GB/T 7714	郑丽. 条件反射性免疫抑制及其脑机制的c-fos研究[D]. 中国科学院心理研究所. 中国科学院心理研究所,2000.

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