【摘要】：目的:血管性癡呆(Vascular Dementia, VD)是由各種腦血管因素,如腦缺血、腦出血等導(dǎo)致的腦組織損傷,從而引起以認(rèn)知功能障礙為主要特征的癡呆綜合征。VD是一種慢性進(jìn)行性疾病,也是導(dǎo)致老年期癡呆的一個重要原因。在歐美等西方國家,VD是導(dǎo)致癡呆的第二位原因,而在一些亞洲國家VD則是導(dǎo)致癡呆的最主要原因。近年來,隨著全球人口的老齡化,VD的發(fā)病率逐年增高,嚴(yán)重威脅老年人的身體健康和生活質(zhì)量。 建立穩(wěn)定、可復(fù)制的動物模型對于研究VD的發(fā)生發(fā)展機(jī)制、防治措施及相關(guān)藥物的療效評價至關(guān)重要。目前,國內(nèi)外常用的VD模型主要以大鼠和小鼠為研究對象。大鼠模型的制備方法有血管阻斷法VD模型、去腦皮層VD模型、高血壓復(fù)合VD模型、VD自發(fā)模型、靜脈注入四氧化三鐵VD模型等。小鼠VD動物模型則主要為不完全性腦缺血再灌注模型,其中較經(jīng)典的是雙側(cè)頸總動脈缺血—再灌注加尾部放血法。目前,國內(nèi)外關(guān)于VD動物模型制備的研究和探討雖然取得了很大的進(jìn)步,但仍然存在著諸多問題,如:癡呆模型制作標(biāo)準(zhǔn)不統(tǒng)一;可重復(fù)性差;個別方法操作復(fù)雜,動物存活率低;動物模型的病理生理學(xué)改變與臨床患者差異較大,不利于長期觀察等。理想的VD動物模型,理論上應(yīng)與臨床患者的病理損害一致,并伴有動物的智能損害;同時,模型的制備還應(yīng)具有容易操作、穩(wěn)定可靠、重復(fù)性強(qiáng)、便于各種電生理檢查及智能測試的特點。但是,目前尚無完全達(dá)到此種理想程度的動物模型。 八臂迷宮實驗通過觀察動物尋找食物過程中所走的路程長度及典型錯誤的次數(shù)評價動物的空間學(xué)習(xí)記憶能力,能較客觀地反映動物的癡呆程度。此外,除了行為學(xué)指標(biāo),病理組織學(xué)結(jié)果也是判斷VD模型成功與否的一項重要依據(jù)。海馬作為參與學(xué)習(xí)與記憶功能的重要結(jié)構(gòu),對腦組織缺血缺氧非常敏感,反復(fù)、適時的腦缺血—再灌注會導(dǎo)致海馬CA1區(qū)神經(jīng)元受損。因此,觀察海馬神經(jīng)元的損傷程度有助于判斷VD模型的成功情況。 綜上所述,本實驗旨在既往實驗基礎(chǔ)上制備四種小鼠VD模型,通過八臂迷宮實驗檢測其空間學(xué)習(xí)記憶能力;同時輔以病理組織學(xué)觀察海馬CA1區(qū)錐體神經(jīng)元損傷情況,以評價模型的效果,為VD的基礎(chǔ)研究及疾病防治研究提供實驗依據(jù)。 動物分組及方法:150只雄性成年昆明小鼠,體重34±2.5 g,實驗室環(huán)境中飼養(yǎng)1周,隨機(jī)分為以下5組(n=30): (1) Sham組:僅暴露雙側(cè)頸總動脈,不阻斷血流; (2)雙側(cè)夾閉20分鐘模型:用無損傷小動脈夾夾閉雙側(cè)頸總動脈20 min,松開血管夾再灌流10 min,反復(fù)3次,同時尾端放血0.3 ml; (3)雙側(cè)夾閉30分鐘模型:用無損傷小動脈夾夾閉雙側(cè)頸總動脈30 min,松開血管夾再灌流10 min,反復(fù)3次,同時尾端放血0.3 ml; (4)右側(cè)結(jié)扎+左側(cè)夾閉模型:用無菌絲線永久結(jié)扎右側(cè)頸總動脈,同時用無損傷小動脈夾夾閉左側(cè)頸總動脈30 min,松開血管夾再灌流10 min,反復(fù)3次; (5)左側(cè)結(jié)扎+右側(cè)夾閉模型:用無菌絲線永久結(jié)扎左側(cè)頸總動脈,同時用無損傷小動脈夾夾閉右側(cè)頸總動脈30 min,松開血管夾再灌流10 min,反復(fù)3次。 以上各組動物根據(jù)再灌注后的時間進(jìn)一步分為15天、30天及45天亞組,每個亞組10只動物:分別于術(shù)后第15天、30天、45天開始八臂迷宮實驗,記錄小鼠找到所有食物走過的路程長度(路程)以及小鼠進(jìn)入無食物臂的典型錯誤次數(shù)(典型錯誤),連續(xù)觀察10天以反映其空間學(xué)習(xí)記憶能力情況;后隨機(jī)選取6只斷頭取腦,常規(guī)石蠟切片,硫堇染色,確定CA1區(qū)錐體神經(jīng)元遲發(fā)性死亡(delayed neuronal death, DND)情況。