【摘要】：研究目的： 本研究的主要目的是探討在新生期大鼠慢性給予苯環(huán)己哌啶（一種NMDA受體拮抗劑，英文名為Phencyclidine, PCP）處理后，大鼠能否在青春期表現(xiàn)出髓鞘的發(fā)育缺陷及類精神分裂癥樣行為，從而發(fā)展出一種新的可用于研究精神分裂癥髓鞘/少突膠質(zhì)細胞異常假說的動物模型。同時，本研究還選擇了喹硫平這一對髓鞘損害有保護作用的非典型抗精神病藥物，觀察其對PCP誘導的精神分裂癥樣行為及髓鞘異常的影響，以進一步確立該模型的預測效度。 研究方法： 本研究中所有的實驗均為動物實驗，共分為兩部分進行：第一部分為PCP干預后對大鼠的髓鞘變化及行為學異常的觀察，第二部分則是探討喹硫平能否逆轉(zhuǎn)PCP誘導的精神分裂癥樣行為及髓鞘異常。 在第一部分，動物被隨機分為兩組：（1）生理鹽水對照組，從出生后第2天起即給予實驗動物（新生大鼠）連續(xù)14天的生理鹽水頸部皮下注射，至出生后15天止，注射劑量為1ml/kg；（2）PCP干預組，從出生后第2天起即給予實驗動物連續(xù)14天的PCP頸部皮下注射，PCP注射液濃度為1mg/ml，注射劑量為10mg/kg。 在第二部分，動物被隨機分為四組：（1）生理鹽水對照組，從出生后第2天起即給予實驗動物每天2次、連續(xù)14天的生理鹽水頸部皮下注射，至出生后第15天止，每天2次注射的間隔時間為30min。從出生后第16天至出生后第20天給予實驗動物每天1次的生理鹽水注射。生理鹽水每次注射劑量均為1ml/kg；（2）PCP干預組，從出生后第2天起即給予實驗動物連續(xù)14天的生理鹽水和PCP分次頸部皮下注射，先注射生理鹽水，后注射PCP，2次注射的間隔時間為30min。從出生后第16天至出生后第20天給予實驗動物每天1次的生理鹽水注射。PCP注射液濃度為1mg/ml，注射劑量為10mg/kg。生理鹽水每次注射劑量均為1ml/kg。（3）喹硫平干預組，從出生后第2天起即給予實驗動物連續(xù)14天的喹硫平和生理鹽水分次頸部皮下注射，先注射喹硫平，后注射生理鹽水，2次注射的間隔時間為30min。從出生后第16天至出生后第20天給予實驗動物每天1次的喹硫平注射。喹硫平注射液濃度為1mg/ml，注射劑量為10mg/kg。生理鹽水每次注射劑量均為1ml/kg。（4）喹硫平及PCP雙干預組，從出生后第2天起即給予實驗動物連續(xù)14天的喹硫平和PCP分次頸部皮下注射，先注射喹硫平，后注射PCP，2次注射的間隔時間為30min。從出生后第16天至出生后第20天給予實驗動物每天1次的喹硫平注射。喹硫平及PCP的注射液濃度均為1mg/ml，注射劑量均為10mg/kg。 觀察指標有兩個方面，一是行為學觀察：（1）自發(fā)活動測試，用來評定大鼠的自發(fā)活動增強現(xiàn)象；（2）PPI測試，用來評定大鼠的感覺運動門控功能損害程度。二是髓鞘發(fā)育情況的觀察：運用免疫組織化學、Westernblot及電子顯微鏡等技術(shù)觀察實驗動物腦內(nèi)PFC區(qū)的髓鞘發(fā)育變化情況。 結(jié)果：在實驗的第一部分，給予新生期大鼠PCP干預后，我們發(fā)現(xiàn)在大鼠出生后第16天、第22天、第32天均可檢測到大腦PFC區(qū)的髓鞘發(fā)育缺陷，主要表現(xiàn)為成熟少突膠質(zhì)細胞數(shù)量的減少、髓鞘束分布范圍的縮小以及MBP蛋白表達的降低，在出生后第32天還發(fā)現(xiàn)了白質(zhì)的超微結(jié)構(gòu)病理改變。同時，在出生后第30天和第31天進行的行為學檢測發(fā)現(xiàn)這些大鼠可產(chǎn)生精神分裂癥樣行為。具體如下： 1.我們對大鼠出生后第16天的髓鞘發(fā)育情況進行了觀察。首先，與生理鹽水對照組相比，PCP組大鼠腦PFC區(qū)的成熟少突膠質(zhì)細胞（GST-π陽性細胞）數(shù)目明顯減少（P 0.05, t-test）；其次，在對照組大鼠腦切片的PFC區(qū)存在比較致密的由抗-MBP抗體免疫標記的髓鞘束，而在PCP組大鼠的相同區(qū)域卻觀察到了髓鞘束的分布范圍的減少，對其光密度值進行的定量分析表明，與對照組相比，PCP組大鼠PFC區(qū)的髓鞘束密度明顯降低（P 0.05, t-test）；最后，對實驗大鼠的腦PFC區(qū)的MBP蛋白進行了Western Blot檢測，對Western Blot條帶的光密度進行的定量分析顯示，與對照組相比，PCP組大鼠腦PFC區(qū)的MBP表達明顯降低（P 0.05, t-test）。 2.我們對大鼠出生后第22天的髓鞘發(fā)育情況進行了觀察。結(jié)果發(fā)現(xiàn)，與生理鹽水對照組相比，PCP組大鼠腦PFC區(qū)的GST-π陽性細胞數(shù)目仍然明顯減少（P 0.05, t-test），其髓鞘束密度明顯降低（P 0.05, t-test），且其MBP的表達仍然顯著低于對照組（P 0.05, t-test）。但與出生后第16天相比，對照組及PCP組大鼠腦PFC區(qū)的髓鞘束均顯得更為致密，且覆蓋范圍更廣，提示在此期間，髓鞘/少突膠質(zhì)細胞正在迅速的發(fā)育。 3.我們對大鼠出生后第32天的髓鞘發(fā)育情況進行了觀察。結(jié)果發(fā)現(xiàn)，，PCP組大鼠腦PFC區(qū)僅在MBP的表達上顯著低于對照組（P 0.05, t-test），而GST-π陽性細胞數(shù)和髓鞘束密度與對照組相比無明顯差異（P0.05）。這種結(jié)果的不一致可能是檢測方法的靈敏度不同所導致的（Western Blot檢測具有更高的靈敏度）。另外，電子顯微鏡觀察顯示，在PCP組的某些髓鞘部位可看到髓鞘層的局部降解以及致密的層間小體正在形成。 4.為了評估PCP干預造成的精神分裂癥樣行為，我們對出生后第30和第31天的大鼠進行了自發(fā)活動及PPI的檢測。結(jié)果表明，與對照組相比，PCP干預組大鼠自發(fā)活動明顯增多（P 0.05, t-test），且PCP干預對PPI產(chǎn)生了明顯影響[F(1,34)=13.48, P=0.0008]，Post-hoc分析顯示，與對照組相比，PCP組大鼠在PP8和PP16水平，其PPI(%)顯著降低（P 0.05）。 在實驗的第二部分，我們發(fā)現(xiàn)喹硫平在10mg/kg劑量下不能改善PCP引起的髓鞘發(fā)育缺陷，也不能改善與髓鞘異常相關(guān)的反映精神分裂癥認知癥狀的PPI的損害，但能夠緩解PCP引起的反映精神分裂癥陽性癥狀的模型動物自發(fā)活動增多。具體如下： 1.我們對四組大鼠出生后第16天的髓鞘發(fā)育情況進行了觀察。單因素方差分析顯示，四組實驗大鼠PFC區(qū)的GST-π陽性細胞數(shù)目存在明顯差異[F(3,12)=5.493, P=0.0131]，髓鞘束分布范圍存在明顯差異[F(3,12)=30.93, P 0.0001]，且MBP的表達亦存在明顯差異[F(3,12)=37.77, P 0.0001]。