Neurobehavioral Mechanisms of Cognitive Impairment

认知障碍的神经行为机制

• 批准号: 6900495
• 负责人: EDWARD D LEVIN
• 金额: $ 24.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900495
• 关键词: animal developmental psychology; anxiety; attention; behavior test; behavioral /social science research tag; choline acetyltransferase; cholinergic receptors; chordate locomotion; cognition disorders; developmental disease /disorder; developmental neurobiology; dopamine; environmental exposure; environmental toxicology; enzyme activity; laboratory rat; mood disorders; neurotoxicology; norepinephrine; organophosphorus insecticide; sensory signal detection; serotonin receptor; short term memory; tyrosine 3 monooxygenase; zebrafish

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.

超级基金清单上的多种化学物质，如农药、金属和多卤代烃，被发现会损害认知功能，包括学习、记忆和注意力。我们的重点是确定发育性农药接触引起认知障碍的神经机制。使用发育神经行为毒理学的经典大鼠模型，我们在该中心的第一个资助期间表明，有机磷杀虫剂毒死蜱会对工作记忆和参考记忆造成持续影响。我们采取了两阶段方法来确定这些影响的神经基础。 Slotkin 实验室的神经化学研究表明 毒死蜱引起胆碱能、儿茶酚胺能和血清素能递质系统的破坏。莱文实验室的神经行为研究已经通过药理学探针证明，发育期接触毒死蜱会破坏毒蕈碱乙酰胆碱系统在记忆功能中发挥的功能作用。我们将毒死蜱对斑马鱼认知功能发育影响的研究扩展到斑马鱼，以更好地了解这种损害背后的分子效应。我们发现斑马鱼在发育过程中接触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对学习、注意力和情绪反应产生影响的神经机制。学习（重复获取）、注意力（操作信号）的具体测试 检测）和焦虑（高架十字迷宫）将与胆碱能、儿茶酚胺能和血清素能递质受体系统的药理学探针一起使用，不仅确定毒死蜱对这些神经行为功能的影响，还确定这些递质系统在神经行为功能中的功能作用。毒死蜱对神经行为的持续影响。将针对这些影响对毒死蜱的特殊性或对其他有机磷农药的普遍性进行初步研究。斑马鱼研究将提供有关农药如何影响认知发展的分子控制的关键信息。