參照Kitagawa和Kato分級方法,對海馬CA1區(qū)組織學(xué)改變進(jìn)行分級,標(biāo)準(zhǔn)如下:0級,無神經(jīng)元死亡;Ⅰ級,散在的神經(jīng)元死亡;Ⅱ級,大片的神經(jīng)元死亡;Ⅲ級,幾乎全部的神經(jīng)元死亡。高倍鏡下計數(shù)雙側(cè)海馬CA1區(qū)1 mm區(qū)段內(nèi)胞膜完整、胞核飽滿、核仁清楚的錐體細(xì)胞數(shù)目,每側(cè)海馬CA1區(qū)各計數(shù)3個區(qū)段,取平均數(shù)為神經(jīng)元密度(neuronal density),作為判定遲發(fā)性神經(jīng)元損傷程度的依據(jù)。 結(jié)果: 1空間學(xué)習(xí)記憶能力的變化 1.1四種VD模型小鼠同一時間點空間學(xué)習(xí)記憶能力的差異 1.1.1四種VD模型小鼠15天空間學(xué)習(xí)記憶能力的差異 與sham組相比,雙側(cè)夾閉20分鐘模型組、雙側(cè)夾閉30分鐘模型組、左側(cè)結(jié)扎+右側(cè)夾閉模型組小鼠的路程及典型錯誤均無明顯改變(P0.05);而右側(cè)結(jié)扎+左側(cè)夾閉模型組,路程明顯延長、典型錯誤明顯增多(P0.05),提示小鼠的學(xué)習(xí)記憶能力明顯降低。 1.1.2四種VD模型小鼠30天空間學(xué)習(xí)記憶能力的差異 與sham組比較,雙側(cè)夾閉20分鐘模型組小鼠的路程及典型錯誤無明顯變化(P0.05);而雙側(cè)夾閉30分鐘模型組、左側(cè)結(jié)扎+右側(cè)夾閉模型組及右側(cè)結(jié)扎+左側(cè)夾閉模型組的小鼠,路程明顯增加、典型錯誤也明顯增多(P0.05)。并且,上述各組中右側(cè)結(jié)扎+左側(cè)夾閉模型組的路程及典型錯誤變化最為明顯,提示小鼠的學(xué)習(xí)記憶能力最差。 1.1.3四種VD模型小鼠45天空間學(xué)習(xí)記憶能力的差異 與sham組比較,上述4組VD模型組小鼠的路程及典型錯誤均明顯增加(P0.05),其中右側(cè)結(jié)扎+左側(cè)夾閉模型組小鼠的結(jié)果最為顯著。 1.2同一模型組小鼠不同時間點空間學(xué)習(xí)記憶能力的差異sham組三個時間點路程及典型錯誤比較,無顯著性差別(P0.05)。因此,隨機(jī)取其一作為4種VD模型的sham組。 1.2.1雙側(cè)夾閉20分鐘模型 與sham組比較, 15天模型組及30天模型組小鼠的路程無明顯延長、典型錯誤無明顯增多(P0.05),而45天模型組小鼠的路程及典型錯誤均明顯增加(P0.05)。 1.2.2雙側(cè)夾閉30分鐘模型 結(jié)果顯示,與sham組相比,15天模型組小鼠的路程及典型錯誤均無明顯增加(P0.05),而30天模型組、45天模型組小鼠的路程明顯增加(P0.05),并且典型錯誤也明顯增多(P0.05)。 1.2.3右側(cè)結(jié)扎+左側(cè)夾閉模型 與sham組相比,15天模型組、30天模型組及45天模型組小鼠的路程延長及典型錯誤增加(P0.05),并且30天模型組及45天模型組小鼠的空間學(xué)習(xí)記憶能力最差。 1.2.4左側(cè)結(jié)扎+右側(cè)夾閉模型 與sham組相比,15天模型組小鼠的路程、典型錯誤均無統(tǒng)計學(xué)差異(P0.05),而30天模型組、45天模型組小鼠的路程延長、典型錯誤增加,與sham組相比有統(tǒng)計學(xué)差異(P0.05)。 2海馬CA1區(qū)組織病理學(xué)評價 2.1四種VD模型小鼠同一時間點海馬CA1區(qū)組織病理學(xué)變化 2.1.1四種VD模型小鼠15天組海馬CA1區(qū)組織病理學(xué)變化Sham組小鼠海馬CA1區(qū)有3~5層錐體細(xì)胞,排列整齊致密、細(xì)胞形態(tài)完整、胞核飽滿、核仁清晰,無細(xì)胞損傷。雙側(cè)夾閉20分鐘模型組、雙側(cè)夾閉30分鐘模型組及左側(cè)結(jié)扎+右側(cè)夾閉模型組海馬CA1區(qū)無明顯的神經(jīng)元損傷。然而,右側(cè)結(jié)扎+左側(cè)夾閉模型組小鼠海馬CA1區(qū)錐體神經(jīng)元出現(xiàn)明顯損傷,與sham組比較,HG明顯升高(P0.05),ND值顯著降低(P0.05)。 2.1.2四種VD模型小鼠30天組海馬CA1區(qū)組織病理學(xué)變化雙側(cè)夾閉20分鐘模型組小鼠海馬CA1區(qū)無明顯的DND,神經(jīng)元密度略有降低、組織學(xué)分級略有升高,但與sham組比較無明顯的統(tǒng)計學(xué)差異(P0.05)。