LEAD TOXICITY--MIDBRAIN DOPAMINERGIC SYSTEM

大量证据表明，铅（Pb）对中脑多巴胺能（DA）系统有显著的发育影响，并表明该系统在低水平暴露时可能受到影响。由于DA系统被认为在认知、注意、学习和运动行为中起作用，因此DA系统在铅的神经毒性作用中的作用与儿童铅暴露后观察到的神经系统特征是一致的。神经化学报告表明，铅改变DA的周转、释放和突触后DA受体的发育。然而，在体内细胞水平上，对产后暴露对多巴胺能系统的影响知之甚少。关于铅对DA神经元脉冲产生或DA神经元活力的影响的任何信息的缺乏代表了我们对铅对DA系统影响的理解的严重差距。本实验将采用单细胞电生理记录技术检测中脑含da神经元和纹状体、伏隔核靶神经元的电生理活动。此外，免疫组织化学技术和特定行为分析将分别用于检测铅对DA神经元存活的影响和DA系统调节的行为。该方法将提供对DA神经元活动的全面分析，并提供将电生理、免疫组织化学和行为结果与血液和脑铅水平相关联的能力。将使用两种不同的暴露方案。在断奶前试验方案中，将通过饮用铅处理过的饮用水的哺乳期公鼠的乳汁将铅提供给后代。在断奶后方案中，铅将通过断奶仔猪的饮用水直接提供给断奶仔猪。总的假设是，出生后的铅暴露改变了中脑DA神经元的电生理活动和/或存活。对DA系统的突触前成分（即DA神经元）的影响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有助于我们理解低水平铅暴露对人类大脑发育的影响，并将在细胞水平上提供与这种暴露相关的神经问题的更详细的见解。

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.