MECHANISMS RESPONSIBLE FOR COGNITIVE IMPAIRMENT CAUSED BY EXPOSURE TO PCBS

因接触多氯联苯而导致认知障碍的机制

• 批准号: 6106219
• 负责人: DAVID Orlo CARPENTER
• 金额: $ 23.08万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106219
• 关键词: calcium flux; cellular pathology; central neural pathway /tract; cholinergic receptors; developmental neurobiology; dopamine; electrophysiology; environmental toxicology; flow cytometry; free radicals; glutamate receptor; halobiphenyl /halotriphenyl compound; hippocampus; laboratory rat; learning; long term potentiation; membrane potentials; memory; mossy fiber; neural plasticity; neurotransmitter transport; protein kinase C; thyroid function

PCBs are known to have a variety of effects on the nervous system, but one of the potentially most serious is the decrement in cognitive potential that has been reported in children having elevated body burdens. The goal of this investigation is to determine whether PCBs alter a variety of neuronal processes in a animal model system that are known to be important in learning and memory. We propose to use acute and chronic exposure to Aroclor 1248 and four single PCB congeners, and a combination of electrophysiologic and flow cytometric techniques. The major hypothesis to be tested is the PCBs will reduce or block the process of long-term potentiation (LTP), which is one of the best available model systems for learning and memory. If this is the case, and our preliminary results suggest that it is, we will attempt to determine the mechanism(s) of action responsible. Using electrophysiological recordings, we will study synaptic transmission in two hippocampal circuits, the Schaffer collateral-CA1 pathway and the mossy fiber-CA3 pathway. We will investigate normal transmitter release and post-synaptic responses and several indicators of neuronal plasticity [pot-tetanic potentiation (PTP, LTP, paired pulse potentiation, phorbol ester-induced potentiation]. We expect to find a selective action on one or more of these complex responses, and if so, we will attempt to determine the mechanism. We will investigate effects on responses to specific neurotransmitter receptors (N-methyl-D-aspartate, acetylcholine), various kinases, including protein kinase C and calcium entry and/or release. In order to directly monitor calcium we will use cerebellar granule neurons studies in a flow cytometer, and determine whether there are direct effects of PCBs on calcium flux, as well as effects of PCBs on calcium entry or release triggered by five different pathways. We will monitor effects of PCBs on membrane potential changes and on generation of free radicals in the cells by different pathways. If effects are found, we will attempt to determine which congeners are responsible, whether the effects are mediated via interference with thyroid function or dopamine depletion, or whether some whether mechanism is responsible.

众所周知，多氯联苯对神经系统有多种影响，但只有一种 其中可能最严重的是认知潜力的下降 据报道，体重负担过重的儿童出现了这种情况。目标是 这项研究的目的是确定多氯联苯是否会改变各种 动物模型系统中已知的重要的神经元过程 在学习和记忆方面。我们建议使用急性和慢性暴露于 Aroclor 1248和四个单一的印刷电路板同系物，以及 电生理和流式细胞仪技术。主要的假设是 被检测的是多氯联苯会减少或长期阻断的过程 增强(LTP)，这是最好的可用的模型系统之一 学习和记忆。如果是这样的话，我们的初步结果 建议是，我们将尝试确定(S)的作用机制 负责任。利用电生理记录，我们将研究突触 Schaffer侧支CA1在两个海马区的传递 苔藓纤维-CA3途径。我们会调查正常情况 递质释放和突触后反应以及几个指标 神经元可塑性[强直性增强(PTP，LTP，配对脉冲 增强，佛波酯诱导的增强作用]。我们希望能找到一个 对一个或多个这些复杂的反应采取选择性行动，如果是这样的话，我们 将试图确定这一机制。我们将调查对 对特定神经递质受体(N-甲基-D-天冬氨酸， 乙酰胆碱)，各种激酶，包括蛋白激酶C和钙 进入和/或释放。为了直接监测钙离子，我们将使用 用流式细胞仪对小脑颗粒神经元进行研究，并确定 多氯联苯是否对钙流动有直接影响，以及 多氯联苯对五种不同方式引起的钙离子内流或释放的影响 小路。我们将监测多氯联苯对膜电位变化的影响 以及通过不同的途径在细胞内产生自由基。如果 如果发现了影响，我们将尝试确定哪些同系物是 负责，影响是否通过干扰甲状腺来调节 功能或多巴胺耗竭，或是否有某种机制 负责任。