【摘要】：慢性鉛暴露引發(fā)多重學(xué)習(xí)記憶和認(rèn)知能力的損害。海馬的突觸可塑性是學(xué)習(xí)記憶的重要細胞模型，得到了廣泛的重視和研究，包括長時程增強(long-termpotentiation, LTP)和長時程壓抑(long-term depression, LTD)兩種重要形式。去增強(Depotentiation, DP)是突觸可塑性的另外一種形式。以往的研究結(jié)果表明，慢性鉛暴露可以損傷海馬CA1區(qū)和齒狀回(dentate gyrus, DG)的LTP/LTD誘導(dǎo)。本文用場電位記錄方法研究了μ型阿片受體激動劑DAMGO對慢性鉛暴露大鼠突觸可塑性損傷的影響和Galantamine對慢性鉛暴露大鼠突觸可塑性損傷的修復(fù)和保護作用。研究方法和結(jié)果如下： 新生的Wistar大鼠從出生起到斷乳通過飲用0.2%醋酸鉛溶液染鉛。在27-30日齡大鼠海馬離體腦片齒狀回記錄興奮性突觸后電位。結(jié)果表明：DAMGO在鉛暴露組和control組都誘導(dǎo)得到LTP幅度增加，并且鉛暴露組比control組升高更明顯。NMDA受體阻斷劑AP5不能完全阻斷DAMGO誘導(dǎo)的LTP。鉛暴露損傷了高頻刺激誘導(dǎo)的LTP，DAMGO對這種損傷沒有明顯的修復(fù)，對control組的HFS-LTP也沒有明顯的影響。結(jié)果說明，DAMGO可以在慢性鉛暴露組誘導(dǎo)比control組更高的LTP，其機制部分來源于NMDA受體途徑的參與；DAMGO對HFS-LTP組別沒有明顯作用，可能與鉛神經(jīng)毒理作用在兩種LTP誘導(dǎo)過程中位點差異有關(guān)。 新生的Wistar大鼠自出生到成年通過飲用0.2%醋酸鉛溶液染鉛。在成年大鼠(60-90日齡)的海馬齒狀回記錄興奮性突觸后電位和群峰電位。進行實驗前兩周起通過腹腔注射為Galantamine組別動物給藥(1 mg/100 g體重每天)。結(jié)果顯示，慢性鉛暴露損傷了大鼠海馬DG區(qū)LTP/DP的誘導(dǎo)，而Galantamine可以顯著的升高鉛暴露大鼠LTP/DP的幅度，但是在非鉛暴露組只有不明顯的升高。這個結(jié)果提示Galantamine可以逆轉(zhuǎn)鉛導(dǎo)致的大鼠突觸可塑性損傷，，并且可能是有效的鉛所致認(rèn)知障礙治療藥物。 通過以上的實驗，我們研究了DAMGO和Galantamine對慢性鉛暴露造成的突觸可塑性損傷的影響，了解了可能的作用機制。為進一步了解了鉛的神經(jīng)毒理機制，尋求新的治療途徑提供理論支持。
[Abstract]:Chronic lead exposure leads to multiple learning, memory and cognitive impairment. Synaptic plasticity in hippocampus is an important cellular model of learning and memory, which has been widely studied, including long-term potentiation (long-termpotentiation, LTP) and long-term depression (long-term depression, LTD). Deactivation of (Depotentiation, DP) is another form of synaptic plasticity. Previous studies have shown that chronic lead exposure can damage the LTP/LTD induction of CA1 area and (dentate gyrus, DG) in dentate gyrus. The effects of 渭 opioid receptor agonist DAMGO on synaptic plasticity in rats exposed to chronic lead and the repair and protection of Galantamine on synaptic plasticity in rats exposed to chronic lead were studied by field potential recording. The methods and results were as follows: newborn Wistar rats were exposed to lead from birth to weaning by drinking 0.2% lead acetate solution. Excitatory postsynaptic potentials were recorded in the dentate gyrus of 27-30 day old rats. The results showed that the amplitude of LTP induced by DAMGO was increased in both lead exposure group and control group, and that in lead exposure group was significantly higher than that in control group. AP5, a NMDA receptor blocker, could not completely block DAMGO induced LTP.. LTP,DAMGO induced by high frequency stimuli was not significantly repaired by lead exposure, nor did it affect HFS-LTP in control group. The results showed that DAMGO could induce a higher level of LTP, in chronic lead exposure group than that in control group. The mechanism was partly due to the involvement of NMDA receptor pathway. DAMGO had no obvious effect on HFS-LTP group, which might be related to the difference of site in the induction of lead neurotoxicology between the two types of LTP. Newborn Wistar rats were exposed to lead by drinking 0.2% lead acetate solution from birth to adulthood. Excitatory postsynaptic potentials and group peak potentials were recorded in the dentate gyrus of adult rats (60-90 days old). Two weeks before the experiment, animals in the Galantamine group were injected intraperitoneally (1 mg/100 g BW per day). The results showed that chronic lead exposure induced LTP/DP in the DG area of hippocampus of rats, while Galantamine could significantly increase the amplitude of LTP/DP in lead exposed rats, but it was not significantly increased in non-lead exposed group. These results suggest that Galantamine can reverse the synaptic plasticity injury induced by lead in rats and may be an effective therapy for cognitive impairment induced by lead. The effects of DAMGO and Galantamine on synaptic plasticity induced by chronic lead exposure were studied and the possible mechanism was investigated. In order to further understand the neurotoxicological mechanism of lead and seek a new therapeutic approach to provide theoretical support.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R114

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