雙側(cè)夾閉30分鐘模型組、右側(cè)結(jié)扎+左側(cè)夾閉模型組、左側(cè)結(jié)扎+右側(cè)夾閉模型組小鼠海馬CA1區(qū)均出現(xiàn)了明顯的DND,與sham組相比,HG顯著升高(P0.05),ND值顯著降低(P0.05)。其中右側(cè)結(jié)扎+左側(cè)夾閉模型組海馬CA1區(qū)損傷最為嚴(yán)重。 2.1.3四種VD模型小鼠45天組海馬CA1區(qū)組織病理學(xué)變化 結(jié)果顯示,與sham相比,4個模型組小鼠海馬CA1區(qū)均出現(xiàn)明顯的DND,HG顯著升高(P0.05),ND值顯著降低(P0.05)。上述變化以右側(cè)結(jié)扎+左側(cè)夾閉模型組最明顯。 2.2同一模型組小鼠不同時間點海馬CA1區(qū)組織病理學(xué)變化 sham組三個時間點海馬CA1區(qū)錐體神經(jīng)元的HG、ND值比較,無顯著性差別(P0.05)。因此,隨機(jī)取其一作為4種VD模型的sham組。 2.2.1雙側(cè)夾閉20分鐘模型 15天模型組及30天模型組小鼠海馬CA1區(qū)無明顯的DND。與sham組相比,45天模型組海馬CA1區(qū)出現(xiàn)明顯的DND,其HG顯著升高(P0.05),ND值顯著降低(P0.05)。 2.2.2雙側(cè)夾閉30分鐘模型 結(jié)果顯示,15天模型組小鼠海馬CA1區(qū)無明顯的DND。而30天模型組、45天模型組海馬CA1區(qū)錐體神經(jīng)元損傷嚴(yán)重,與sham相比HG顯著升高(P0.05),ND值顯著降低(P0.05)。 2.2.3右側(cè)結(jié)扎+左側(cè)夾閉模型 本VD模型小鼠在15天、30天和45天組海馬CA1區(qū)均出現(xiàn)了明顯的DND,與sham組相比,HG顯著升高(P0.05),ND值顯著降低(P0.05),其中30天、45天模型組改變最為明顯。 2.2.4左側(cè)結(jié)扎+右側(cè)夾閉模型 硫堇染色顯示,15天模型組小鼠海馬CA1區(qū)無明顯的DND,與sham組比較,HG和ND無統(tǒng)計學(xué)意義(P0.05)。30天模型組、45天模型組小鼠海馬CA1區(qū)錐體神經(jīng)元損傷嚴(yán)重,與sham組比較HG顯著升高(P0.05)、ND值顯著降低(P0.05)。 結(jié)論: 所建立的4種VD模型中,小鼠分別在不同時段表現(xiàn)出空間學(xué)習(xí)記憶障礙及海馬CA1區(qū)錐體神經(jīng)元的延遲性死亡,其中右側(cè)結(jié)扎+左側(cè)夾閉模型組小鼠最為顯著。
[Abstract]:Objective: Vascular dementia (VD) is a kind of dementia syndrome characterized by cognitive impairment caused by various cerebrovascular factors, such as cerebral ischemia and cerebral hemorrhage. VD is a chronic progressive disease and an important cause of senile dementia. VD is the second leading cause of dementia, and in some Asian countries VD is the main cause of dementia. In recent years, with the aging of the global population, the incidence of VD increases year by year, seriously threatening the health and quality of life of the elderly.
Establishing a stable and reproducible animal model is very important to study the mechanism of VD, the prevention and treatment measures and the efficacy evaluation of related drugs.At present, the commonly used models of VD at home and abroad mainly focus on rats and mice.The preparation methods of