【作者】 罗云云；

【导师】 阮迪云；

【作者基本信息】 中国科学技术大学 ， 生物物理学， 2012， 博士

【摘要】 慢性铅暴露引发多重学习记忆和认知能力的损害。海马的突触可塑性是学习记忆的重要细胞模型，得到了广泛的重视和研究，包括长时程增强(long-termpotentiation, LTP)和长时程压抑(long-term depression, LTD)两种重要形式。去增强(Depotentiation, DP)是突触可塑性的另外一种形式。以往的研究结果表明，慢性铅暴露可以损伤海马CA1区和齿状回(dentate gyrus, DG)的LTP/LTD诱导。本文用场电位记录方法研究了μ型阿片受体激动剂DAMGO对慢性铅暴露大鼠突触可塑性损伤的影响和Galantamine对慢性铅暴露大鼠突触可塑性损伤的修复和保护作用。研究方法和结果如下：新生的Wistar大鼠从出生起到断乳通过饮用0.2%醋酸铅溶液染铅。在27-30日龄大鼠海马离体脑片齿状回记录兴奋性突触后电位。结果表明：DAMGO在铅暴露组和control组都诱导得到LTP幅度增加，并且铅暴露组比control组升高更明显。NMDA受体阻断剂AP5不能完全阻断DAMGO诱导的LTP。铅暴露损伤了高频刺激诱导的LTP，DAMGO对这种损伤没有明显的修复，对control组的HFS-LTP也没有明显的影响。结果说明，DAMGO可以在慢性铅暴露组诱导比control组更高的LTP，其机制部分来源于NMDA受体途径的参与；DAMGO对HFS-LTP组别没有明显作用，可能与铅神经毒理作用在两种LTP诱导过程中位点差异有关。新生的Wistar大鼠自出生到成年通过饮用0.2%醋酸铅溶液染铅。在成年大鼠(60-90日龄)的海马齿状回记录兴奋性突触后电位和群峰电位。进行实验前两周起通过腹腔注射为Galantamine组别动物给药(1 mg/100 g体重每天)。结果显示，慢性铅暴露损伤了大鼠海马DG区LTP/DP的诱导，而Galantamine可以显著的升高铅暴露大鼠LTP/DP的幅度，但是在非铅暴露组只有不明显的升高。这个结果提示Galantamine可以逆转铅导致的大鼠突触可塑性损伤，并且可能是有效的铅所致认知障碍治疗药物。通过以上的实验，我们研究了DAMGO和Galantamine对慢性铅暴露造成的突触可塑性损伤的影响，了解了可能的作用机制。为进一步了解了铅的神经毒理机制，寻求新的治疗途径提供理论支持。更多还原

【Abstract】 Chronic lead exposure causes a variety of impairments in learning and memoryand cognitive function. And synaptic plasticity in hippocampus is an extensivelystudied cellular model of learning and memory, which includes long-term potentiation(LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is anotherform of synaptic plasticity. Previous studies show that chronic lead exposure candamage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas.The studies of thesis were carried out of investigate the effects on chronic lead-causedsynaptic plasticity impairment by DAMGO, a selectiveμ-opioid receptor agonists，and we investigated the repair and protection on lead-caused synaptic plasticityimpairment by Galantamine, using field potential recording on chronic lead exposurerats. The methods and results are as follows：Neonatal Wistar rats were exposed to lead from parturition to weaning via milkof dams whose drinking water contained 0.2% lead acetate. Field excitatorypostsynaptic potentials (fEPSPs) in DG area of hippocampus were recorded onpostnatal days 27-30. DAMGO application was followed by an increase in EPSPslopes in both control and lead-exposed rats, while the amplitude of DAMGO-LTP inthe lead-exposed rats was significantly greater than that in controls. DAMGO-LTPcan not be blocked by NMDA receptor antagonist AP5 completely. Chronic leadexposure causes impairment in the amplitude of HFS-LTP, and the impairment wasnot significantly affected by DAMGO treatment, the DAMGO application also didnot influence the amplitude of HFS-LTP in control group. These results indicate thatthe amplitude of DAMGO-LTP in lead-exposured group was greater than controlgroup, and it was depends on the activity of NMDA receptor partly. No significanteffect of DAMGO on HFS-LTP groups is the result of different sites of leadneurotoxicity.Neonatal Wistar rats were exposed to lead from parturition through adulthood bythe drinking of 0.2% lead acetate. Galantamine was applied by intraperitonealinjection every day (1 mg/day/100 g body weight) twoweeks before theelectrophysiological recording. The results showed that chronic lead exposureimpaired LTP/DP induction in DG area of the hippocampus, and Galantamine causeda significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that Galantamine couldreverse the lead-induced impairments of synaptic plasticity in rats and might be aneffective medicine to cure the cognitive deficits induced by lead.By these experiments, we studied the effects on the chronic lead-exposuredimpairments of synaptic plasticity by DAMGO and Galantamine, and possiblemechanisms. All of these findings provided us a more comprehensive understandingabout the toxicity of lead.更多还原