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）：由于其广泛用作农药及其在恐怖袭击中的潜在就业，有机磷酸盐（OPS）对人类健康构成了不断威胁。 OPS的急性毒性已被广泛研究。但是，对没有产生明显急性毒性迹象的OP水平的长时间或反复暴露的后果知之甚少。此外，有临床证据表明，这种低级对OPS的暴露导致认知缺陷，尽管这种作用的机制尚不清楚。我们实验室的一项长期目标是阐明负责与慢性低级OP暴露相关的长期神经行为缺陷的机制，从而可以开发出更有效的治疗策略。我们在初始资金期间进行的实验结果表明，低水平的商业农药毒死rif虫的暴露导致预脉冲抑制作用（一种前处理前处理的模型）和空间学习的延伸不足，而无需显着影响显着功能。此外，毒死rif毒素与大脑区域中神经营养蛋白受体和胆碱能蛋白的降低有关，这对认知功能很重要。这些缺陷伴随着在体内坐骨神经中测得的轴突转运的降低。但是，尚不清楚轴突转运缺陷的分子机制以及对大脑中轴突转运的影响的程度尚不清楚。该应用的目的是确定负责轴突运输改变的机制，并进一步定义低级OP暴露对认知功能的长期影响。我们的中心假设是，OPS共价修改了参与轴突转运的关键蛋白，并且这种修饰损害了支持认知功能的神经元途径的功能。为了实现我们的目标，我们提出了三个具体目的：1）确定慢性低水平暴露于对注意力和认知灵活性的代表性OP的后果，2）确定慢性低水平暴露于大脑中轴突转运的慢性低水平暴露于代表性OP的后果，以及3）确定分子机制，导致OP诱导的轴突转运中的OP诱导缺陷。为了解决这些目标，我们将使用五个选择的串行反应时间任务来评估持续的关注，水迷宫任务，以测量灭绝（一种认知灵活性的形式）和对可追溯性敏感性的立体定位注射，免疫组织化学，质谱和质谱仪，以确定对大脑中轴突运输的OP效果。该项目的重要性及其与公共卫生的相关性是，通过基于其对动物信息处理基本组成部分的长期影响的机械定义OPS的相关性，我们将在我们了解OP可能如何影响人类随着时间的时候的基本差距。这些实验将有助于更好地理解与一类化学物质相关的毒性，这些化学物质继续对全球数百万人构成巨大的环境风险。公共卫生相关性有机磷酸盐是剧毒的化学物质，在我们的环境中几乎无处不在，因此，它们对全球数百万人构成了重大的健康风险。尽管已经对这些药物的急性毒性进行了广泛的研究，但对有机磷酸盐的慢性低水平暴露（尤其是在认知和支持认知的神经元过程中）的影响很少。本应用程序中提出的实验旨在通过基于对轴突转运（神经元中的基本过程）和认知功能（即注意力和认知灵活性）的长期影响来解决啮齿动物模型中的这些问题。