本文選題：缺氧缺血性腦損傷 + 行為學(xué)�。� 參考：《南方醫(yī)科大學(xué)》2012年碩士論文

【摘要】：研究背景 新生兒缺氧缺血性腦損傷(Hypoxic-ischemic brain damage, HIBD)是指各種圍產(chǎn)期窒息引起的部分或完全缺氧、腦血流減少或暫停而導(dǎo)致胎兒或新生兒腦損傷,臨床出現(xiàn)一系列中樞神經(jīng)系統(tǒng)異常的表現(xiàn),是引起新生兒急性死亡和慢性神經(jīng)系統(tǒng)損傷的主要原因之一,將遺留諸多后遺癥,如腦性癱瘓、智力低下、癲癇及發(fā)育遲緩等。隨著新生兒重癥監(jiān)護(hù)室的建立和醫(yī)療技術(shù)水平的提高,許多中、重度缺氧缺血性腦損傷患兒得以生存,但存活兒永久性腦功能障礙發(fā)病率仍較高。HIBD是一種彌漫性損傷,病變主要在大腦海馬、皮層、紋狀體、基底節(jié)、丘腦等部位,發(fā)病機(jī)制較復(fù)雜,是由多種機(jī)制綜合作用所致的一系列生化連鎖反應(yīng)或稱(chēng)缺氧缺血性瀑布的結(jié)果。目前臨床上對(duì)于新生兒HIBD治療多采用對(duì)癥處理、營(yíng)養(yǎng)支持及早期干預(yù)等綜合治療,尚缺乏特效、經(jīng)濟(jì)的方法來(lái)治療新生兒HIBD,因此深入探究HIBD機(jī)制和修復(fù)機(jī)制,尋找有效的防治措施,對(duì)于提高新生兒HIBD存活率,減少存活兒遠(yuǎn)期神經(jīng)系統(tǒng)后遺癥,提高我國(guó)人口質(zhì)量均有重要意義。 新生兒處在大腦發(fā)育關(guān)鍵期,而且新生兒HIBD具有非進(jìn)行性、無(wú)持續(xù)性的缺血缺氧因素存在等特點(diǎn),生后7d SD大鼠腦與新生兒腦發(fā)育相似,而且造成一過(guò)性腦缺氧缺血條件也與HIBD相似,因此,國(guó)內(nèi)外以生后7d新生SD大鼠為研究對(duì)象,參照Rice方法,建立新生鼠HIBD動(dòng)物模型,該模型被廣泛應(yīng)用于研究HIBD相關(guān)課題。在上述基礎(chǔ)上,利用動(dòng)物模型,深入探討HIBD后的損傷機(jī)制,了解缺氧缺血對(duì)新生大鼠遠(yuǎn)期神經(jīng)功能和超微結(jié)構(gòu)的影響,探索合理、全面的判斷預(yù)后和評(píng)估療效的方法,進(jìn)一步尋求有效、經(jīng)濟(jì)的干預(yù)措施,并探討干預(yù)措施的修復(fù)機(jī)制。 HIBD是一種彌漫性損傷,由于HIBD致病因素的復(fù)雜性,加上嬰幼兒腦發(fā)育的特殊性和可塑性,臨床上要準(zhǔn)確地評(píng)價(jià)HIBD的遠(yuǎn)期預(yù)后及干預(yù)療效相當(dāng)困難,許多患兒的預(yù)后與急性期損傷的嚴(yán)重程度并無(wú)一致的線(xiàn)性相關(guān)。而目前關(guān)于HIBD動(dòng)物實(shí)驗(yàn)研究中,對(duì)于HIBD遠(yuǎn)期預(yù)后及干預(yù)措施療效的評(píng)價(jià)多停留在行為學(xué)及上述兩個(gè)腦區(qū)損傷后常規(guī)病理學(xué)改變的觀察上,鮮有超微結(jié)構(gòu)的研究。突觸是神經(jīng)元和效應(yīng)細(xì)胞之間傳遞信息的功能部位,與行為學(xué)表現(xiàn)之間關(guān)系密切,也是腦發(fā)育可塑性的核心。因此,觀察突觸超微結(jié)構(gòu)的改變不僅可以深入探究HIBD機(jī)理及修復(fù)機(jī)制,還可以了解其與行為學(xué)之間的相關(guān)性,從而有望對(duì)HIBD遠(yuǎn)期預(yù)后及干預(yù)療效做出早期客觀的評(píng)價(jià)。 目前對(duì)于新生兒HIBD的治療措施主要有高壓氧、亞低溫、神經(jīng)營(yíng)養(yǎng)藥物及一般支持對(duì)癥處理,高壓氧治療方法受醫(yī)院條件設(shè)備限制、早期病情程度亦影響其應(yīng)用,且治療時(shí)間窗、療程尚無(wú)統(tǒng)一定論等,而亞低溫治療方法不僅療效不確定,而且應(yīng)用范圍較為局限,神經(jīng)營(yíng)養(yǎng)藥物目前研究報(bào)道僅提示對(duì)疾病急性期有一定效果,且治療費(fèi)用高,影響其在臨床上的應(yīng)用。