rat models include VD model by blocking blood vessels, VD model by removing cerebral cortex and VD model by combining hypertension. The animal model of VD in mice is mainly incomplete cerebral ischemia-reperfusion model, among which the classical method is bilateral common carotid artery ischemia-reperfusion plus tail bleeding. However, there are many problems, such as: the standard of making dementia model is not uniform; the repeatability is poor; individual methods are complex and the survival rate of animals is low; the pathophysiological changes of animal models are quite different from clinical patients, which is not conducive to long-term observation. The ideal animal model of VD should be consistent with the pathological damage of clinical patients in theory, and accompanied by movement. At the same time, the preparation of the model should be easy to operate, stable and reliable, repeatable, easy to conduct various electrophysiological examinations and intelligent testing. However, there is no animal model to achieve this ideal level.
The eight-arm maze experiment can objectively reflect the dementia degree of animals by observing the distance and the number of typical errors in the process of looking for food. In order to participate in the important structure of learning and memory function, it is very sensitive to cerebral ischemia and hypoxia. Repeated cerebral ischemia-reperfusion can lead to damage of neurons in hippocampal CA1 area. Therefore, it is helpful to judge the success of VD model to observe the degree of damage of hippocampal neurons.
To sum up, this experiment aims to prepare four kinds of mice VD models on the basis of previous experiments, and test their spatial learning and memory ability by eight-arm maze experiment, and observe the damage of pyramidal neurons in hippocampal CA1 area with pathological histology, so as to evaluate the effect of the model, and provide experimental basis for the basic research of VD and disease prevention and treatment.