而Post-hoc分析顯示，與對照組相比，PCP干預造成了GST-π陽性細胞數(shù)量的減少、髓鞘束的分布范圍的減少以及MBP蛋白表達的減少，而在PCP注射前加用10mg/kg的喹硫平并不能逆轉(zhuǎn)這些病理及生化變化（P 0.05）。 2.我們對四組大鼠出生后第32天的髓鞘發(fā)育情況進行了觀察。單因素方差分析顯示，四組實驗大鼠腦PFC區(qū)僅在MBP的表達上存在顯著差異[F(3,12)=23.30, P 0.0001]，而在GST-π陽性細胞數(shù)量[F(3,12)=0.6297, P=0.6097]及髓鞘束的分布范圍[F(3,12)=0.3711, P=0.7754]上無統(tǒng)計學差異。Post-hoc分析顯示，與對照組相比，PCP干預造成了MBP表達的下降，而在PCP注射前加用10mg/kg的喹硫平并不能逆轉(zhuǎn)這種變化（P0.05）。 3.我們對出生后第30和第31天的大鼠進行了自發(fā)活動及PPI的檢測。結(jié)果表明，四組大鼠間的自發(fā)活動存在明顯差異[F(3,34)=3.625, P=0.0226]，PCP和/或QUE干預對PPI有顯著影響[F(3,64)=8.235, P=0.0001]。與對照組相比，PCP干預組大鼠自發(fā)活動明顯增多，PPI%顯著下降，而在PCP注射前加用10mg/kg的喹硫平能夠緩解PCP引起的模型動物自發(fā)活動增多，但不能逆轉(zhuǎn)PPI的損害（P 0.05）。 結(jié)論： 在新生期大鼠慢性給予PCP處理后，大鼠在青春期會表現(xiàn)出髓鞘的發(fā)育缺陷以及類精神分裂癥樣行為，且兩者間有一定的相關(guān)性，提示髓鞘異常在精神分裂癥的病理發(fā)生中扮演著一定的作用，可將該模型用于研究精神分裂癥的髓鞘/少突膠質(zhì)細胞異常假說研究。同時，喹硫平在10mg/kg劑量下不能改善PCP引起的髓鞘發(fā)育缺陷，也不能改善與髓鞘異常相關(guān)的反映精神分裂癥認知癥狀的PPI的損害，但能夠緩解PCP引起的反映精神分裂癥陽性癥狀的自發(fā)活動增多。
[Abstract]:Research purposes:
The aim of this study was to investigate whether chronic administration of phenylcycloperidine (PCP), a NMDA receptor antagonist, could induce developmental deficiency of myelin sheath and schizophrenic-like behavior during puberty in neonatal rats, thereby developing a new type of myelin sheath/oligospermia that can be used to study schizophrenia. At the same time, we selected quetiapine, an atypical antipsychotic drug with protective effect on myelin sheath damage, to observe its effect on schizophrenia-like behavior and myelin sheath abnormality induced by PCP, in order to further establish the predictive validity of the model.
Research methods:
All the experiments in this study are animal experiments, divided into two parts: the first part is the observation of myelin sheath changes and behavioral abnormalities in rats after PCP intervention, the second part is to explore whether quetiapine can reverse the PCP-induced schizophrenia-like behavior and myelin sheath abnormalities.
In the first part, the animals were randomly divided into two groups: (1) saline control group, from the second day after birth, the experimental animals (neonatal rats) were given saline subcutaneously for 14 consecutive days, until 15 days after birth, the dose of injection was 1ml/kg; (2) PCP intervention group, from the second day after birth, the experimental animals were given PCP neck for 14 consecutive days. Subcutaneous injection, PCP injection concentration of 1mg/ml, injection volume of 10mg/kg.