運(yùn)動(dòng)訓(xùn)練是指通過(guò)病人自身力量或治療師的輔助操作或借助于器械所進(jìn)行的主動(dòng)或被動(dòng)運(yùn)動(dòng)以改善局部或全身功能為目的的一種治療方法。因其實(shí)施方便、費(fèi)用低、治療可長(zhǎng)期堅(jiān)持并可在家中實(shí)施,在臨床上已應(yīng)用于新生兒HIBD的治療,取得一定療效,但其具體機(jī)制尚未完全明確。一方面因?yàn)樾律鷥捍竽X正處在發(fā)育關(guān)鍵期,存在著較強(qiáng)可塑性,對(duì)損傷有一定自身修復(fù)能力,臨床上很難判斷患兒的進(jìn)步是否與此干預(yù)治療相關(guān)。另外,研究表明,適時(shí)適量的運(yùn)動(dòng)訓(xùn)練不僅能改善運(yùn)動(dòng)功能,而且可以提高人和動(dòng)物的學(xué)習(xí)記憶能力。新生兒HIBD除運(yùn)動(dòng)功能障礙外,許多伴有智力低下、感覺(jué)統(tǒng)合失調(diào)等問(wèn)題,早期運(yùn)動(dòng)訓(xùn)練是否也能改善患兒這些功能呢?是通過(guò)何種可能途徑改善的呢? 據(jù)研究報(bào)道,適宜的運(yùn)動(dòng)訓(xùn)練可以引起中樞神經(jīng)系統(tǒng)內(nèi)cAMP、Ca2+等第二信使適量增加,從而誘導(dǎo)c-fos基因表達(dá),控制下游靶基因的轉(zhuǎn)錄,從而合成新的蛋白質(zhì)。在正常情況下,c-fos蛋白參與細(xì)胞生長(zhǎng)、分化、信息傳遞、學(xué)習(xí)和記憶等生理過(guò)程,它對(duì)于編碼記憶,形成大多數(shù)的長(zhǎng)時(shí)程增強(qiáng)(Long-term potentiation, LTP)有著十分重要的作用,而LTP是神經(jīng)元可塑性的反映。因此,有利于大腦的記憶功能,這為運(yùn)動(dòng)對(duì)學(xué)習(xí)記憶的促進(jìn)作用在分子水平上提供一個(gè)證據(jù)。 已有研究指出突觸素(p38)是突觸重建的重要標(biāo)志,因?yàn)閜38參與神經(jīng)元發(fā)育和分化過(guò)程。發(fā)育中神經(jīng)元p38的表達(dá)優(yōu)先于突觸的構(gòu)成,即在突觸結(jié)構(gòu)形成之前就已經(jīng)有p38存在和表達(dá),隨著神經(jīng)元發(fā)育成熟、突觸成熟,p38的表達(dá)也相應(yīng)增加。p38還直接參與了突觸的形成及調(diào)節(jié)與突觸相關(guān)的其它突觸蛋白的表達(dá)。因此該蛋白被廣泛用于標(biāo)記突觸終末。 基于以上理論,本研究采用Rice方法建立新生大鼠HIBD模型,觀察大鼠遠(yuǎn)期行為學(xué)、病理學(xué)及超微結(jié)構(gòu)的改變,探索HIBD機(jī)制,重點(diǎn)觀察超微結(jié)構(gòu)的改變及其意義,指導(dǎo)HIBD遠(yuǎn)期預(yù)后及療效評(píng)估。之后早期給予運(yùn)動(dòng)訓(xùn)練干預(yù),觀察其對(duì)新生大鼠HIBD遠(yuǎn)期運(yùn)動(dòng)、學(xué)習(xí)記憶能力及感覺(jué)功能的療效,并利用免疫組織化學(xué)方法檢測(cè)c-fos、突觸素的表達(dá),來(lái)初步探索其療效機(jī)制。 具體研究?jī)?nèi)容包括以下兩個(gè)部分： 第一部分構(gòu)建新生大鼠HIBD動(dòng)物模型,觀察遠(yuǎn)期行為學(xué)及超微結(jié)構(gòu)改變目的 建立新生大鼠缺氧缺血性腦損傷(Hypoxic-ischemic brain damage, HIBD)模型,觀察遠(yuǎn)期行為學(xué)及超微結(jié)構(gòu)改變,提供HIBD遠(yuǎn)期功能評(píng)價(jià)方法及指導(dǎo)臨床治療。 