Animal grouping and methods: 150 adult male Kunming mice weighing 34 + 2.5 g were randomly divided into the following five groups (n = 30):
(1) group Sham: only bilateral carotid arteries were exposed without blocking blood flow.
(2) 20-minute bilateral clamping model: the bilateral common carotid artery was clamped with non-invasive small artery clamp for 20 minutes, the clamp was loosened and then perfused for 10 minutes, repeated 3 times, and the tail bleeding was 0.3 ml.
(3) 30-minute bilateral clamping model: the bilateral common carotid artery was clamped with non-invasive small artery clamp for 30 minutes, the clamp was loosened and then perfused for 10 minutes, repeated three times, and the tail bleeding was 0.3 ml.
(4) The right common carotid artery was permanently ligated with hyphal-free thread, and the left common carotid artery was clamped with non-invasive small artery for 30 minutes. The clamp was loosened for 10 minutes and then perfused for 3 times.
(5) The left common carotid artery was permanently ligated with hyphal-free thread, and the right common carotid artery was clamped with noninvasive small artery for 30 minutes. The clamp was loosened for 10 minutes and then perfused for 3 times.
Each group was further divided into 15 days, 30 days and 45 days subgroups according to the time after reperfusion. Each subgroup consisted of 10 animals. The eight-arm maze test was performed on the 15th, 30th and 45th days after reperfusion. The length of the journey (the journey) for which the mice found all the food and the number of typical errors (the typical error) for which the mice entered the food-free arm were recorded. After 10 days of observation, 6 severed heads were randomly selected to observe their spatial learning and memory abilities. The delayed neuronal death (DND) in CA1 region was determined by routine paraffin section and staining with thionine. Neuronal death; Grade I, scattered neuron death; Grade II, large neuron death; Grade III, almost all neuron death. At high power microscopy, the number of pyramidal cells in 1 mm segment of bilateral hippocampal CA1 region was counted intact, the nucleus was plump, and the nucleolus was clear. The average number of pyramidal cells in each hippocampal CA1 region was 3 segments, and the average number was neu. Ronal density) as a basis for judging the degree of delayed neuronal damage.
Result:
1 changes in spatial learning and memory abilities
1.1 the difference of spatial learning and memory ability between four VD mice at the same time.
Differences in learning and memory ability of 15 mouse models in four 1.1.1 VD models
Compared with sham group, there were no significant changes in the course and typical errors in the 20-minute clipping model group, 30-minute clipping model group, left ligation + right clipping model group (P 0.05), while the right ligation + left clipping model group, the course was significantly prolonged and the typical errors were significantly increased (P 0.05), suggesting that the learning and memory abilities of mice were significantly decreased. Low.
Differences in learning and memory ability of 30 mouse models in four 1.1.2 VD models
Compared with sham group, there were no significant changes in the distance and typical errors of mice in bilateral clamping 20 minutes model group (P 0.05), while the distance and typical errors of mice in bilateral clamping 30 minutes model group, left ligation + right clamping model group and right ligation + left clamping model group were significantly increased (P 0.05). The changes of distance and typical errors were the most obvious in the ligation + left clipping model group, suggesting that the learning and memory abilities of the mice were the worst.
Differences in learning and memory ability of 45 mouse models in four 1.1.3 VD models
Compared with sham group, the routing and typical errors of VD model mice in the above four groups were significantly increased (P 0.05), and the results of right ligation + left clipping model mice were the most significant.
1.2 There was no significant difference in the spatial learning and memory abilities between the same model group and the sham group at different time points (P 0.05). Therefore, one of the four VD models was randomly selected as the sham group.
1.2.1 bilateral occlusion 20 minute model
Compared with the sham group, the 15-day model group and 30-day model group showed no significant prolongation of the distance and no significant increase in typical errors (P 0.05), while the 45-day model group showed significant increase in the distance and typical errors (P 0.05).
