LEAD TOXICITY--MIDBRAIN DOPAMINERGIC SYSTEM

大量证据表明，铅对中脑多巴胺能系统有显著的发育影响，并表明该系统在低水平的暴露下会受到影响。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，因此DA系统在铅的神经毒性效应中的作用与儿童铅暴露后观察到的神经学特征是一致的。神经化学研究表明，铅改变了DA的转换、DA的释放和突触后DA受体的发育。然而，对于出生后暴露在体内细胞水平上的多巴胺能系统的后果，人们知之甚少。缺乏关于铅对DA神经元冲动产生或DA神经元活性影响的任何信息，表明我们对铅对DA系统的影响的理解存在严重差距。本实验将利用单细胞电生理记录技术检测纹状体和伏隔核靶向神经元和中脑DA神经元的电生理活动。此外，还将利用免疫组织化学技术和特定的行为分析技术，分别检测铅对DA神经元存活的影响和DA系统对行为的调节。这种方法将提供对DA神经元活动的彻底分析，并提供将电生理、免疫组织化学和行为发现与血和脑铅水平相关联的能力。将使用两种不同的曝光方案。在断奶前的方案中，铅将通过哺乳母坝的牛奶提供给后代，这些哺乳母坝消耗经过铅处理的饮用水。在断奶后协议中，铅将通过断奶仔猪的饮用水直接提供给它们。总体假设是，出生后铅暴露改变了中脑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)的影响可能会影响突触后成分，这将被视为突触后DA受体反应和特定的DA相关行为的变化。这些研究的结果将有助于我们了解低水平铅暴露对人脑发育的影响，并将在细胞水平上为与这种暴露相关的神经问题提供更详细的见解。

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.