方法 60只7日齡新生SD大鼠隨機(jī)分為HIBD組和假手術(shù)組,每組30只。生后5周進(jìn)行Morris水迷宮及感覺(jué)功能測(cè)試；取腦組織切片行尼氏染色計(jì)數(shù)神經(jīng)元數(shù)目；取皮層、海馬行透射電鏡,觀察突觸結(jié)構(gòu)、測(cè)量突觸后致密區(qū)厚度及活性區(qū)長(zhǎng)度,并與行為學(xué)結(jié)果進(jìn)行相關(guān)分析。 結(jié)果 Morris水迷宮測(cè)試中,HIBD組大鼠尋找平臺(tái)潛伏期時(shí)間明顯長(zhǎng)于假手術(shù)組(P0.05);HIBD組大鼠穿越平臺(tái)次數(shù)較假手術(shù)組少(P0.05)。HIBD組感覺(jué)運(yùn)動(dòng)功能測(cè)試結(jié)果明顯差于假手術(shù)組。尼氏染色提示HIBD組神經(jīng)元數(shù)目明顯減少(P0.01)。電鏡顯示,HIBD組大鼠突觸數(shù)量減少,突觸后致密區(qū)厚度及活性區(qū)長(zhǎng)度變薄變短。HIBD組大鼠海馬突觸后致密區(qū)厚度與Morris水迷宮尋找平臺(tái)潛伏期時(shí)間呈負(fù)相關(guān)(r=-0.861,P=0.006),與三項(xiàng)感覺(jué)功能評(píng)估得分之和呈負(fù)相關(guān)性(r=-0.758,P=0.029)。 結(jié)論 缺氧缺血可致新生鼠遠(yuǎn)期神經(jīng)元減少和超微結(jié)構(gòu)損傷,造成遠(yuǎn)期行為學(xué)功能障礙,超微結(jié)構(gòu)改變?cè)谝欢ǔ潭壬蟽?yōu)于病理觀察,有助于更好評(píng)估預(yù)后和評(píng)價(jià)療效,基于未成熟腦突觸的可塑性,在腦發(fā)育關(guān)鍵期指導(dǎo)臨床治療。 第二部分早期運(yùn)動(dòng)訓(xùn)練對(duì)新生大鼠HlBD遠(yuǎn)期神經(jīng)功能的影響 目的 探討早期運(yùn)動(dòng)訓(xùn)練對(duì)新生大鼠缺氧缺血性腦損傷遠(yuǎn)期病理、超微結(jié)構(gòu)、神經(jīng)功能的影響。 方法 90只7日齡SD大鼠隨機(jī)分為運(yùn)動(dòng)組、對(duì)照組和假手術(shù)組。運(yùn)動(dòng)組和對(duì)照組建立HIBD模型,運(yùn)動(dòng)組于HIBD后1周開(kāi)始每天給予抓握、旋轉(zhuǎn)、行走、平衡等訓(xùn)練。4周后檢測(cè)各組大鼠神經(jīng)功能評(píng)分、空間學(xué)習(xí)記憶和皮層感覺(jué)功能、透射電鏡觀察突觸和神經(jīng)元超微結(jié)構(gòu),HE染色觀察腦組織病理改變,尼氏染色計(jì)數(shù)神經(jīng)元數(shù)目,并檢測(cè)突觸素、c-fos表達(dá)水平。 結(jié)果 運(yùn)動(dòng)組神經(jīng)功能評(píng)分、空間學(xué)習(xí)記憶、皮層感覺(jué)功能均優(yōu)于對(duì)照組,和假手術(shù)組間差異無(wú)統(tǒng)計(jì)學(xué)意義。透射電鏡下對(duì)照組大鼠海馬和皮層突觸損傷嚴(yán)重,神經(jīng)氈區(qū)突觸減少,突觸前膨大腫脹、輪廓不清晰,突觸小泡溶解空泡形成,PSD變薄、薄厚不均,而運(yùn)動(dòng)組未見(jiàn)明顯異常。HE染色提示對(duì)照組神經(jīng)元數(shù)目明顯減少,可見(jiàn)腫脹壞死細(xì)胞,運(yùn)動(dòng)組與假手術(shù)組比較未見(jiàn)明顯異常,尼氏染色提示對(duì)照組神經(jīng)元數(shù)目明顯減少,與運(yùn)動(dòng)組及假手術(shù)組比較差異有統(tǒng)計(jì)學(xué)意義。運(yùn)動(dòng)組大鼠海馬和皮層突觸素、c-fos表達(dá)水平明顯高于對(duì)照組(均P0.05)。 結(jié)論 早期運(yùn)動(dòng)訓(xùn)練可減少缺氧缺血后海馬和皮層神經(jīng)元死亡,增強(qiáng)突觸可塑性,從而改善HIBD后遠(yuǎn)期神經(jīng)功能。早期運(yùn)動(dòng)訓(xùn)練使突觸素和c-fos在海馬和皮層強(qiáng)表達(dá)可能是其改善的機(jī)制之一。
