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dc.contributor.authorRisher, Mary-Louise
dc.date.accessioned2014-03-04T19:00:08Z
dc.date.available2014-03-04T19:00:08Z
dc.date.issued2010-12
dc.identifier.otherrisher_mary-louise_201012_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/risher_mary-louise_201012_phd
dc.identifier.urihttp://hdl.handle.net/10724/26993
dc.description.abstractThe risk of exposure to significant levels of organophosphate (OP)-based chemicals such as chlorpyrifos (CPF) is substantial for humans worldwide given their widespread use as pesticides in household, agricultural, and industrial environments. The acute toxicity of OPs (including CPF) to target and non-target organisms has been extensively studied and is believed to result from irreversible acetylcholinesterase inhibition and subsequent overstimulation of cholinergic neurons. However, the consequences of repeated exposures to levels of OPs that produce no overt signs of acute toxicity (i.e., subacute levels) are poorly understood. There is substantial epidemiologic evidence that this type of exposure results in prolonged deficits in attention and other domains of cognition long after cholinesterase activity has normalized. However, few prospective studies have addressed this subject and moreover, potential neuronal mechanisms for the reported cognitive deficits have not been adequately investigated. Therefore, the objectives of this thesis project were to 1) investigate (prospectively) the effects of repeated sub-acute exposures to CPF on cognition (particularly attention) in an animal model and 2) investigate potential neuronal mechanisms for prolonged OP-related effects on cognition in vitro. To address the first objective, adult rats were trained to stably perform a task of sustained attention, the five choice serial reaction time task, then treated with vehicle or CPF 18.0 mg/kg for 14 consecutive days or every other day for 30 days. Behavioral testing was performed daily during the CPF-exposure period and throughout a 30 day washout to assess recovery. CPF-treated animals exhibited protracted impairments of sustained attention and an increase in impulsive behaviors without signs of impaired motivation or overt toxicity. For the second objective, rat primary cortical neurons were used to evaluate mitochondrial axonal transport and morphology after 1-24 hours of exposure to various concentrations of CPF and CPFoxon (active metabolite). Imaging studies revealed a concentration-dependent increase in mitochondrial length, a decrease in mitochondrial number, and impaired axonal transport of mitochondria at CPF concentrations that did not inhibit acetylcholinesterase. Given the importance of mitochondrial dynamics and axonal transport to neuronal function, these in vitro results provide potential mechanisms for CPF-related deficits in cognitive function observed in vivo.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectChlorpyrifos
dc.subjectPesticides
dc.subjectCognition
dc.subject5-Choice Serial Reaction Time Task
dc.subjectAttention
dc.subjectMitochondria
dc.subjectAxonal Transport
dc.subjectMitochondrial Dynamics
dc.titleChlorpyrifos exposure results in altered mitochondrial dynamics, deficits in axonal transport and impairments of sustained attention
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentClinical and Administrative Pharmacy
dc.description.majorPharmacy
dc.description.advisorAlvin Terry, Jr.
dc.description.committeeAlvin Terry, Jr.
dc.description.committeeRandall L. Tackett
dc.description.committeeGreene Shepherd
dc.description.committeeSusan Fagan
dc.description.committeeAzza El-Remessy


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