LEAD TOXICITY--MIDBRAIN DOPAMINERGIC SYSTEM

大量证据表明，铅（Pb）对中脑多巴胺（DA）系统有显着的发育影响，并表明该系统可以在低水平的暴露受到影响。 由于DA系统被认为在认知，注意力，学习和运动行为中发挥作用，DA系统在铅的神经毒性作用中的作用与儿童期铅暴露后观察到的神经学特征一致。神经化学研究表明，铅可改变DA的周转、DA的释放和突触后DA受体的发育。然而，很少有人知道的后果，出生后暴露在体内细胞水平上的多巴胺能系统。 没有任何关于铅对DA神经元冲动产生或DA神经元活力的影响的信息，这代表了我们对铅对DA系统影响的理解存在严重差距。 拟进行的实验将采用单细胞电生理记录技术，研究中脑DA能神经元和纹状体及延髓核内靶神经元的电生理活动。此外，免疫组织化学技术和特定的行为分析将被用来检查铅对DA神经元的存活和DA系统调制的行为的影响。 这种方法将提供一个全面的分析DA神经元的活动，并提供相关的电生理，免疫组织化学和行为的结果与血液和大脑铅水平的能力。 将使用两种不同的暴露方案。 在断奶前方案中，将通过食用经Pb处理的饮用水的哺乳期母鼠的乳汁向后代提供Pb。 在断奶后方案中，将通过饮水直接向断奶仔猪提供铅。 总体假设是，出生后铅暴露改变中脑DA神经元的电生理活动和/或生存。 对DA系统的突触前成分的影响（即，DA神经元）可能会对突触后成分产生影响，这将被视为突触后DA受体反应和特定DA相关行为的变化。 从这些研究中获得的结果将是相关的，我们了解低水平铅暴露对人脑发育的影响，并将提供更详细的了解与这种暴露在细胞水平上的神经系统问题。

Substantial evidence indicates that lead (Pb) has a significant developmental impact on the midbrain dopaminergic (DA) system, and suggests that this system can be affected at low levels of exposure. Since the DA system is thought to play a role in cognition, attention, learning, and motor behavior, a role of the DA system in the neurotoxic effects of Pb is consistent with the neurological profile observed following childhood Pb exposure. Neurochemical reports have indicated that Pb alters DA turnover, DA release and the development of postsynaptic DA receptors. However, very little is known about the consequences of postnatal exposure on the dopaminergic system at the cellular level in vivo. The absence of any information concerning the effects of Pb on impulse generation in DA neurons or DA neuron viability represents a serious gap in our understanding of the impact of Pb on the DA system. The proposed experiments will examine the electrophysiological activity of the midbrain DA-containing neurons and target neurons in the striatum and nucleus accumbens by using single-cell electrophysiological recording techniques. In addition, immuno-histochemical techniques and specific behavioral assays will be used to examine the impact of Pb on DA neuron survival and the behaviors modulated by the DA system respectively. This approach will provide a thorough analysis of DA neuronal activity and provide the ability to correlate electrophysiological, immuno-histochemical and behavioral findings with blood and brain Pb levels. Two different exposure protocols will be used. In the pre-weaning protocol Pb will be provided to offspring via the milk of lactating dams that consume Pb-treated drinking water. In the post-weaning protocol Pb will be provided directly to weanlings via their drinking water. The overall hypothesis is that postnatal Pb exposure alters the electrophysiological activity and/or survival of midbrain DA neurons. The effects on the presynaptic component of the DA system (i.e., DA neurons) may then have an impact on the postsynaptic component, and this would be seen as changes in postsynaptic DA receptor responses and specific DA-related behaviors. Results obtained from these studies will be relevant to our understanding of the impact of low level Pb exposure on human brain development, and will provide more detailed insight into the neurological problems associated with such exposure at the cellular level.