發(fā)布時(shí)間：2018-03-14 15:55

  本文選題：早年應(yīng)激　切入點(diǎn)：N-甲基-D-天冬氨酸受體　出處：《山西醫(yī)科大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：臨床研究和流行病學(xué)調(diào)查顯示，早年應(yīng)激（Early life stress，ELS）是精神疾病發(fā)病的重要危險(xiǎn)因素之一，兒童期創(chuàng)傷性經(jīng)歷會(huì)增加個(gè)體對(duì)具有環(huán)境發(fā)病風(fēng)險(xiǎn)的精神疾�。ㄈ缫钟簟⒔箲]障礙等）的易感性。前腦（海馬、前額葉）既是應(yīng)激的高位調(diào)節(jié)中樞，也是認(rèn)知相關(guān)的重要腦區(qū)，在精神疾病的機(jī)制學(xué)研究中占有重要地位。動(dòng)物模型相關(guān)研究中，早年應(yīng)激誘發(fā)的前腦突觸可塑性改變和認(rèn)知功能損傷為精神疾病發(fā)病機(jī)制的研究提供了獨(dú)特的研究角度。谷氨酸是重要的中樞興奮性遞質(zhì)，主要通過(guò)與突觸后膜谷氨酸NMDA（N-methyl-D-aspartate，N-甲基-D-天冬氨酸）受體結(jié)合，發(fā)揮重要的生理作用。研究發(fā)現(xiàn)，早年應(yīng)激通過(guò)作用于谷氨酸系統(tǒng)，引起NMDA受體改變和認(rèn)知功能受損。同時(shí)動(dòng)物研究顯示早期處理（early handling）中，重復(fù)注射MK-801（dizocilpine maleate，地卓西平馬來(lái)酸鹽）通過(guò)阻斷NMDA受體會(huì)誘發(fā)嚙齒類動(dòng)物認(rèn)知功能損害。本研究通過(guò)早期MK-801處理模擬早年應(yīng)激，研究其對(duì)大鼠前腦NMDA受體亞基表達(dá)的改變。 實(shí)驗(yàn)一 目的：本研究選擇早期MK-801處理模擬早年應(yīng)激，檢測(cè)其對(duì)不同發(fā)育階段NMDA受體亞基的影響。 方法：選用非選擇性NMDA受體拮抗劑MK-801（dizocilpine maleate，地卓西平馬來(lái)酸鹽），于PND（postnatal day，出生后）5~14天重復(fù)注射,研究其對(duì)大鼠不同發(fā)育階段（幼年期、青春期、成年期）前腦（海馬和前額葉皮質(zhì)腦區(qū)）NMDA受體亞基（NR1、NR2A、NR2B）表達(dá)的影響。 結(jié)果： 1.幼年期（PND15）與對(duì)照組相比，應(yīng)激組大鼠海馬與前額葉皮質(zhì)腦區(qū)NMDA受體各亞基表達(dá)水平均無(wú)統(tǒng)計(jì)學(xué)差異（P0.05）； 2.青春期（PND42）與對(duì)照組相比，應(yīng)激組大鼠海馬與前額葉皮質(zhì)腦區(qū)NMDA受體各亞基表達(dá)水平均無(wú)統(tǒng)計(jì)學(xué)差異（P0.05）； 3.成年期（PND70）應(yīng)激組大鼠海馬NR1、NR2A表達(dá)水平較對(duì)照組增加[NR1：（149.55±12.08）vs.（100.00±14.34）；NR2A：（171.54±8.88）vs.（100.00±22.83）]，差異均有統(tǒng)計(jì)學(xué)意義（P0.05）；海馬NR2B及前額葉皮質(zhì)腦區(qū)NMDA受體各亞基表達(dá)水平在兩組間無(wú)統(tǒng)計(jì)學(xué)差異。 綜上，新生期重復(fù)注射MK-801選擇性上調(diào)成年大鼠海馬NMDA受體亞基NR1和NR2A的表達(dá)水平，提示新生期阻斷NMDA受體引起持久的神經(jīng)發(fā)育異常，進(jìn)而引起一系列精神疾病相關(guān)的行為異常。認(rèn)為早期MK-801處理對(duì)大鼠大腦的神經(jīng)發(fā)育產(chǎn)生遠(yuǎn)期影響，其具體作用機(jī)制仍需進(jìn)一步研究，，此將對(duì)精神疾病的臨床治療及預(yù)后有重要指導(dǎo)意義。相關(guān)研究提出單純的環(huán)境應(yīng)激模型（心理應(yīng)激）能更合理地模擬早年應(yīng)激，以更好地研究早年應(yīng)激對(duì)成年嚙齒類動(dòng)物認(rèn)知功能的影響。第二部分實(shí)驗(yàn)選擇限制筑窩材料和墊料（limited nesting and bedding material）模型，研究其對(duì)成年小鼠前腦c-fos基礎(chǔ)表達(dá)水平的影響。 實(shí)驗(yàn)二 目的：研究早年應(yīng)激對(duì)成年小鼠前腦（海馬和前額葉皮質(zhì)腦區(qū)）即早基因c-fos表達(dá)水平的影響。 方法：選用限制筑窩材料和墊料模型，于PND2~PND9造模處理。 結(jié)果： 1.應(yīng)激組與對(duì)照組相比，小鼠海馬腦區(qū)c-fos表達(dá)水平無(wú)統(tǒng)計(jì)學(xué)差異（P0.05） 2.應(yīng)激組與對(duì)照組相比，小鼠前額葉皮質(zhì)腦區(qū)c-fos表達(dá)水平無(wú)統(tǒng)計(jì)學(xué)差異（P0.05） 綜上，應(yīng)激組小鼠與對(duì)照組小鼠c-fos基礎(chǔ)表達(dá)水平無(wú)明顯差異，提示早年應(yīng)激未影響成年期小鼠前腦的c-fos基礎(chǔ)表達(dá)。