本文選題：大腦皮質(zhì)發(fā)育畸形　切入點(diǎn)：雷帕霉素　出處：《西南醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:探討雷帕霉素(RAP)對X-射線宮內(nèi)照射誘導(dǎo)大腦皮質(zhì)發(fā)育畸形(MCD)模型大鼠老年期認(rèn)知損害及行為學(xué)的影響,為進(jìn)一步研究MCD的發(fā)病機(jī)制及早期干預(yù)、治療打下基礎(chǔ)。方法:(1)將6只健康妊娠17天的SD(E17)大鼠隨機(jī)分配為3組,即正常組、二甲基亞砜(DMSO)注射的175cGy X-射線照射組(DMSO組)、RAP治療的175cGy射線照射組(RAP組)各2只,各孕鼠所生鼠一代(F1)飼養(yǎng)至老年期(滿18月齡)后作為實(shí)驗(yàn)對象;(2)行為學(xué)觀察:采用視頻監(jiān)控自然光線下進(jìn)行連續(xù)24小時(shí)錄像,對治療前、治療中、及治療后期間監(jiān)控,持續(xù)3月,抽取其中30天,每天抽取10小時(shí),人工觀察分析大鼠活動(dòng)、飲水、攝食、晝夜節(jié)律及是否有自發(fā)性癲癇發(fā)作等;(3)水迷宮實(shí)驗(yàn):通過Morris水迷宮(MWM)測定大鼠藥物治療前后的定位航行及空間探索實(shí)驗(yàn),比較大鼠空間學(xué)習(xí)記憶能力的變化。(4)實(shí)驗(yàn)動(dòng)物于實(shí)驗(yàn)終止后或死亡后取腦組織,觀察大鼠腦大體標(biāo)本,進(jìn)行巨檢標(biāo)本采圖,對腦組織分別進(jìn)行冰凍切片,行Nissl染色分析。結(jié)果:(1)行為學(xué)觀察:藥物治療前、治療中及治療后三月期間,老年大鼠活動(dòng)性較青年均減少,正常組無自發(fā)性癲癇發(fā)作,MCD大鼠較正常組夜間活動(dòng)多(洗臉、舔毛、搔癢等動(dòng)作較多,追逐、打架行為頻繁)。隨著鼠齡的增加,活動(dòng)逐漸減少,行動(dòng)變緩等情況。治療前,DMSO組、RAP組≤2級(Racine分級)的癲癇發(fā)作次數(shù)較正常組多,藥物治療后RAP組癲癇發(fā)作次數(shù)減,整個(gè)實(shí)驗(yàn)過程中未見典型的Racine分級三級及其以上的自發(fā)性癲癇發(fā)作。(2)MWM藥物治療前定位航行實(shí)驗(yàn):3組大鼠隨著訓(xùn)練天數(shù)的增加,逃避潛伏期逐漸縮短,DMSO組、RAP素組逃避潛伏期較正常組延長,差異具有統(tǒng)計(jì)學(xué)意義(p0.05),DMSO組與RAP組比較差異無統(tǒng)計(jì)學(xué)意義;藥物治療后:DMSO組、RAP組逃避潛伏期仍較正常組延長,差異有統(tǒng)計(jì)學(xué)意義(p0.05)。DMSO組與RAP組相比,逃避潛伏期無明顯差異,藥物治療后各組逃避潛伏期與藥物治療前比較差異無統(tǒng)計(jì)學(xué)意義�？臻g探索測定:藥物治療前DMSO組、RAP組穿越平臺次數(shù)、目標(biāo)象限時(shí)間比明顯少于正常組(p0.05),DMSO組與RAP組比較無差異;藥物治療后RAP組、DMSO組目標(biāo)象限時(shí)間比、穿越平臺次數(shù)較正常組減少(p0.05),RAP組與DMSO組比較無差異。正常組、DMSO組、RAP組治療后與治療前比較無差異。(3)大體標(biāo)本及病理學(xué)分析:DMSO組、RAP組腦體積較正常組減小,以大腦半球縮小明顯,四疊體暴露。冠狀切面觀察:胼胝體可見缺失,皮質(zhì)變薄;切片過程中,3組均可見腦組織多發(fā)白色鈣化點(diǎn),主要分布于白質(zhì)。Nissl染色:DMSO組、RAP組大鼠與正常組比較六層皮質(zhì)變薄,皮質(zhì)結(jié)構(gòu)紊亂,縱向、橫向皮質(zhì)層次分界模糊,細(xì)胞排列紊亂、稀疏,皮質(zhì)內(nèi)及皮質(zhì)下組織可見大小不等的神經(jīng)元異位結(jié)節(jié)。RAP組、DMSO組可見海馬結(jié)構(gòu)異常,連續(xù)性中斷,CA 1、CA 2區(qū)可見數(shù)量、大小不等的異位結(jié)節(jié)。海馬結(jié)構(gòu)可見神經(jīng)元分散現(xiàn)象。根據(jù)FCD分級:RAP組、DMSO組均可見有皮層異位結(jié)節(jié),胼胝體缺失、海馬異常,FCD分型為FCDⅠ-Ⅱ型。結(jié)論:(1)X-射線宮內(nèi)照射E17大鼠能較好的模擬人類MCD,具有腦皮質(zhì)結(jié)構(gòu)紊亂、室管膜下結(jié)節(jié)、海馬結(jié)構(gòu)異常、認(rèn)知損害及行為學(xué)改變等特點(diǎn)。(2)X-射線誘導(dǎo)的MCD大鼠老年期具有出現(xiàn)認(rèn)知能力功能早,認(rèn)知損害嚴(yán)重的特點(diǎn)。(3)RAP對MCD模型大鼠老年期具有保護(hù)作用,改善行為學(xué)表現(xiàn)及低級別的癲癇發(fā)作,但不能改善認(rèn)知損害及逆轉(zhuǎn)病理學(xué)損害。
[Abstract]:Objective: To investigate the effect of rapamycin (RAP) on X- ray irradiation induced intrauterine cortical malformation (MCD) effect of senile rat model of cognitive impairment and behavior, for further study of pathogenesis of MCD and early intervention, to lay the foundation for treatment. Methods: (1) 6 healthy pregnant 17 days SD (E17) rats were randomly divided into 3 groups, namely the normal group, two dimethyl sulfoxide (DMSO) 175cGy X- ray injection group (group DMSO), 175cGy ray irradiation group RAP treatment (group RAP) 2 rats each, the pregnant rats born generation rats (F1) fed to the old age (18 month old) as the experimental object; (2) behavioral observation: the use of video surveillance under natural light for 24 hours of video, before treatment, treatment, after treatment and during continuous monitoring, March, from which 30 days, every day from 10 hours, were analyzed by artificial observation activities, drinking water, food intake the circadian rhythm, and whether there is spontaneous epilepsy Seizure; (3) water maze test: the Morris water maze (MWM) determination of positioning navigation and space of rats before and after drug treatment experiment, changes of spatial learning and memory abilities of rats. (4) experimental animal experiment after the termination or after the death of brain tissue, observing specimen of rat brain giant, biopsy specimens of brain tissue were collected, frozen