1.2.2 bilateral occlusion 30 minute model
The results showed that compared with the sham group, the 15-day model group had no significant increase in the distance and typical errors (P 0.05), while the 30-day model group and the 45-day model group had significant increase in the distance (P 0.05) and the typical errors (P 0.05).
1.2.3 ligation + left clipping model
Compared with sham group, the 15-day model group, 30-day model group and 45-day model group had longer distance and more typical errors (P 0.05), and the 30-day model group and 45-day model group had the worst spatial learning and memory ability.
1.2.4 ligation plus right clipping model
Compared with the sham group, there was no significant difference in the typical errors of the 15-day model group (P 0.05), while the 30-day model group and 45-day model group had longer and more typical errors, which was significantly different from the sham group (P 0.05).
2 histopathological evaluation of hippocampal CA1 area
2.1 histopathological changes in hippocampal CA1 area of four VD mice at the same time point.
2.1.1 Histopathological changes in CA1 area of hippocampus of four VD model mice in 15 days Sham group had 3-5 layers of pyramidal cells in CA1 area of hippocampus, arranged neatly and tightly, with complete cell morphology, full nucleus, clear nucleolus and no cell damage. However, the pyramidal neurons in the CA1 area of the hippocampus in the right ligation + left clipping model group were significantly damaged. Compared with the sham group, HG increased significantly (P 0.05), and ND decreased significantly (P 0.05).
2.1.2 Histopathological changes of CA1 area in hippocampus of mice with three kinds of VD after 30 days occlusion for 20 minutes showed no obvious DND, slightly decreased neuron density and slightly increased histological grade in CA1 area of hippocampus of mice with bilateral occlusion for 30 minutes. There was no significant difference between the two groups (P 0.05). DND was found in the CA1 area of the hippocampus in the left ligation + right clipping model group, and HG was significantly increased (P 0.05) and ND was significantly decreased (P 0.05) compared with the sham group.
Histopathological changes in hippocampal CA1 area of mice in 45 days of 2.1.3 four VD models
The results showed that compared with sham, DND, HG and ND were significantly increased (P 0.05) and decreased (P 0.05) in CA1 area of hippocampus in the four model groups.
2.2 histopathological changes in hippocampal CA1 area of mice in the same model group at different time points
There was no significant difference in HG and ND values of pyramidal neurons in hippocampal CA1 region at three time points in sham group (P 0.05).
2.2.1 bilateral occlusion 20 minute model
There was no significant DND in CA1 area of hippocampus in 15-day model group and 30-day model group. Compared with sham group, DND appeared in CA1 area of hippocampus in 45-day model group, and HG increased significantly (P 0.05), ND decreased significantly (P 0.05).
2.2.2 bilateral occlusion 30 minute model
The results showed that there was no obvious DND in CA1 area of hippocampus in 15-day model group, but in 30-day model group, pyramidal neurons in CA1 area of hippocampus in 45-day model group were severely damaged, HG was significantly increased (P 0.05) and ND was significantly decreased (P 0.05) compared with sham.
2.2.3 ligation + left clipping model
DND in hippocampal CA1 region of VD model mice appeared on 15 days, 30 days and 45 days. Compared with sham group, HG increased significantly (P 0.05), ND decreased significantly (P 0.05), and the change was most obvious in 30 days and 45 days model group.
2.2.4 ligation plus right clipping model
Thionine staining showed that there was no significant DND in CA1 area of hippocampus in the 15-day model group, and there was no significant difference in HG and ND between the sham group and the 15-day model group (P 0.05). Pyramidal neurons in CA1 area of hippocampus in the 45-day model group were severely damaged, and HG was significantly increased (P 0.05) and ND was significantly decreased (P 0.05).
Conclusion:
Among the four VD models, mice showed spatial learning and memory impairment and delayed neuronal death in hippocampal CA1 region at different time points, especially in the right ligation + left clipping group.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2011
【分類號】：R749.16;R-332

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