Neurobehavioral Mechanisms of Cognitive Impairment

超级基金清单上的各种化学品，如杀虫剂、金属和多卤代烃，已被发现损害认知功能，包括学习、记忆和注意力。我们一直专注于确定潜在的认知障碍的神经机制所造成的发展农药暴露。使用经典的发育神经行为毒理学大鼠模型，我们已经表明，在该中心的第一个资助期，有机磷杀虫剂毒死蜱对工作记忆和参考记忆造成持续影响。我们采取了两个阶段的方法来确定这些影响的神经基础。斯洛特金实验室的神经化学研究表明， 毒死蜱引起的胆碱能、儿茶酚胺能和胆碱能递质系统的破坏。Levin实验室的神经行为学研究已经用药理学探针证明，发育中的毒死蜱暴露破坏了毒蕈碱乙酰胆碱系统在记忆功能中所起的功能作用。我们将毒死蜱对斑马鱼认知功能发育影响的研究扩展到更好地了解这种损害的分子效应。我们发现斑马鱼在发育过程中暴露于毒死蜱会导致持续的认知障碍。吗啉抑制乙酰胆碱酯酶的初步研究表明斑马鱼存在认知障碍。这些研究将确定毒死蜱诱导的学习，注意力和情绪反应的神经机制。学习（重复习得）、注意力（操作性信号）的具体测试 检测）和焦虑（高架十字迷宫）将与胆碱能、儿茶酚胺能和胆碱能递质受体系统的药理学探针一起使用，以确定毒死蜱对这些神经行为功能的影响，并确定这些递质系统在毒死蜱持续的神经行为影响中的功能作用。初步研究了这些效应对毒死蜱的特异性或对其它有机磷农药的普遍性。斑马鱼的研究将为农药如何影响认知发育的分子控制提供关键信息。

A variety of chemicals on the Superfund list, such as pesticides, metals and polyhalogenated hydrocarbons have been found to impair cognitive function, including learning, memory and attention. We have focused on determining the neural mechanisms underlying the cognitive impairments caused by developmental pesticide exposure. Using the classic rat model of developmental neurobehavioral toxicology, we have shown in the first funding period of this center that the organophosphate insecticide chlorpyrifos causes persistent effects on working and reference memory. We have taken a two-stage approach to determine the neural underpinnings of these effects. Neurochemical studies in the Slotkin lab have demonstrated the chlorpyrifos-induced disruptions of cholinergic, catecholaminergic and serotonergic transmitter systems. Neurobehaviorai studies in the Levin iab have demonstrated with pharmacoiogicai probes that developmental chlorpyrifos exposure disrupts the functional role played by muscarinic acetylcholine systems in memory function. We extended study of developmental chlorpyrifos effects on cognitive function to zebrafish to better understand the molecular effects underlying this impairment. We found with zebrafish that chlorpyrifos exposure during development causes persisting cognitive impairment. Initial studies with morpholino suppression of acetylcholinesterase show cognitive impairments in zebrafish. These studies will determine the neural mechanisms underlying ehlorpyrifos-induced effects on learning, attention and emotional response. Specific tests of learning (repeated acquisition), attention (operant signal detection) and anxiety (elevated plus maze) will be used together with pharmacological probes of choliriergic, catecholaminergic and serotonergic transmitter receptor systems to determine not only the impact of chlorpyrifos on these neurobehavioral functions but alto to determine the functional role of these transmitter systems in the persisting neurobehavioral effects of chlorpyrifos. Initial studies will be made oncerning the specificity of these effects to chlorpyrifos or generality to other organophosphate pesticides. Zebrafish studies will provide critical information of how pesticides affect molecular controls over cognitive development.