Cholinesterase Inhibitors, Axonal Transport, and Memory

胆碱酯酶抑制剂、轴突运输和记忆

• 批准号: 7848580
• 负责人: ALVIN V TERRY
• 金额: $ 1.71万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848580
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Address; Affect; Agriculture; Amyloid beta-Protein Precursor; Animals; Attention; Axonal Transport; Behavioral; Biotin; Brain; Brain region; Chemicals; Chlorpyrifos; Cholinesterase Inhibitors; Cholinesterases; Chronic; Clinical; Cognition; Cognitive; Cytoskeletal Proteins; Data; Dextrans; Employment; Environment; Environmental Risk Factor; Enzymes; Exposure to; Extinction (Psychology); Functional disorder; Funding; Goals; Health; Hippocampus (Brain); Human; Immunohistochemistry; Impairment; In Vitro; Injection of therapeutic agent; Insecticides; Isoflurophate; Kinesin; Knowledge; Laboratories; Lead; Learning; Long-Term Effects; Mass Spectrum Analysis; Measures; Memory; Methodology; Microtubules; Military Personnel; Modeling; Modification; Molecular; Nerve Growth Factor Receptors; Neurobiology; Neurons; Neurotransmitters; Organophosphates; Pathway interactions; Performance; Peripheral; Pesticides; Poison; Prefrontal Cortex; Procedures; Process; Proteins; Public Health; Rattus; Reaction Time; Risk; Rodent Model; Series; Symptoms; Therapeutic; Time; Toxic effect; Tubulin; Water; Work; alkylphosphate; base; cell motility; cholinergic; cognitive function; design; dextran; flexibility; information processing; nerve agent; neurobehavioral; polymerization; prepulse inhibition; public health relevance; research study; sciatic nerve; therapeutic target; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): Organophosphates (OPs) pose a constant threat to human health due to their widespread use as pesticides and their potential employment in terrorist attacks. The acute toxicity of OPs has been extensively studied; however, the consequences of prolonged or repeated exposure to levels of OPs that produce no overt signs of acute toxicity are poorly understood. Further, there is clinical evidence that such low-level exposures to OPs leads to prolonged deficits in cognition, although the mechanism for this effect is unknown. One long- term goal of our laboratories is to elucidate the mechanisms responsible for the prolonged neurobehavioral deficits associated with chronic low-level OP exposures such that more effective therapeutic strategies can be developed. The results of our experiments conducted during the initial funding period established that low- level exposures to the commercial pesticide, chlorpyrifos, resulted in protracted deficits in prepulse inhibition (a model of pre-attentive processing) and spatial learning without significantly affecting locomotor function. Further, chlorpyrifos was associated with decreases in neurotrophin receptors and cholinergic proteins in brain regions that are important to cognitive function. These deficits were accompanied by decreases in axonal transport measured in sciatic nerves ex vivo. However, the molecular mechanisms for the deficits in axonal transport and the extent to which such effects on axonal transport occur in the brain are unclear. The objective of this application is to identify the mechanisms responsible for alterations in axonal transport as well as to further define the long-term effects of low-level OP exposure on cognitive function. Our central hypothesis is that OPs covalently modify key proteins that are involved in axonal transport and that such modifications compromise the function of neuronal pathways that support cognitive function. To achieve our objective, we propose three specific aims: 1) Determine the consequences of chronic low-level exposure to representative OPs on attention and cognitive flexibility, 2) Determine the consequences of chronic low-level exposure to representative OPs on axonal transport in the brain, and 3) Identify the molecular mechanisms responsible for OP-induced deficits in axonal transport. To address these aims, we will use a five choice serial reaction time task to assess sustained attention, a water maze task to measure extinction (a form of cognitive flexibility) and stereotaxic injections of traceable dextrans, immunohistochemistry, and mass spectrometry to determine OP effects on axonal transport in the brain and the consequences of its impairment. The significance of this project and its relevance to public health is that by mechanistically defining OPs based on their long-term effects on essential components of information processing in animals, we will have addressed a fundamental gap in our knowledge of how OPs likely affect humans over time. The experiments will contribute to a better understanding of the toxicity associated with a class of chemicals that continues to pose a significant environmental risk to millions of people worldwide. PUBLIC HEALTH RELEVANCE Organophosphates are highly toxic chemicals that are almost ubiquitous in our environment and, accordingly, they pose a significant health risk to millions of people worldwide. While the acute toxicity of these agents has been extensively studied, the effects of chronic low-level exposures to organophosphates (especially on cognition and the neuronal processes that support cognition) are poorly understood. The experiments proposed in this application have been designed to address these issues in the rodent model by mechanistically defining organophosphates based on their long-term effects on axonal transport (a fundamental process in neurons) and specific domains of cognitive function (i.e., attention and cognitive flexibility).

描述（由申请人提供）：有机磷酸盐（OPs）由于其作为杀虫剂的广泛使用以及在恐怖袭击中的潜在用途，对人类健康构成持续威胁。OPs的急性毒性已被广泛研究；然而，长期或反复暴露于不产生明显急性毒性迹象的OPs水平的后果尚不清楚。此外，有临床证据表明，如此低水平的暴露于OPs会导致长期的认知缺陷，尽管这种影响的机制尚不清楚。我们实验室的一个长期目标是阐明与慢性低水平OP暴露相关的长期神经行为缺陷的机制，以便开发更有效的治疗策略。我们在最初资助期间进行的实验结果表明，低水平暴露于商业农药毒死蜱，会导致脉冲前抑制（一种预先注意处理模型）和空间学习的长期缺陷，而不会显著影响运动功能。此外，毒死蜱与大脑中对认知功能重要的神经营养因子受体和胆碱能蛋白的减少有关。这些缺陷伴随着离体坐骨神经轴突运输的减少。然而，轴突运输缺陷的分子机制以及这种影响在大脑轴突运输中发生的程度尚不清楚。本应用程序的目的是确定轴突运输改变的机制，并进一步确定低水平OP暴露对认知功能的长期影响。我们的中心假设是，OPs共价修饰参与轴突运输的关键蛋白，这种修饰损害了支持认知功能的神经元通路的功能。为了实现我们的目标，我们提出了三个具体目标：1)确定慢性低水平暴露于具有代表性的OPs对注意力和认知灵活性的影响；2)确定慢性低水平暴露于具有代表性的OPs对大脑轴突运输的影响；3)确定op诱导轴突运输缺陷的分子机制。为了实现这些目标，我们将使用五个选择序列反应时间任务来评估持续注意力，一个水迷宫任务来测量消退（认知灵活性的一种形式），立体定向注射可追踪的右旋糖酐，免疫组织化学和质谱来确定OP对大脑轴突运输的影响及其损害的后果。该项目的重要性及其与公共卫生的相关性在于，通过根据OPs对动物信息处理基本组成部分的长期影响来机械地定义OPs，我们将解决OPs如何随时间影响人类的知识方面的一个根本空白。这些实验将有助于更好地了解与一类化学品有关的毒性，这些化学品继续对全世界数百万人构成重大的环境风险。与公共卫生有关的有机磷酸盐是剧毒化学品，在我们的环境中几乎无处不在，因此，它们对全世界数百万人的健康构成重大风险。虽然这些试剂的急性毒性已被广泛研究，但慢性低水平暴露于有机磷的影响（特别是对认知和支持认知的神经元过程的影响）知之甚少。本应用程序中提出的实验旨在解决啮齿动物模型中的这些问题，通过基于其对轴突转运（神经元的基本过程）和特定认知功能领域（即注意力和认知灵活性）的长期影响来机械地定义有机磷酸盐。