section, Nissl stain analysis. Results: (1) the behavior observation: drug therapy before March, during and after the treatment period, aged rats compared to young activity decreased, the normal group without spontaneous seizures, compared with normal MCD rats group activities at night (wash his hair, more, itch action chase, frequent fights). With the age of rats, activity decreased, action slow. Before treatment, DMSO group, RAP group is less than or equal to 2 grade (Racine grade) the number of seizures compared with the normal group, drug therapy Group RAP after seizure frequency reduction, the whole experiment process no typical Racine grade three and above spontaneous seizures. (2) MWM before drug treatment navigation test: 3 groups of rats with the increase of the number of training days, the escape latency shortened gradually, DMSO group, RAP group, the escape latency longer than normal group, the difference was statistically significant (P0.05), DMSO group and RAP group had no significant difference; after drug treatment: DMSO group, RAP group, the escape latency is still longer than normal group, the difference was statistically significant (P0.05) in.DMSO group compared with RAP group, the escape latency had no significant difference after treatment were compared to escape the incubation period and before drug treatment was not statistically significant. The determination of space exploration: before drug treatment group DMSO, RAP group the number of crossing platform, the target quadrant time ratio is lower than normal group (P0.05), there was no significant difference between DMSO group and RAP group; After treatment, RAP group, DMSO group of target quadrant time ratio, the number of crossing platform less than the normal group (P0.05), there was no significant difference between RAP group and DMSO group. The normal group, DMSO group, RAP group before and after treatment. No difference (3) specimens and pathological analysis: DMSO group, RAP brain volume group than the normal group decreased to cerebral hemisphere reduced significantly, quadrigeminal exposure. Coronal section observation: corpus callosum visible lack of cortical thinning; slice process, 3 groups were seen in brain tissue of multiple white calcification, mainly distributed in the white matter of.Nissl staining: DMSO group, RAP group and normal group rats comparison of six layers of cortical thinning, disorder, cortical structure of longitudinal, lateral cortical level fuzzy boundaries, the cells arranged in disorder, sparse, ectopic neuronal nodules of.RAP group showed the size of the organization within the cortical and subcortical hippocampus, DMSO group showed abnormal structure, continuous interruption, CA 1, CA 2 showed a large number. Small nodules ranging from ectopic hippocampal neurons. The visible dispersion phenomenon. According to FCD classification: RAP group, DMSO group showed a cortical heterotopic nodules, agenesis of the corpus callosum, hippocampus, FCD type of FCD I / II. Conclusion: (1) X- ray irradiation of intrauterine E17 rats can mimic human MCD. That is the cerebral cortex structure disorder, subependymal nodules, hippocampal structural abnormalities, characteristics of cognitive impairment and behavioral changes. (2) X- ray induced senile MCD rats with cognitive function appeared early, severe cognitive impairment characteristics. (3) RAP has a protective effect on senile MCD rats rats, improve the behavioral performance and low level of epilepsy, but can not improve the cognitive impairment and reversion of pathological damage.

【學(xué)位授予單位】：西南醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R742

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