[Abstract]:Research background
Neonatal hypoxic ischemic brain damage (Hypoxic-ischemic brain damage, HIBD) refers to the partial or complete hypoxia caused by perinatal asphyxia. The decrease or suspension of cerebral blood flow leads to brain damage in the fetus or newborn. A series of abnormalities of the central nervous system appear in the clinic, which causes acute death of the newborn and the chronic nervous system damage. One of the main causes of injury will remain a number of sequelae, such as cerebral palsy, mental retardation, epilepsy and retardation. With the establishment of the neonatal intensive care unit and the improvement of the level of medical technology, many of the children with severe hypoxic ischemic brain damage can survive, but the incidence of permanent brain dysfunction is still higher in.HIBD. The disease is mainly in the hippocampus, cortex, striatum, basal ganglia, thalamus, and other parts of the brain. The pathogenesis is complicated. It is the result of a series of biochemical chain reactions or hypoxic ischemic falls, which are caused by a variety of mechanisms. At present, most of the new HIBD treatments are treated with symptomatic treatment, nutritional support and early stage. Comprehensive treatment, such as intervention, is still lack of special effects and economic methods for the treatment of neonatal HIBD. Therefore, it is of great significance to explore the mechanism of HIBD and repair mechanism and find effective measures to improve the survival rate of the newborn HIBD, reduce the sequelae of the long-term nervous system and improve the quality of the human mouth of our country.