結(jié)論：本研究發(fā)現(xiàn)早年應(yīng)激中早期MK-801處理會(huì)引起大鼠成年期NMDA受體亞基表達(dá)異常，提示其對(duì)大鼠神經(jīng)發(fā)育產(chǎn)生了遠(yuǎn)期影響。同時(shí)實(shí)驗(yàn)二顯示早年生活應(yīng)激對(duì)小鼠成年期c-fos的基礎(chǔ)表達(dá)無(wú)影響，為進(jìn)一步實(shí)驗(yàn)提供基礎(chǔ)。下一步實(shí)驗(yàn)通過(guò)檢測(cè)成年小鼠學(xué)習(xí)記憶相關(guān)行為改變和c-fos表達(dá)的變化，研究早年應(yīng)激對(duì)成年小鼠認(rèn)知功能的影響。進(jìn)而為臨床精神疾病發(fā)病機(jī)制研究、治療及預(yù)防提供重要依據(jù)。
[Abstract]:According to the epidemiological and clinical studies, early life stress (Early life stress, ELS) is one of the important risk factors for the incidence of mental illness, childhood traumatic experiences of individuals with mental illness will increase the environmental risk (such as depression, anxiety disorder, etc.). Susceptibility to forebrain (hippocampus, prefrontal) is a high stress adjustment the central, is also important cognitive brain areas related to the mechanism of mental illness in school plays an important role in the study. The related research in animal models, provides a unique perspective on forebrain synaptic plasticity changes and cognitive function in early stress induced damage to the pathogenesis of mental illness. Glutamate is an important excitatory neurotransmitter in central, mainly through the glutamate and postsynaptic membrane NMDA (N-methyl-D-aspartate, N- methyl -D- aspartate) receptors play an important physiological role. The study found that early should Induced by acting on the glutamate system, caused by NMDA receptor changes and impaired cognitive function. At the same time, animal studies have shown that early treatment (early handling), MK-801 (dizocilpine maleate, repeated injection to Xiping Zhuo maleate) by blocking NMDA receptors induced by rodents cognitive impairment. This study through the simulation of early stress in early MK-801 treatment on the subunit expression changes in rat forebrain NMDA receptors.
Experiment 1
Objective: in this study, early MK-801 treatment was selected to simulate early stress and to detect its effect on NMDA receptor subunits at different developmental stages.
Methods: the non selective NMDA receptor antagonist MK-801 (dizocilpine, maleate, Zhuo Xiping maleate), PND (postnatal day, 5~14 days after birth) repeated injection, on the rats at different developmental stages (early childhood, adolescence, adulthood) forebrain (hippocampus and prefrontal cortex) NMDA receptor subunits (NR1, NR2A, NR2B) on the expression.
Result錛

本文編號(hào)：1611904