In the second part, the animals were randomly divided into four groups: (1) saline control group, the experimental animals were given saline subcutaneously twice daily for 14 days from the second day after birth, and the interval between the two injections was 30 minutes from the 15th day after birth. Each injection dose of saline was 1 ml/kg; (2) PCP intervention group, from the second day after birth, was given 14 consecutive days of saline and PCP subcutaneous injection of cervical, first injection of saline, then injection of PCP, the interval between the two injections was 30 minutes. The experimental animals were injected with normal saline once a day. The concentration of PCP injection was 1 mg/ml and the dosage of PCP injection was 10 mg/kg. The dosage of physiological saline was 1 ml/kg per injection. The interval between the two injections was 30 minutes. From the 16th day after birth to the 20th day after birth, the experimental animals were given quetiapine injection once a day. The concentration of quetiapine injection was 1 mg/ml and the dosage of quetiapine injection was 10 mg/kg. The animals were subcutaneously injected with quetiapine and PCP for 14 consecutive days. The interval between the two injections was 30 minutes. From the 16th day to the 20th day after birth, the animals were injected with quetiapine once a day. The concentrations of quetiapine and PCP injection were 1 mg/ml, and the doses were 10 mg/kg.
There are two aspects to observe the indexes, one is behavioral observation: (1) spontaneous activity test, used to assess the phenomenon of spontaneous activity enhancement in rats; (2) PPI test, used to assess the degree of sensorimotor gating function damage in rats. The other is the observation of myelin sheath development: using immunohistochemistry, Western blot and electron microscopy technology observation. The development of myelin sheath in PFC region of experimental animals.
RESULTS: In the first part of the experiment, after PCP intervention in neonatal rats, we found that myelin sheath defects were detected on the 16th, 22nd and 32nd day after birth in rats, mainly manifested by the decrease of the number of mature oligodendrocytes, the narrowing of myelin bundle distribution and the decrease of MBP protein expression. Ultrastructural and pathological changes of white matter were also observed on the 32nd day after birth. Behavioral tests on the 30th and 31st days after birth showed that these rats had schizophrenic behavior.
1. We observed the myelin sheath development on the 16th day after birth in rats. Firstly, compared with the normal saline control group, the number of mature oligodendrocytes (GST-pi positive cells) in the PFC region of the rat brain in the PCP group was significantly decreased (P 0.05, t-test); secondly, there was a relatively dense immunization from anti-MBP antibody in the PFC region of the rat brain slices in the control group. Compared with the control group, the density of myelin bundles in the PFC region of the rats in the PCP group decreased significantly (P 0.05, t-test), and the MBP protein in the PFC region of the brain of the experimental rats was detected by Western blot. Blot assay showed that the expression of MBP in the PFC region of the rat brain in the PCP group was significantly lower than that in the control group (P 0.05, t-test).