The newborns are in the key stage of brain development, and the HIBD of the newborn is non progressive and has no persistent ischemic and anoxic factors. The brain of the 7d SD rats after birth is similar to the brain development of the newborn, and the condition of the hypoxic-ischemic cerebral ischemia is similar to that of the HIBD. Therefore, the newborn 7d newborn SD rat is the research object at home and abroad, with reference to Rice Methods the animal model of neonatal rat HIBD was established, and the model was widely used in the research of HIBD related subjects. On the basis of the above, the damage mechanism of HIBD was explored by animal model, and the effects of hypoxia ischemia on the long-term neural function and ultrastructure of neonatal rats were investigated. We should further seek effective and economic intervention measures and explore the repair mechanism of intervention measures.
HIBD is a diffuse injury. Due to the complexity of the pathogenic factors of HIBD and the specificity and plasticity of the brain development of infants, it is very difficult to accurately evaluate the long-term prognosis of HIBD and the effect of intervention. The prognosis of many children has no linear correlation with the severity of the acute phase. At present, the HIBD animal is real. In the study, the evaluation of the long-term prognosis of HIBD and the effect of intervention measures remained mostly in the observation of behavior and the routine pathological changes of the two brain regions, and there were few ultrastructural studies. The synapse is the functional part of the transmission of information between the neurons and the effector cells, which is closely related to the behavior and the development of the brain. Therefore, observing the changes in the synaptic ultrastructure can not only explore the mechanism of HIBD and the mechanism of repair, but also understand the correlation between the ultrastructure and the behavior. It is expected to make an early and objective evaluation of the long-term prognosis of HIBD and the effect of intervention.
At present, the treatment measures for neonatal HIBD mainly include hyperbaric oxygen, hypothermia, neurotrophic drugs and general support for symptomatic treatment. Hyperbaric oxygen therapy is restricted by hospital condition equipment, and the early condition also affects its application, and the treatment time window has no definite theory, and the mild hypothermia therapy not only has no definite effect, but the treatment of mild hypothermia is not effective, but the treatment of mild hypothermia is not definite, but And the application scope is limited. The present study of neurotrophic drugs only suggests that it has some effect on the acute phase of the disease, and the cost of treatment is high, which affects its clinical application. Exercise training refers to the improvement of the local or the whole by the auxiliary operation of the patient's own strength or therapist or by the active or passive motion of the apparatus. Physical function is a kind of therapeutic method. Because of its convenient implementation, low cost, the treatment can be persisted in the long term and can be implemented in the home. It has been applied to the treatment of HIBD in the newborn, and has achieved certain effect. But the specific mechanism is not completely clear. On the one hand, the brain is in the key stage of development, and there is a strong plasticity. It is difficult to judge whether the progress of the children is related to the intervention treatment in clinic. In addition, the study shows that appropriate exercise training can not only improve the exercise function, but also improve the learning and memory ability of the human and animal. In addition to the dysfunction of the movement of the newborn HIBD, many of them are accompanied by mental retardation. Problems such as maladjustment and so on, can early exercise training improve these functions of children?
According to the study, appropriate exercise training can cause the cAMP, Ca2+ and other two messenger to increase in the central nervous system, thus inducing c-fos gene expression, controlling the transcription of the target genes downstream, and synthesizing new proteins. Under normal conditions, c-fos protein participates in cell growth, differentiation, information transmission, learning and memory, and other physiological processes. Long-term potentiation (LTP) plays a very important role in coding memory, and LTP is a reflection of the plasticity of neurons. Therefore, it is beneficial to the memory function of the brain, which provides an evidence on the molecular level of the effect of exercise on learning and memory.
It has been pointed out that synaptophysin (p38) is an important sign of synaptic reconstruction, because p38 participates in the process of neuronal development and differentiation. The expression of p38 in the developing neuron is preceded by the composition of the synapse, that is, the presence and expression of p38 before the formation of the synapse structure, with the maturation of the neurons, the maturation of the synapses, and the corresponding increase of.P38 in the expression of p38. It also directly participates in synapse formation and regulates the expression of other synapses related to synapses. Therefore, the protein is widely used to mark synaptic terminals.
Based on the above theory, the Rice method was used to establish the HIBD model of neonatal rats, to observe the changes in the long term behavior, pathology and ultrastructure of rats, to explore the HIBD mechanism, to observe the changes and significance of the ultrastructure, to guide the long-term prognosis and the evaluation of the curative effect of HIBD. BD long term exercise, learning and memory ability and sensory function, and using immunohistochemical method to detect the expression of c-fos and synaptophysin to explore its therapeutic mechanism.
