【摘要】： 慢性鉛暴露可以引起學(xué)習記憶和認知功能的損傷,長時程增強(long-termpotentiation,LTP)被認為是與學(xué)習記憶相關(guān)的一種突觸可塑性模型,被廣泛應(yīng)用于研究學(xué)習記憶的細胞機制。已有研究結(jié)果表明,在發(fā)育早期(孕期和哺乳期),慢性鉛暴露損傷了大鼠空間學(xué)習記憶,同時損傷了海馬CA1區(qū)和DG區(qū)的LTP的誘導(dǎo)。目前臨床上治療鉛中毒的主要藥物為鰲合劑,由于其并不能修復(fù)因鉛引起的學(xué)習記憶損傷及其本身的副作用等弊端,鰲合劑不適合長期低鉛暴露的兒章。因此,積極探索治療效果明顯且能有效修復(fù)其學(xué)習記憶損傷的藥物和有關(guān)心理行為干預(yù)方法顯得意義重大。有文獻報道腺苷蛋氨酸(S -adenosyl-L-methionine,SAM)能降低鉛中毒大鼠及病人血鉛濃度及升高血δ-氨基乙酰丙酸脫水酶(δ-Aminolevulinic Acid Dehydratase,ALAD)活力,但其對鉛暴露導(dǎo)致的學(xué)習記憶功能損傷有無作用國內(nèi)外未見報道,由于該藥對兒童尚未發(fā)現(xiàn)明顯的毒副作用,因此對該藥進行進一步的研究非常有實際意義。豐富的環(huán)境刺激這一低成本低風險的心理行為干預(yù)方法已被廣泛用于如低出生體重、缺血缺氧性腦病等腦發(fā)育異常的干預(yù),對于發(fā)育早期鉛中毒的神經(jīng)毒性方面的干預(yù)研究較少。本文運用Morris水迷宮作為大鼠空間學(xué)習記憶的測試工具,并用在位場電位記錄的方法在發(fā)育早期(孕期和哺乳期)慢性鉛暴露大鼠模型上分別研究了藥物腺苷蛋氨酸和心理行為干預(yù)——豐富的環(huán)境刺激對發(fā)育早期慢性鉛暴露造成的空間學(xué)習記憶和突觸可塑性損傷的修復(fù)和保護作用,主要的研究方法和結(jié)果如下: 1.自母鼠受孕第1天至仔鼠斷奶為止給予母鼠1.5g/L的醋酸鉛飲用水染鉛,對照組則飲用自來水,仔鼠斷奶后選取雄性仔鼠每天腹腔注射20mg/kg的SAM或10ml/kg的生理鹽水,為期22天,在44—54天時進行Morris水迷宮試驗及在海馬DG區(qū)記錄興奮性突觸后電位(excitatory postsynaptic potential,EPSP)和群峰電位(population spike,PS),并檢測血鉛和血、腦、海馬的氧化指標。結(jié)果表明:發(fā)育早期慢性鉛暴露可以明顯延長大鼠在水迷宮的逃避潛伏期、縮短在原平臺象限的游泳時間,并且明顯降低DG區(qū)誘導(dǎo)的EPSP和PS LTP幅度,而在鉛+SAM組發(fā)現(xiàn)其對鉛暴露引起的空間學(xué)習記憶損傷和海馬LTP損傷有明顯的改善作用。同時還發(fā)現(xiàn)給予SAM能降低鉛組大鼠的血鉛濃度,提高了肝臟、腦及海馬組織中GSH含量,降低了肝臟、腦組織中MDA含量。結(jié)果提示SAM對臨床上慢性鉛中毒兒童,尤其對學(xué)習記憶功能損傷的修復(fù)可能具有一定意義。 2。自母鼠受孕第1天至仔鼠斷奶為止給予母鼠1.5g/L的醋酸鉛飲用水染鉛,對照組則飲用自來水,21天斷奶后停止喂鉛,將兩組仔鼠中的雄鼠用以接下來的實驗:兩組中各隨機挑選一半為普通環(huán)境飼養(yǎng),另一半在豐富的環(huán)境條件下飼養(yǎng),直至實驗結(jié)束,這樣就將動物最終分成了四組:正常對照組(Con)、對照+豐富環(huán)境組(Con/EE)、鉛組(Pb)、鉛+豐富環(huán)境組(Pb/EE)。在大鼠出生后56天時對四組大鼠實施Morris水迷宮試驗及在海馬DG區(qū)記錄興奮性突觸后電位(excitatory postsynaptic potential,BPSP)和群峰電位(population spike,PS),結(jié)果發(fā)現(xiàn)豐富的環(huán)境刺激能修復(fù)發(fā)育期鉛暴露所致的空間學(xué)習記憶損傷和因鉛暴露而受損的大鼠海馬DG區(qū)的EPSP和PSLTP,與對照組相比差異無顯著性。
[Abstract]:Long-term potentiation (LTP) is considered to be a synaptic plasticity model associated with learning and memory. It has been widely used to study the cellular mechanism of learning and memory. At present, the main drug for the treatment of lead poisoning is Ao Mixture. Because it can not repair the learning and memory damage caused by lead and its own side effects, Ao Mixture is not suitable for children with long-term low lead exposure. It has been reported that S-adenosyl-L-methionine (SAM) can reduce blood lead concentration and increase blood delta-aminolevulinic acid dehydratase (delta-Aminolevulinic acid Dehydratase) in lead poisoned rats and patients. E, ALAD) activity, but its effect on learning and memory impairment induced by lead exposure has not been reported at home and abroad. As the drug has not yet found obvious toxic side effects in children, it is very meaningful to further study the drug. Rich environmental stimuli, a low-cost and low-risk psychological and behavioral intervention method, have been widely used. Interventions for brain developmental abnormalities such