2. We observed the myelin sheath development of rats on the 22nd day after birth. The results showed that compared with the control group, the number of GST-pi positive cells in PFC area of PCP group was still significantly decreased (P 0.05, t-test), the density of myelin bundle was significantly decreased (P 0.05, t-test), and the expression of MB P was still significantly lower than that of the control group (P 0.05, t-test). But the myelin sheath bundles in the PFC area of the control group and the PCP group were more dense and more extensive than those on the 16th day after birth, suggesting that myelin/oligodendrocytes were developing rapidly during this period.
3. We observed the myelin sheath development on the 32nd day after birth in rats. The results showed that the expression of MB P in PFC region of PCP group was significantly lower than that of control group (P 0.05, t-test), but there was no significant difference in the number of GST-pi positive cells and the density of myelin bundle between the two groups (P 0.05). In addition, electron microscopy showed that local degradation of the myelin sheath and formation of dense interlaminar bodies could be seen in some parts of the myelin sheath in the PCP group.
4. In order to evaluate the schizophrenia-like behavior induced by PCP intervention, the spontaneous activity and PPI of rats on the 30t h and 31st days after birth were measured. The results showed that the spontaneous activity of rats in PCP intervention group was significantly higher than that in control group (P 0.05, t-test), and PCP intervention had a significant effect on PPI [F (1,34) = 13.48, P = 0.0008], Post-h OC analysis showed that compared with the control group, the PPI (%) of the PCP group decreased significantly at PP8 and PP16 levels (P 0.05).
In the second part of the experiment, we found that quetiapine at a dose of 10 mg/kg did not ameliorate myelin dysplasia caused by PCP, nor did it ameliorate the damage of PPI associated with abnormal myelin sheath that reflects cognitive symptoms of schizophrenia, but could alleviate the increase in spontaneous activity of model animals with positive symptoms of schizophrenia induced by PCP. Below:
1. The development of myelin sheath was observed on the 16th day after birth in four groups of rats. The results of one-way ANOVA showed that there were significant differences in the number of GST-pi positive cells in PFC region [F(3,12) = 5.493, P = 0.0131], and significant differences in the distribution of myelin bundles [F(3,12) = 30.93, P 0.0001], and the expression of MB P was also significantly poor. Pos-hoc analysis showed that PCP intervention resulted in a decrease in the number of GST-pi positive cells, a decrease in the distribution of myelin bundles and a decrease in the expression of MBP protein compared with the control group, but the addition of 10 mg/kg quetiapine before PCP injection could not reverse these pathological and biochemical changes (P 0.05).
2. We observed the myelin sheath development on the 32nd day after birth in four groups of rats. One-way ANOVA showed that there were significant differences in the expression of MB P only in the PFC region of the four groups of rats [F(3,12) = 23.30, P 0.0001], but in the number of GST-pi positive cells [F(3,12) = 0.6297, P = 0.6097] and the distribution range of myelin tracts [F(3,12) = 0.3711, P = 0.0001]. Post-hoc analysis showed that PCP intervention resulted in a decrease in MBP expression compared with the control group, but the addition of 10 mg/kg quetiapine before PCP injection could not reverse the change (P 0.05).
3. Spontaneous activity and PPI were measured in rats on the 30th and 31st day after birth. The results showed that there was a significant difference in spontaneous activity among the four groups [F(3,34)=3.625, P=0.0226]. PCP and/or QUE intervention had a significant effect on PPI [F(3,64)=8.235, P=0.0001]. Compared with the control group, the spontaneous activity of the PCP intervention group was significantly increased, and PP was significantly increased. I% decreased significantly, and the addition of 10 mg/kg quetiapine before PCP injection could alleviate the increase of spontaneous activity induced by PCP, but could not reverse the damage of PPI (P 0.05).
Conclusion:
After chronic administration of PCP in neonatal rats, the developmental deficiency of myelin sheath and schizophrenic-like behavior in adolescence were observed in rats, and there was a certain correlation between the two, suggesting that abnormal myelin sheath played a certain role in the pathogenesis of schizophrenia. The model could be used to study the myelin sheath/oligodendroid process in schizophrenia. At the same time, quetiapine at a dose of 10 mg/kg did not ameliorate the myelin dysplasia induced by PCP, nor did it ameliorate the damage of PPI associated with myelin dysplasia, which reflected the cognitive symptoms of schizophrenia, but could alleviate the increase in spontaneous activity of positive symptoms of schizophrenia induced by PCP.
【學位授予單位】：第四軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R749.3

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