Neurobehavioral Mechanisms of Cognitive Impairment

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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.