as low birth weight, hypoxic-ischemic encephalopathy, and so on, have little research on the neurotoxicity of lead poisoning in early developmental stages. Morris water maze was used as a spatial learning and memory test tool in rats, and in situ field potential recording was used to record chronic lead in early developmental stages (pregnancy and lactation). The effects of adenosylmethionine (AM) and psycho-behavioral interventions, rich environmental stimuli, on the repair and protection of spatial learning and memory and synaptic plasticity impairment induced by chronic lead exposure in early developmental stage were studied in rats.
1. From the first day of conception to the weaning of the offspring, the mother rats were given lead acetate drinking water of 1.5 g/L, while the control rats were given tap water. After weaning, the male offspring were injected with 20 mg/kg SAM or 10 ml/kg saline intraperitoneally every day for 22 days. Morris water maze test was conducted at 44-54 days and excitatory processes were recorded in DG area of the hippocampus. The results showed that chronic lead exposure at early stage of development could significantly prolong the escape latency of rats in the water maze, shorten the swimming time in the original platform quadrant, and significantly reduce the seduction in DG area. The amplitudes of EPSP and PSLTP in the lead + SAM group were significantly improved in the lead exposure-induced spatial learning and memory impairment and hippocampal LTP impairment. It was also found that SAM could decrease the blood lead concentration, increase the GSH content in liver, brain and hippocampus, and decrease the MDA content in liver and brain. M may play a role in the repair of learning and memory impairment in children with chronic lead poisoning.
2. From the first day of conception to the weaning of the offspring, the female rats were given lead acetate drinking water of 1.5 g/L, while the control rats were given tap water. After 21 days of weaning, the male rats in the two groups were stopped feeding lead. The male rats in the two groups were used for the following experiment: half of the two groups were randomly selected to be fed in normal environment, the other half was fed in rich environment until the weaning. At the end of the experiment, the animals were divided into four groups: normal control group (Con), control + enriched environment group (Con / EE), lead group (Pb), lead + enriched environment group (Pb / EE). The results showed that abundant environmental stimuli could repair the spatial learning and memory impairment induced by lead exposure and the EPSP and PSLP in the DG area of the hippocampus of rats damaged by lead exposure. There was no significant difference between the two groups.
【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】：2008
【分類號】：R363;R114

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