发育期铅暴露对大鼠学习记忆功能的损伤及药物和行为的干预
发布时间：2018-08-18 11:10
【摘要】： 慢性铅暴露可以引起学习记忆和认知功能的损伤,长时程增强(long-termpotentiation,LTP)被认为是与学习记忆相关的一种突触可塑性模型,被广泛应用于研究学习记忆的细胞机制。已有研究结果表明,在发育早期(孕期和哺乳期),慢性铅暴露损伤了大鼠空间学习记忆,同时损伤了海马CA1区和DG区的LTP的诱导。目前临床上治疗铅中毒的主要药物为鳌合剂,由于其并不能修复因铅引起的学习记忆损伤及其本身的副作用等弊端,鳌合剂不适合长期低铅暴露的儿章。因此,积极探索治疗效果明显且能有效修复其学习记忆损伤的药物和有关心理行为干预方法显得意义重大。有文献报道腺苷蛋氨酸(S -adenosyl-L-methionine,SAM)能降低铅中毒大鼠及病人血铅浓度及升高血δ-氨基乙酰丙酸脱水酶(δ-Aminolevulinic Acid Dehydratase,ALAD)活力,但其对铅暴露导致的学习记忆功能损伤有无作用国内外未见报道,由于该药对儿童尚未发现明显的毒副作用,因此对该药进行进一步的研究非常有实际意义。丰富的环境刺激这一低成本低风险的心理行为干预方法已被广泛用于如低出生体重、缺血缺氧性脑病等脑发育异常的干预,对于发育早期铅中毒的神经毒性方面的干预研究较少。本文运用Morris水迷宫作为大鼠空间学习记忆的测试工具,并用在位场电位记录的方法在发育早期(孕期和哺乳期)慢性铅暴露大鼠模型上分别研究了药物腺苷蛋氨酸和心理行为干预——丰富的环境刺激对发育早期慢性铅暴露造成的空间学习记忆和突触可塑性损伤的修复和保护作用,主要的研究方法和结果如下: 1.自母鼠受孕第1天至仔鼠断奶为止给予母鼠1.5g/L的醋酸铅饮用水染铅,对照组则饮用自来水,仔鼠断奶后选取雄性仔鼠每天腹腔注射20mg/kg的SAM或10ml/kg的生理盐水,为期22天,在44—54天时进行Morris水迷宫试验及在海马DG区记录兴奋性突触后电位(excitatory postsynaptic potential,EPSP)和群峰电位(population spike,PS),并检测血铅和血、脑、海马的氧化指标。结果表明:发育早期慢性铅暴露可以明显延长大鼠在水迷宫的逃避潜伏期、缩短在原平台象限的游泳时间,并且明显降低DG区诱导的EPSP和PS LTP幅度,而在铅+SAM组发现其对铅暴露引起的空间学习记忆损伤和海马LTP损伤有明显的改善作用。同时还发现给予SAM能降低铅组大鼠的血铅浓度,提高了肝脏、脑及海马组织中GSH含量,降低了肝脏、脑组织中MDA含量。结果提示SAM对临床上慢性铅中毒儿童,尤其对学习记忆功能损伤的修复可能具有一定意义。 2。自母鼠受孕第1天至仔鼠断奶为止给予母鼠1.5g/L的醋酸铅饮用水染铅,对照组则饮用自来水,21天断奶后停止喂铅,将两组仔鼠中的雄鼠用以接下来的实验:两组中各随机挑选一半为普通环境饲养,另一半在丰富的环境条件下饲养,直至实验结束,这样就将动物最终分成了四组:正常对照组(Con)、对照+丰富环境组(Con/EE)、铅组(Pb)、铅+丰富环境组(Pb/EE)。在大鼠出生后56天时对四组大鼠实施Morris水迷宫试验及在海马DG区记录兴奋性突触后电位(excitatory postsynaptic potential,BPSP)和群峰电位(population spike,PS),结果发现丰富的环境刺激能修复发育期铅暴露所致的空间学习记忆损伤和因铅暴露而受损的大鼠海马DG区的EPSP和PSLTP,与对照组相比差异无显著性。
[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.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R363;R114
[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.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R363;R114
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