The specific research contents include the following two parts:
The first part is to construct the neonatal rat HIBD animal model, and to observe the long-term behavior and ultrastructural changes.
To establish the Hypoxic-ischemic brain damage (HIBD) model of neonatal rats, observe the long-term behavioral and ultrastructural changes, provide the method of evaluating the long-term function of HIBD and guide the clinical treatment.
Method
60 newborn SD rats at 7 days of age were randomly divided into HIBD group and sham operation group, with 30 rats in each group. The Morris water maze and sensory function test were carried out at 5 weeks after birth. The number of neurons was counted by Nissl staining in the brain tissue sections. The cortex and hippocampal transmission electron microscope were used to observe the synaptic structure, and the thickness of the dense area and the length of the active area after the contact were measured, and the behavior was measured and acted on the behavior. The results of the study were analyzed.
Result
In the Morris water maze test, the latency time of the HIBD group was significantly longer than that of the sham operation group (P0.05), and the number of HIBD rats crossing the platform was less than the sham operation group (P0.05).HIBD group was significantly worse than the sham operation group. Nissl staining suggested that the number of neurons in the HIBD group decreased significantly (P0.01). The electron microscope showed that the HIBD group was large. The number of rat synapses was reduced, the thickness of the post synaptic density and the length of the active region became thinner in the.HIBD group. The thickness of the postsynaptic density in the hippocampus of the hippocampus was negatively correlated with the latency time of the Morris water maze finding platform (r=-0.861, P=0.006), which was negatively correlated with the sum of three sensory evaluation scores (r=-0.758, P=0.029).
conclusion
Hypoxic-ischemic can cause long-term neuronal reduction and ultrastructural damage in neonatal rats, resulting in long-term behavioral dysfunction. Ultrastructural changes are superior to pathological observation to a certain extent. It is helpful to better evaluate the prognosis and evaluate the curative effect. Based on the plasticity of immature brain synapses, it guides clinical treatment at the critical stage of brain development.
The second part is the effect of early exercise training on the long-term neurological function of neonatal rats with HlBD.
objective
Objective to investigate the effects of early exercise training on long-term pathology, ultrastructure and neurological function in neonatal rats with hypoxic-ischemic brain damage.
Method
90 7 day old SD rats were randomly divided into exercise group, control group and sham operation group. HIBD model was established in the exercise group and the control group. The exercise group began to grasp, rotate, walk and balance every day after the 1 weeks of HIBD. After.4 weeks, the neural function score of each group was detected, the space learning memory and cortical sensory function were observed, and the synapse and the God were observed by transmission electron microscope. The pathological changes of brain tissue were observed by HE staining, Nissl staining was used to count the number of neurons, and synaptophysin and c-fos expression levels were detected.
Result
The neural function score, spatial learning and memory, cortical sensory function in the exercise group were better than the control group, and there was no statistical difference between the sham operation group and the sham operation group. Under transmission electron microscope, the hippocampus and cortical synapses in the control group were seriously damaged, the synapses in the nerve felt area decreased, the swelling of the synapse was not clear, the synaptic vesicle dissolved vacuoles, the PSD thinner, and the thinning of the synapse. There was no obvious abnormal.HE staining in the exercise group, which showed that the number of neurons in the control group decreased significantly, and the swelling and necrotic cells were visible. The number of neurons in the exercise group and the sham operation group was not obvious. The number of neurons in the control group decreased significantly, and the difference was statistically significant between the control group and the sham operation group. The expression levels of synaptophysin and c-fos in horses and cortex were significantly higher than those in control group (P0.05).
conclusion
Early exercise training can reduce the death of hippocampal and cortical neurons after hypoxia and ischemia, enhance synaptic plasticity, and improve the long-term neurological function after HIBD. Early exercise training may be one of the mechanisms for improving the expression of synaptophysin and c-fos in the hippocampus and cortex.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R722.1

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