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.

已经发现，超级基金列表上的各种化学物质，例如农药，金属和多面化的碳氢化合物，都损害了认知功能，包括学习，记忆和注意力。我们专注于确定由发育性农药暴露引起的认知障碍的基础神经机制。使用经典的大鼠发育神经行为毒理学模型，我们在该中心的第一个资金期间表明，有机磷酸盐杀虫剂毒性菌属对工作和参考记忆产生持久影响。我们采取了两阶段的方法来确定这些作用的神经基础。 Slotkin实验室中的神经化学研究表明 毒藻引起的胆碱能，儿茶酚胺能和血清素能发射器系统的破坏。 Levin IAB中的Neurobehaviorai研究证明了Pharmacoiogicai探针表明，发育性毒性菌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。我们扩展了对毒性雌雄同体对认知功能的影响的研究到斑马鱼，以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毒死rif会导致持续的认知障碍。乙酰胆碱酯酶的形态抑制作用的最初研究表明斑马鱼的认知障碍。这些研究将确定Ehlorpyrifos诱导的对学习，注意力和情绪反应的影响的神经机制。特定的学习测试（重复获取），注意力（操作信号 检测）和焦虑症（升高的迷宫）将与胆碱，儿茶酚胺能和血清素能发射器受体系统的药理学探针一起使用，不仅确定毒死rif虫对这些神经行为功能的影响，还确定这些持久性效应的神经be虫功能，以确定这些持久型Neurobebeshavior的功能作用。将对这些作用对毒恐或对其他有机磷酸盐农药的普遍性的特异性进行初步研究。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。